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Sample records for resuscitation induced lung

  1. Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep

    PubMed Central

    2009-01-01

    Background Initiation of ventilation using high tidal volumes in preterm lambs causes lung injury and inflammation. Antenatal corticosteroids mature the lungs of preterm infants and postnatal corticosteroids are used to treat bronchopulmonary dysplasia. Objective To test if antenatal or postnatal corticosteroids would decrease resuscitation induced lung injury. Methods 129 d gestational age lambs (n = 5-8/gp; term = 150 d) were operatively delivered and ventilated after exposure to either 1) no medication, 2) antenatal maternal IM Betamethasone 0.5 mg/kg 24 h prior to delivery, 3) 0.5 mg/kg Dexamethasone IV at delivery or 4) Cortisol 2 mg/kg IV at delivery. Lambs then were ventilated with no PEEP and escalating tidal volumes (VT) to 15 mL/kg for 15 min and then given surfactant. The lambs were ventilated with VT 8 mL/kg and PEEP 5 cmH20 for 2 h 45 min. Results High VT ventilation caused a deterioration of lung physiology, lung inflammation and injury. Antenatal betamethasone improved ventilation, decreased inflammatory cytokine mRNA expression and alveolar protein leak, but did not prevent neutrophil influx. Postnatal dexamethasone decreased pro-inflammatory cytokine expression, but had no beneficial effect on ventilation, and postnatal cortisol had no effect. Ventilation increased liver serum amyloid mRNA expression, which was unaffected by corticosteroids. Conclusions Antenatal betamethasone decreased lung injury without decreasing lung inflammatory cells or systemic acute phase responses. Postnatal dexamethasone or cortisol, at the doses tested, did not have important effects on lung function or injury, suggesting that corticosteroids given at birth will not decrease resuscitation mediated injury. PMID:20003512

  2. Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury.

    PubMed

    Shenkar, R; Coulson, W F; Abraham, E

    1994-03-01

    Acute pulmonary injury occurs frequently following hemorrhage and injury. In order to better examine the sequence of events leading to lung injury in this setting, we investigated lung histology as well as in vivo mRNA levels for cytokines with proinflammatory and immunoregulatory properties (IL-1 beta, IL-6, IL-10, TNF-alpha, TGF-beta, IFN-gamma) over the 3 days following hemorrhage and resuscitation. Significant increases in mRNA levels for IL-1 beta, IL-6, IL-10, and IFN-gamma, but not TNF-alpha, were present among intraparenchymal pulmonary mononuclear cells obtained 1 and 3 days after hemorrhage. Among alveolar macrophages, TNF-alpha and IL-1 beta mRNA levels were increased 3 days after hemorrhage. Few changes in cytokine mRNA levels, with the exception of TNF-alpha at 3 days after hemorrhage, were present among peripheral blood mononuclear cells. Histologic examination of lungs from hemorrhaged animals showed no alterations 1 day after hemorrhage, but neutrophil and mononuclear cell infiltrates, edema, intra-alveolar hemorrhage, and fibrin generation were present 3 days after hemorrhage. These results suggest that hemorrhage-induced enhancement of proinflammatory cytokine gene transcription may be an important mechanism contributing to the frequent development of acute lung injury following blood loss and injury.

  3. Lung physiology during ECS resuscitation of DCD donors followed by in situ assessment of lung function.

    PubMed

    Reoma, Junewai L; Rojas, Alvaro; Krause, Eric M; Obeid, Nabeel R; Lafayette, Nathan G; Pohlmann, Joshua R; Padiyar, Niru P; Punch, Jeffery D; Cook, Keith E; Bartlett, Robert H

    2009-01-01

    Extracorporeal cardiopulmonary support (ECS) of donors after cardiac death (DCD) has been shown to improve abdominal organs for transplantation. This study assesses whether pulmonary congestion occurs during ECS with the heart arrested and describes an in vivo method to assess if lungs are suitable for transplantation from DCD donors after ECS resuscitation. Cardiac arrest was induced in 30 kg pigs, followed by 10 min of warm ischemia. Cannulae were placed into the right atrium (RA) and iliac artery, and veno-arterial ECS was initiated for 90 min with lungs inflated, group 1 (n = 5) or deflated, group 2 (n = 3). Left atrial pressures were measured as a marker for pulmonary congestion. After 90 min of ECS, lung function was evaluated. Cannulae were placed into the pulmonary artery (PA) and left ventricle (LV). A second pump was included, and ECS was converted to a bi-ventricular (bi-VAD) system. The RVAD drained from the RA and pumped into the PA, and the LVAD drained the LV and pumped into the iliac. This brought the lungs back into circulation for a 1-hr assessment period. The oxygenator was turned off, and ventilation was restarted. Flows, blood gases, PA and left atrial pressures, and compliance were recorded. In both the groups, LA pressure was <15 mm Hg during ECS. During the lung assessment period, PA flows were 1.4-2.2 L/min. PO2 was >300 mm Hg, with normal PCO2. Extracorporeal cardiopulmonary support resuscitation of DCD donors is feasible and allows for assessment of function before procurement. Extracorporeal cardiopulmonary support does not cause pulmonary congestion, and the lungs retain adequate function for transplantation. Compliance correlated with lung function.

  4. Parecoxib Reduces Systemic Inflammation and Acute Lung Injury in Burned Animals with Delayed Fluid Resuscitation

    PubMed Central

    Chong, Si Jack; Wu, Jian; Lu, Jia; Moochhala, Shabbir M.

    2014-01-01

    Burn injuries result in the release of proinflammatory mediators causing both local and systemic inflammation. Multiple organ dysfunctions secondary to systemic inflammation after severe burn contribute to adverse outcome, with the lungs being the first organ to fail. In this study, we evaluate the anti-inflammatory effects of Parecoxib, a parenteral COX-2 inhibitor, in a delayed fluid resuscitation burned rat model. Anaesthetized Sprague Dawley rats were inflicted with 45% total body surface area full-thickness scald burns and subsequently subjected to delayed resuscitation with Hartmann's solution. Parecoxib (0.1, 1.0, and 10 mg/kg) was delivered intramuscularly 20 min after injury followed by 12 h interval and the rats were sacrificed at 6 h, 24 h, and 48 h. Burn rats developed elevated blood cytokines, transaminase, creatinine, and increased lung MPO levels. Animals treated with 1 mg/kg Parecoxib showed significantly reduced plasma level of CINC-1, IL-6, PGEM, and lung MPO. Treatment of 1 mg/kg Parecoxib is shown to mitigate systemic and lung inflammation without significantly affecting other organs. At present, no specific therapeutic agent is available to attenuate the systemic inflammatory response secondary to burn injury. The results suggest that Parecoxib may have the potential to be used both as an analgesic and ameliorate the effects of lung injury following burn. PMID:24579056

  5. Induced hypothermia during resuscitation from hemorrhagic shock attenuates microvascular inflammation in the rat mesenteric microcirculation.

    PubMed

    Coyan, Garrett N; Moncure, Michael; Thomas, James H; Wood, John G

    2014-12-01

    Microvascular inflammation occurs during resuscitation following hemorrhagic shock, causing multiple organ dysfunction and mortality. Preclinical evidence suggests that hypothermia may have some benefit in selected patients by decreasing this inflammation, but this effect has not been extensively studied. Intravital microscopy was used to visualize mesenteric venules of anesthetized rats in real time to evaluate leukocyte adherence and mast cell degranulation. Animals were randomly allocated to normotensive or hypotensive groups and further subdivided into hypothermic and normothermic resuscitation (n = 6 per group). Animals in the shock groups underwent mean arterial blood pressure reduction to 40 to 45 mmHg for 1 h via blood withdrawal. During the first 2 h following resuscitation by infusion of shed blood plus double that volume of normal saline, rectal temperature of the hypothermic groups was maintained at 32°C to 34°C, whereas the normothermic groups were maintained between 36°C to 38°C. The hypothermic group was then rewarmed for the final 2 h of resuscitation. Leukocyte adherence was significantly lower after 2 h of hypothermic resuscitation compared with normothermic resuscitation: (2.8 ± 0.8 vs. 8.3 ± 1.3 adherent leukocytes, P = 0.004). Following rewarming, leukocyte adherence remained significantly different between hypothermic and normothermic shock groups: (4.7 ± 1.2 vs. 9.5 ± 1.6 adherent leukocytes, P = 0.038). Mast cell degranulation index (MDI) was significantly decreased in the hypothermic (1.02 ± 0.04 MDI) versus normothermic (1.22 ± 0.07 MDI) shock groups (P = 0.038) after the experiment. Induced hypothermia during resuscitation following hemorrhagic shock attenuates microvascular inflammation in rat mesentery. Furthermore, this decrease in inflammation is carried over after rewarming takes place.

  6. Abrupt reflow enhances cytokine-induced proinflammatory activation of endothelial cells during simulated shock and resuscitation.

    PubMed

    Li, Ranran; Zijlstra, Jan G; Kamps, Jan A A M; van Meurs, Matijs; Molema, Grietje

    2014-10-01

    Circulatory shock and resuscitation are associated with systemic hemodynamic changes, which may contribute to the development of MODS (multiple organ dysfunction syndrome). In this study, we used an in vitro flow system to simulate the consecutive changes in blood flow as occurring during hemorrhagic shock and resuscitation in vivo. We examined the kinetic responses of different endothelial genes in human umbilical vein endothelial cells preconditioned to 20 dyne/cm unidirectional laminar shear stress for 48 h to flow cessation and abrupt reflow, respectively, as well as the effect of flow cessation and reflow on tumor necrosis factor-α (TNF-α)-induced endothelial proinflammatory activation. Endothelial CD31 and VE-cadherin were not affected by the changes in flow in the absence or presence of TNF-α. The messenger RNA levels of proinflammatory molecules E-selectin, VCAM-1 (vascular cell adhesion molecule 1), and IL-8 (interleukin 8) were significantly induced by flow cessation respectively acute reflow, whereas ICAM-1 (intercellular adhesion molecule 1) was downregulated on flow cessation and induced by subsequent acute reflow. Flow cessation also affected the Ang/Tie2 (Angiopoietin/Tie2 receptor tyrosine kinase) system by downregulating Tie2 and inducing its endothelial ligand Ang2, an effect that was further extended on acute reflow. Furthermore, the induction of proinflammatory adhesion molecules by TNF-α under flow cessation was significantly enhanced on subsequent acute reflow. This study demonstrated that flow alterations per se during shock and resuscitation contribute to endothelial activation and that these alterations interact with proinflammatory factors coexisting in vivo such as TNF-α. The abrupt reflow-related enhancement of cytokine-induced endothelial proinflammatory activation supports the concept that sudden regain of flow during resuscitation has an aggravating effect on endothelial activation, which may play a significant role in vascular

  7. Effect of a pharmacologically induced decrease in core temperature in rats resuscitated from cardiac arrest

    EPA Science Inventory

    Targeted temperature management is recommended to reduce brain damage after resuscitation from cardiac arrest in humans although the optimal target temperature remains controversial. 1 4 The American Heart Association (AHA) and the International Liaison Committee on Resuscitation...

  8. Do Sustained Lung Inflations during Neonatal Resuscitation Affect Cerebral Blood Volume in Preterm Infants? A Randomized Controlled Pilot Study

    PubMed Central

    Schwaberger, Bernhard; Pichler, Gerhard; Avian, Alexander; Binder-Heschl, Corinna; Baik, Nariae; Urlesberger, Berndt

    2015-01-01

    Background Sustained lung inflations (SLI) during neonatal resuscitation may promote alveolar recruitment in preterm infants. While most of the studies focus on respiratory outcome, the impact of SLI on the brain hasn’t been investigated yet. Objective Do SLI affect cerebral blood volume (CBV) in preterm infants? Methods Preterm infants of gestation 28 weeks 0 days to 33 weeks 6 days with requirement for respiratory support (RS) were included in this randomized controlled pilot trial. Within the first 15 minutes after birth near-infrared spectroscopy (NIRS) measurements using ‘NIRO-200-NX’ (Hamamatsu, Japan) were performed to evaluate changes in CBV and cerebral tissue oxygenation. Two groups were compared based on RS: In SLI group RS was given by applying 1–3 SLI (30 cmH2O for 15 s) continued by respiratory standard care. Control group received respiratory standard care only. Results 40 infants (20 in each group) with mean gestational age of 32 weeks one day (±2 days) and birth weight of 1707 (±470) g were included. In the control group ΔCBV was significantly decreasing, whereas in SLI group ΔCBV showed similar values during the whole period of 15 minutes. Comparing both groups within the first 15 minutes ΔCBV showed a tendency toward different overall courses (p = 0.051). Conclusion This is the first study demonstrating an impact of SLI on CBV. Further studies are warranted including reconfirmation of the present findings in infants with lower gestational age. Future investigations on SLI should not only focus on respiratory outcome but also on the consequences on the developing brain. Trial Registration German Clinical Trials Register DRKS00005161 https://drks-neu.uniklinik-freiburg.de/drks_web/setLocale_EN.do PMID:26406467

  9. Mesenteric lymph drainage alleviates acute kidney injury induced by hemorrhagic shock without resuscitation.

    PubMed

    Zhao, Zi-Gang; Zhu, Hong-Xia; Zhang, Li-Min; Zhang, Yu-Ping; Niu, Chun-Yu

    2014-01-01

    This study aimed to investigate the effect of mesenteric lymph drainage on the acute kidney injury induced by hemorrhagic shock without resuscitation. Eighteen male Wistar rats were randomly divided into sham, shock, and drainage groups. The hemorrhagic shock model (40 mmHg, 3 h) was established in shock and drainage groups; mesenteric lymph drainage was performed from 1 h to 3 h of hypotension in the drainage group. The results showed that renal tissue damage occurred; the levels of urea, creatinine, and trypsin in the plasma as well as intercellular adhesion molecule-1 (ICAM-1), receptor of advanced glycation end-products (RAGE), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), lactic acid (LA), and 2,3-DPG in the renal tissue were increased in the shock group after 3 h of hypotension. Mesenteric lymph drainage lessened the following: renal tissue damage; urea and trypsin concentrations in the plasma; ICAM-1, RAGE, TNF-α, MDA, and LA levels in the renal tissue. By contrast, mesenteric lymph drainage increased the 2,3-DPG level in the renal tissue. These findings indicated that mesenteric lymph drainage could relieve kidney injury caused by sustained hypotension, and its mechanisms involve the decrease in trypsin activity, suppression of inflammation, alleviation of free radical injury, and improvement of energy metabolism.

  10. Long-Term Stored Hemoglobin-Vesicles, a Cellular Type of Hemoglobin-Based Oxygen Carrier, Has Resuscitative Effects Comparable to That for Fresh Red Blood Cells in a Rat Model with Massive Hemorrhage without Post-Transfusion Lung Injury

    PubMed Central

    Yamasaki, Keishi; Sakai, Hiromi; Otagiri, Masaki

    2016-01-01

    Hemoglobin-vesicles (HbV), encapsulating highly concentrated human hemoglobin in liposomes, were developed as a substitute for red blood cells (RBC) and their safety and efficacy in transfusion therapy has been confirmed in previous studies. Although HbV suspensions are structurally and physicochemically stabile for least 1-year at room temperature, based on in vitro experiments, the issue of whether the use of long-term stored HbV after a massive hemorrhage can be effective in resuscitations without adverse, post-transfusion effects remains to be clarified. We report herein on a comparison of the systemic response and the induction of organ injuries in hemorrhagic shock model rats resuscitated using 1-year-stored HbV, freshly packed RBC (PRBC-0) and by 28-day-stored packed RBC (PRBC-28). The six-hour mortality after resuscitation was not significantly different among the groups. Arterial blood pressure and blood gas parameters revealed that, using HbV, recovery from the shock state was comparable to that when PRBC-0 was used. Although no significant change was observed in serum parameters reflecting liver and kidney injuries at 6 hours after resuscitation among the three resuscitation groups, results based on Evans Blue and protein leakage in bronchoalveolar lavage fluid, the lung wet/dry weight ratio and histopathological findings indicated that HbV as well as PRBC-0 was less predisposed to result in a post-transfusion lung injury than PRBC-28, as evidenced by low levels of myeloperoxidase accumulation and subsequent oxidative damage in the lung. The findings reported herein indicate that 1-year-stored HbV can effectively function as a resuscitative fluid without the induction of post-transfused lung injury and that it is comparable to fresh PRBC, suggesting that HbV is a promising RBC substitute with a long shelf-life. PMID:27798697

  11. DHA-supplemented diet increases the survival of rats following asphyxia-induced cardiac arrest and cardiopulmonary bypass resuscitation

    PubMed Central

    Kim, Junhwan; Yin, Tai; Shinozaki, Koichiro; Lampe, Joshua W.; Becker, Lance B.

    2016-01-01

    Accumulating evidence illustrates the beneficial effects of dietary docosahexaenoic acid (DHA) on cardiovascular diseases. However, its effects on cardiac arrest (CA) remain controversial in epidemiological studies and have not been reported in controlled animal studies. Here, we examined whether dietary DHA can improve survival, the most important endpoint in CA. Male Sprague-Dawley rats were randomized into two groups and received either a control diet or a DHA-supplemented diet for 7–8 weeks. Rats were then subjected to 20 min asphyxia-induced cardiac arrest followed by 30 min cardiopulmonary bypass resuscitation. Rat survival was monitored for additional 3.5 h following resuscitation. In the control group, 1 of 9 rats survived for 4 h, whereas 6 of 9 rats survived in the DHA-treated group. Surviving rats in the DHA-treated group displayed moderately improved hemodynamics compared to rats in the control group 1 h after the start of resuscitation. Rats in the control group showed no sign of brain function whereas rats in the DHA-treated group had recurrent seizures and spontaneous respiration, suggesting dietary DHA also protects the brain. Overall, our study shows that dietary DHA significantly improves rat survival following 20 min of severe CA. PMID:27811958

  12. Simulation education in anesthesia training: a case report of successful resuscitation of bupivacaine-induced cardiac arrest linked to recent simulation training.

    PubMed

    Smith, Hugh M; Jacob, Adam K; Segura, Leal G; Dilger, John A; Torsher, Laurence C

    2008-05-01

    Simulation training is rapidly becoming an integral element of the education curriculum of anesthesia residency programs. We report a case of successful resuscitation of bupivacaine-induced cardiac arrest treated with i.v. lipid emulsion by providers who had recently participated in simulation training involving a scenario nearly identical to this case. Upon debriefing, it was determined that the previous training influenced execution of the following steps: rapid problem recognition, prompt initiation of specific therapy in the setting of supportive advanced cardiac life support measures, and coordinated team efforts. Although the true cause of efficient resuscitation and ultimate recovery cannot be proven, the efficiency of the resuscitation process, including timely administration of lipid emulsion, is evidence that simulation may be useful for training providers to manage rare emergencies.

  13. Burn Resuscitation

    DTIC Science & Technology

    2009-01-01

    areas involving large areas of skin the patient is exposed to death first from shock . . .’’ [10]. In describing the pathophysiology leading to the shock...state seen in burns he postulated that various irritants , mental and physical, caused vasomotor paresis leading to accumulation of blood in the...resuscitation volumes. Subsequent studies suggested a decrease in abdominal compartment syndrome (ACS). Oda et al., in 2006, published their experience

  14. [Neonatal resuscitation].

    PubMed

    Burón Martínez, E; Aguayo Maldonado, J

    2006-11-01

    At birth approximately 10 % of term or near-term neonates require initial stabilization maneuvers to establish a cry or regular breathing, maintain a heart rate greater than 100 beats per minute (bpm), and good color and muscular tone. About 1 % requires ventilation and very few infants receive chest compressions or medication. However, birth asphyxia is a worldwide problem and can lead to death or serious sequelae. Recently, the European Resuscitation Council (ERC) and the International Liaison Committee on Resuscitation (ILCOR) published new guidelines on resuscitation at birth. These guidelines review specific questions such as the use of air or 100 % oxygen in the delivery room, dose and routes of adrenaline delivery, the peripartum management of meconium-stained amniotic fluid, and temperature control. Assisted ventilation in preterm infants is briefly described. New devices to improve the care of newborn infants, such as the laryngeal mask airway or CO2 detectors to confirm tracheal tube placement, are also discussed. Significant changes have occurred in some practices and are included in this document.

  15. Timolol-induced interstitial lung disease

    PubMed Central

    Patel, Hetain; Wilches, Lina Vanessa; Guerrero, Jorge

    2015-01-01

    Timolol maleate is a non-selective beta-adrenergic receptor blocking agent with demonstrated efficacy in the treatment of open-angle glaucoma. A 76 year old female who presented with productive cough, progressive dyspnea and hypoxia after starting timolol maleate opthalamic drops following glaucoma surgery. The patient was diagnosed with interstitial lung disease secondary to timolol treatment and after cessation of the offending agent along with corticosteroid treatment, symptoms improved drastically. Elimination of other possible causes of disease along with evolution of radiological and functional signs left us with a diagnosis of timolol-induced interstitial lung disease. To our knowledge, this is the second reported case of timolol-induced interstitial lung disease. PMID:26236595

  16. Changes in renal tissue proteome induced by mesenteric lymph drainage in rats after hemorrhagic shock with resuscitation.

    PubMed

    Zhao, Zi-Gang; Zhang, Li-Min; Lv, Yong-Zhuang; Si, Yong-Hua; Niu, Chun-Yu; Li, Ji-Cheng

    2014-10-01

    Kidney injury commonly occurs after hemorrhagic shock. Previous studies have shown that post-hemorrhagic shock mesenteric lymph (PHSML) return negatively affects the kidneys and may induce injury. This study investigates the effect of PHSML drainage on the proteome in renal tissue. A controlled hemorrhagic shock model was established in the shock and shock+drainage groups. After 1 h of hypotension, fluid resuscitation was implemented within 30 min. Meanwhile, PHSML was drained in the shock+drainage group. After 3 h of resuscitation, renal tissue was extracted for proteome analysis using two-dimensional fluorescence difference gel electrophoresis. Differential proteins with intensities that either increased or decreased by 1.5-fold or greater were selected for trypsin digestion and analyzed by matrix-assisted laser desorption/ionization time-of-flight (TOF) mass spectrometry and tandem TOF/TOF mass spectrometry. Enzyme-linked immunosorbent assay was used to validate the identified partial proteins. Compared with the sham group, hnRNPC and Starp decreased in the shock group, whereas Hadha, Slc25a13, Atp5b, hnRNPC, Starp, Rps3, and actin were downregulated in the shock+drainage group. Meanwhile, Atp5b and actin decreased in the shock+drainage group relative to the shock group. The identified proteins can be classified into different categories, such as cell proliferation (hnRNPC, Strap, and Rps3), energy metabolism (Hadha, Atp5b, and Slc25a13), cell motility, and cytoskeleton (actin). Moreover, enzyme-linked immunosorbent assay measurement validated the changed levels of Atp5b and Actg2. Our findings provide a starting point for investigating the functions of differentially expressed proteins in acute kidney injury induced by hemorrhagic shock. These findings hold great potential for the development of therapeutic interventions.

  17. Interstitial Lung Disease Induced by Pazopanib Treatment

    PubMed Central

    Ide, Shotaro; Sakamoto, Noriho; Hara, Shintaro; Hara, Atsuko; Kakugawa, Tomoyuki; Nakamura, Yoichi; Futsuki, Yoji; Izumikawa, Koichi; Ishimatsu, Yuji; Yanagihara, Katsunori; Mukae, Hiroshi

    2017-01-01

    Although pneumothorax has been reported to be a major pulmonary adverse event in patients treated with pazopanib, a multikinase inhibitor, drug-induced interstitial lung disease (DILD) has not been reported. A 74-year-old Japanese man who received pazopanib for the treatment of femoral leiomyosarcoma and lung metastasis presented with dyspnea and fatigue. He had mild interstitial pneumonia when pazopanib treatment was initiated. Chest computed tomography revealed progressive bilateral ground-glass opacity (GGO) and traction bronchiectasis. We diagnosed DILD due to pazopanib. The patient's pazopanib treatment was interrupted and a steroid was administered. The symptoms and GGO were improved with treatment. Physicians should be aware of DILD due to pazopanib in patients with pre-existing interstitial lung disease. PMID:28050004

  18. Radiation-induced lung injury

    SciTech Connect

    Rosiello, R.A.; Merrill, W.W. )

    1990-03-01

    The use of radiation therapy is limited by the occurrence of the potentially fatal clinical syndromes of radiation pneumonitis and fibrosis. Radiation pneumonitis usually becomes clinically apparent from 2 to 6 months after completion of radiation therapy. It is characterized by fever, cough, dyspnea, and alveolar infiltrates on chest roentgenogram and may be difficult to differentiate from infection or recurrent malignancy. The pathogenesis is uncertain, but appears to involve both direct lung tissue toxicity and an inflammatory response. The syndrome may resolve spontaneously or may progress to respiratory failure. Corticosteroids may be effective therapy if started early in the course of the disease. The time course for the development of radiation fibrosis is later than that for radiation pneumonitis. It is usually present by 1 year following irradiation, but may not become clinically apparent until 2 years after radiation therapy. It is characterized by the insidious onset of dyspnea on exertion. It most often is mild, but can progress to chronic respiratory failure. There is no known successful treatment for this condition. 51 references.

  19. Oxaliplatin-induced lung fibrosis

    PubMed Central

    Shah, Arpan; Udwadia, Zarir F.; Almel, Sachin

    2009-01-01

    Oxaliplatin has been approved for use as an adjuvant treatment in stage III colorectal carcinoma by the US-FDA. The majority of toxicity caused by this drug is manageable. However, rare, isolated cases of pulmonary fibrosis induced by this drug have been reported in literature. We report one such case of rapidly evolving pulmonary fibrosis following treatment with oxaliplatin. PMID:20838550

  20. Pediatric cardiopulmonary resuscitation.

    PubMed

    Orlowski, J P

    1983-04-01

    Pediatric cardiopulmonary resuscitation refers to those measures used to restore ventilation and circulation in children. This article defines how cardiopulmonary resuscitation in infants, children, and adolescents differs from cardiopulmonary resuscitation in adults and delineates the drugs and dosages to be used in the resuscitation of pediatric patients.

  1. Combined lipid emulsion and ACLS resuscitation following bupivacaine- and hypoxia-induced cardiovascular collapse in unanesthetized swine.

    PubMed

    Bushey, Brent A; Auld, Victor H; Volk, John E; Vacchiano, Charles A

    2011-04-01

    This study examined whether combining lipid emulsion and advanced cardiac life support (ACLS) improves survival in an unanesthetized swine model of bupivacaine- and hypoxia-induced cardiovascular collapse. Arterial and venous catheters and a tracheostomy were surgically placed in 26 swine receiving inhalation anesthesia. After a 1-hour recovery period, bupivacaine (5 mg/kg) was administered intravenously over 15 seconds. Following 1 minute of observation and 3 minutes of mechanical airway obstruction, during which all animals exhibited complete cardiovascular collapse, ACLS was initiated. Animals were randomized to receive either intravenous saline or 20% lipid emulsion commencing with the initiation ofACLS. Survival was defined as a return of spontaneous circulation (ROSC) with unsupported blood pressure greater than 60 mm Hg for 10 minutes after 25 minutes of resuscitation effort. Data collection included electrocardiogram, arterial blood pressure, and arterial and mixed venous oxygen saturations. There was no significant difference in survival between the saline group (4/12, 33%) and lipid emulsion group (6/12, 50%; P > .05). Additionally, there was no significant difference between groups of surviving animals in the time to ROSC (P > .05). The combination of lipid emulsion and ACLS did not improve survival from bupivacaine- and hypoxia-induced cardiovascular collapse in unanesthetized swine.

  2. One-lung overventilation does not induce inflammation in the normally ventilated contralateral lung.

    PubMed

    Almendros, Isaac; Gutierrez, Patricia T; Closa, Daniel; Navajas, Daniel; Farre, Ramon

    2008-06-30

    The aim was to assess whether induction of ventilator-induced lung injury (VILI) in one lung triggers a concomitant inflammatory response in the normally ventilated contralateral lung. To this end, a differential ventilator was used in 6 rats. One lung was normally ventilated (3.5 ml/kg b.w.) and the contralateral lung was overstretched (15 ml/kg b.w.). Six control rats were normally ventilated (3.5 ml/kg b.w. each lung). After 3h, edema and gene expression of MIP-2 in the lung, and plasma and liver TNF-alpha were assessed. Overexpression of MIP-2 and edema were found in the overventilated lung but not in the normally ventilated contralateral lung. No detectable levels of circulating and liver TNF-alpha were detected. These data do not support the hypothesis of an early positive feedback in the lung inflammation during the mechanical ventilation.

  3. Radiation-induced esophagitis in lung cancer

    PubMed Central

    Baker, Sarah; Fairchild, Alysa

    2016-01-01

    Radiation-induced esophagitis is the most common local acute toxicity of radiotherapy (RT) delivered for the curative or palliative intent treatment of lung cancer. Although concurrent chemotherapy and higher RT dose are associated with increased esophagitis risk, advancements in RT techniques as well as adherence to esophageal dosimetric constraints may reduce the incidence and severity. Mild acute esophagitis symptoms are generally self-limited, and supportive management options include analgesics, acid suppression, diet modification, treatment for candidiasis, and maintenance of adequate nutrition. Esophageal stricture is the most common late sequela from esophageal irradiation and can be addressed with endoscopic dilatation. Approaches to prevent or mitigate these toxicities are also discussed. PMID:28210168

  4. Asbestos-induced lung diseases: an update

    PubMed Central

    KAMP, DAVID W.

    2009-01-01

    Asbestos causes asbestosis (pulmonary fibrosis caused by asbestos inhalation) and malignancies (bronchogenic carcinoma and mesothelioma) by mechanisms that are not fully elucidated. Despite a dramatic reduction in asbestos use worldwide, asbestos-induced lung diseases remain a substantial health concern primarily because of the vast amounts of fibers that have been mined, processed, and used during the 20th century combined with the long latency period of up to 40 years between exposure and disease presentation. This review summarizes the important new epidemiologic and pathogenic information that has emerged over the past several years. Whereas the development of asbestosis is directly associated with the magnitude and duration of asbestos exposure, the development of a malignant clone of cells can occur in the setting of low-level asbestos exposure. Emphasis is placed on the recent epidemiologic investigations that explore the malignancy risk that occurs from nonoccupational, environmental asbestos exposure. Accumulating studies are shedding light on novel mechanistic pathways by which asbestos damages the lung. Attention is focused on the importance of alveolar epithelial cell (AEC) injury and repair, the role of iron-derived reactive oxygen species (ROS), and apoptosis by the p53- and mitochondria-regulated death pathways. Furthermore, recent evidence underscores crucial roles for specific cellular signaling pathways that regulate the production of cytokines and growth factors. An evolving role for epithelial-mesenchymal transition (EMT) is also reviewed. The translational significance of these studies is evident in providing the molecular basis for developing novel therapeutic strategies for asbestos-related lung diseases and, importantly, other pulmonary diseases, such as interstitial pulmonary fibrosis and lung cancer. PMID:19304273

  5. Obesity-induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

    2017-03-09

    Obesity is a significant risk factor for the acute respiratory distress syndrome (ARDS). The mechanisms underlying this association are unknown. We recently showed that diet-induced obese (DIO) mice exhibit pulmonary vascular endothelial dysfunction which is associated with enhanced susceptibility to lipopolysaccharide (LPS)-induced lung injury. Here, we demonstrate that lung endothelial dysfunction in DIO mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins including PERK, IREα and ATF6, in whole lung and in lung endothelial cells isolated from DIO mice. Further, we found that lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of DIO mice. Similar changes were observed in lung endothelial cells and in whole lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation; indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-PBA, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in DIO mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the endoplasmic reticulum of pulmonary endothelial cells might protect against ARDS in obese individuals.

  6. Pretreatment with perfluorohexane vapor attenuates fMLP-induced lung injury in isolated perfused rabbit lungs.

    PubMed

    Bleyl, Jörg U; Heller, Axel R; Fehrenbach, Antonia; Heintz, Manuel; Fehrenbach, Heinz; Klenz, Gesa; Gama de Abreu, Marcelo; Hübler, Matthias; Spieth, Peter M; Koch, Thea

    2010-08-01

    The authors investigated the protective effects and dose dependency of perfluorohexane (PFH) vapor on leukocyte-mediated lung injury in isolated, perfused, and ventilated rabbit lungs. Lungs received either 18 vol.% (n = 7), 9 vol.% (n = 7), or 4.5 vol.% (n = 7) PFH. Fifteen minutes after beginning of PFH application, lung injury was induced with formyl-Met-Leu-Phe (fMLP). Control lungs (n = 7) received fMLP only. In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Pulmonary artery pressure (mPAP), peak inspiratory pressure (P(max)), and lung weight were monitored for 90 minutes. Perfusate samples were taken at regular intervals for analysis and representative lungs were fixed for histological analysis. In the control, fMLP application led to a significant increase of mPAP, P(max), lung weight, and lipid mediators. Pretreatment with PFH attenuated the rise in these parameters. This was accompanied by preservation of the structural integrity of the alveolar architecture and air-blood barrier. In uninjured lungs, mPAP, P(max), lung weight, and lipid mediator formation remained uneffected in the presence of PFH. The authors concluded that pretreatment with PFH vapor leads to an attenuation of leukocyte-mediated lung injury. Vaporization of perfluorocarbons (PFCs) offers new therapeutic options, making use of their protective and anti-inflammatory properties in prophylaxis or in early treatment of acute lung injury.

  7. Small Volume Resuscitation of Hypovolemic Shock

    DTIC Science & Technology

    1989-03-01

    the nature of the natriuresis / diuresis ; and the extent of resuscitation induced hypokalemia. Plasma volume expansion was measured during and after a...of hemorrhage with hypertonic saline (7.5%) induces a diuresis / natriuresis equal to that of large volume isotonic resuscitation. Circulatory Shock 24...after HSD (18-22 ml/kg) was similar in both groups; AO and cardiac output (CO) were equally improved in both groups. Dehydration blunted the diuresis of

  8. Linking lung function and inflammatory responses in ventilator-induced lung injury.

    PubMed

    Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D; Zosky, Graeme R

    2011-01-01

    Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.

  9. Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice.

    PubMed

    Podowski, Megan; Calvi, Carla; Metzger, Shana; Misono, Kaori; Poonyagariyagorn, Hataya; Lopez-Mercado, Armando; Ku, Therese; Lauer, Thomas; McGrath-Morrow, Sharon; Berger, Alan; Cheadle, Christopher; Tuder, Rubin; Dietz, Harry C; Mitzner, Wayne; Wise, Robert; Neptune, Enid

    2012-01-01

    Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.

  10. Hypovolemic shock resuscitation.

    PubMed

    Kobayashi, Leslie; Costantini, Todd W; Coimbra, Raul

    2012-12-01

    Several changes in the way patients with hemorrhagic shock are resuscitated have occurred over the past decades, including permissive hypotension, minimal crystalloid resuscitation, earlier blood transfusion, and higher plasma and platelet-to-red cell ratios. Hemostatic adjuncts, such as tranexamic acid and prothrombin complex, and the use of new methods of assessing coagulopathy are also being incorporated into resuscitation of the bleeding patient. These ideas have been incorporated by many trauma centers into institutional massive transfusion protocols, and adoption of these protocols has resulted in improvements in mortality and morbidity. This article discusses each of these new resuscitation strategies and the evidence supporting their use.

  11. Animal models of beryllium-induced lung disease

    SciTech Connect

    Finch, G.L.; Hoover, M.D.; Hahn, F.F.

    1996-10-01

    The Inhalation Toxicology Research Institute (ITRI) is conducting research to improve the understanding of chronic beryllium disease (CBD) and beryllium-induced lung cancer. Initial animal studies examined beagle dogs that inhaled BeO calcined at either 500 or 1000{degrees}C. At similar lung burdens, the 500{degrees}C BeO induced more severe and extensive granulomatous pneumonia, lymphocytic infiltration into the lung, and positive Be-specific lymphocyte proliferative responses in vitro than the 1000{degrees}C BeO. However, the progressive nature of human CBD was not duplicated. More recently, Strains A/J and C3H/HeJ mice were exposed to Be metal by inhalation. This produced a marked granulomatous pneumonia, diffuse infiltrates, and multifocal aggregates of interstitial lymphocytes with a pronounced T helper component and pulmonary in situ lymphocyte proliferation. With respect to lung cancer, at a mean lung burden as low as 17 pg Be/g lung, inhaled Be metal induced benign and/or malignant lung tumors in over 50% of male and female F344 rats surviving {ge}1 year on study. Substantial tumor multiplicity was found, but K-ras and p53 gene mutations were virtually absent. In mice, however, a lung burden of approximately 60 {mu}g ({approximately}300 {mu}g Be/g lung) caused only a slight increase in crude lung tumor incidence and multiplicity over controls in strain A/J mice and no elevated incidence in strain C3H mice. Taken together, this research program constitutes a coordinated effort to understand beryllium-induced lung disease in experimental animal models. 47 refs., 1 fig., 3 tabs.

  12. STUDIES IN RESUSCITATION: I. THE GENERAL CONDITIONS AFFECTING RESUSCITATION, AND THE RESUSCITATION OF THE BLOOD AND OF THE HEART

    PubMed Central

    Pike, F. H.; Guthrie, C. C.; Stewart, G. N.

    1908-01-01

    Our results may be briefly summarized: 1. Blood, when defibrinated, soon loses its power to maintain the activity of the higher nervous centers, and its nutritive properties for all tissues quickly diminish. 2. Artificial fluids, as a substitute for blood, are not satisfactory. 3. The proper oxygenation of the blood is an indispensable adjunct in the resuscitation of an animal. 4. The heart usually continues to beat for some minutes after it ceases to affect a mercury manometer, and resuscitation of it within this period by extra-thoracic massage and artificial respiration is sometimes successful. 5. Resuscitation of the heart by direct massage is the most certain method at our command. 6. A proper blood-pressure is an indispensable condition for the continued normal activity of the heart. 7. Anæsthetics, hemorrhage and induced currents applied to the heart render resuscitation more difficult than asphyxia alone. PMID:19867138

  13. NMDA Receptor Antagonist Attenuates Bleomycin-Induced Acute Lung Injury

    PubMed Central

    Li, Yang; Liu, Yong; Peng, XiangPing; Liu, Wei; Zhao, FeiYan; Feng, DanDan; Han, JianZhong; Huang, YanHong; Luo, SiWei; Li, Lian; Yue, Shao Jie; Cheng, QingMei; Huang, XiaoTing; Luo, ZiQiang

    2015-01-01

    Background Glutamate is a major neurotransmitter in the central nervous system (CNS). Large amount of glutamate can overstimulate N-methyl-D-aspartate receptor (NMDAR), causing neuronal injury and death. Recently, NMDAR has been reported to be found in the lungs. The aim of this study is to examine the effects of memantine, a NMDAR channel blocker, on bleomycin-induced lung injury mice. Methods C57BL/6 mice were intratracheally injected with bleomycin (BLM) to induce lung injury. Mice were randomized to receive saline, memantine (Me), BLM, BLM plus Me. Lungs and BALF were harvested on day 3 or 7 for further evaluation. Results BLM caused leukocyte infiltration, pulmonary edema and increase in cytokines, and imposed significant oxidative stress (MDA as a marker) in lungs. Memantine significantly mitigated the oxidative stress, lung inflammatory response and acute lung injury caused by BLM. Moreover, activation of NMDAR enhances CD11b expression on neutrophils. Conclusions Memantine mitigates oxidative stress, lung inflammatory response and acute lung injury in BLM challenged mice. PMID:25942563

  14. Platelets protect lung from injury induced by systemic inflammatory response

    PubMed Central

    Luo, Shuhua; Wang, Yabo; An, Qi; Chen, Hao; Zhao, Junfei; Zhang, Jie; Meng, Wentong; Du, Lei

    2017-01-01

    Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-β and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses. PMID:28155889

  15. NNK-Induced Lung Tumors: A Review of Animal Model

    PubMed Central

    Zheng, Hua-Chuan; Takano, Yasuo

    2011-01-01

    The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models. PMID:21559252

  16. Molecular features in arsenic-induced lung tumors

    PubMed Central

    2013-01-01

    Arsenic is a well-known human carcinogen, which potentially affects ~160 million people worldwide via exposure to unsafe levels in drinking water. Lungs are one of the main target organs for arsenic-related carcinogenesis. These tumors exhibit particular features, such as squamous cell-type specificity and high incidence among never smokers. Arsenic-induced malignant transformation is mainly related to the biotransformation process intended for the metabolic clearing of the carcinogen, which results in specific genetic and epigenetic alterations that ultimately affect key pathways in lung carcinogenesis. Based on this, lung tumors induced by arsenic exposure could be considered an additional subtype of lung cancer, especially in the case of never-smokers, where arsenic is a known etiological agent. In this article, we review the current knowledge on the various mechanisms of arsenic carcinogenicity and the specific roles of this metalloid in signaling pathways leading to lung cancer. PMID:23510327

  17. Increased isoprostane levels in oleic acid-induced lung injury

    SciTech Connect

    Ono, Koichi; Koizumi, Tomonobu; Tsushima, Kenji; Yoshikawa, Sumiko; Yokoyama, Toshiki; Nakagawa, Rikimaru; Obata, Toru

    2009-10-16

    The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2{alpha}). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.

  18. Body temperature control in sepsis-induced acute lung injury.

    PubMed

    Wang, Giueng-Chueng; Chi, Wei-Ming; Perng, Wan-Cherng; Huang, Kun-Lun

    2003-12-31

    Body temperature is precisely regulated to maintain homeostasis in homeothermic animals. Although it remains unproved whether change of body temperature constitutes a beneficial or a detrimental component of the septic response, temperature control should be an important entity in septic experiments. We investigated the effect of body temperature control on the lipopolysaccharide (LPS)-induced lung injury. Acute lung injury in rats was induced by intratracheal spray of LPS and body temperature was either clamped at 37 degrees C for 5 hours or not controlled. The severity of lung injury was evaluated at the end of the experiment. Intratracheal administration of aerosolized LPS caused a persistent decline in body temperature and a significant lung injury as indicated by an elevation of protein-concentration and LDH activity in the bronchoalveolar lavage (BAL) fluid and wet/dry weight (W/D) ratio of lungs. Administration of LPS also caused neutrophil sequestration and lipid peroxidation in the lung tissue as indicated by increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) production, respectively. Control of body temperature at 37 degrees C after LPS (LPS/BT37, n = 11) significantly reduced acute lung injury as evidenced by decreases in BAL fluid protein concentration (983 +/- 189 vs. 1403 +/- 155 mg/L) and LDH activity (56 +/- 10 vs. 123 +/- 17 deltamAbs/min) compared with the LPS group (n = 11). Although the W/D ratio of lung and MDA level were lower in the rats received temperature control compared with those received LPS only, the differences were not statistically significant. Our results demonstrated that intratracheal administration of aerosolized LPS induced a hypothermic response and acute lung injury in rats and controlling body temperature at a normal range may alleviate the LPS-induced lung injury.

  19. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

    PubMed

    Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

    2015-02-01

    We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

  20. Quality of cardiopulmonary resuscitation affects cardioprotection by induced hypothermia at 34 °C against ischemia/reperfusion injury in a rat isolated heart model.

    PubMed

    Mochizuki, Toshiaki; Jiang, Qiliang; Katoh, Takasumi; Aoki, Katsunori; Sato, Shigehito

    2013-06-01

    In this study, we aimed to compare the effects of low- and high-quality cardiopulmonary resuscitation (CPR) on cardioprotection by induced hypothermia (IH) at 34 °C and examine whether extracellular signal-regulated kinase or endothelial nitric oxide synthase mediates this cardioprotection. Left ventricle infarct sizes were evaluated in six groups of rat hearts (n = 6) following Langendorff perfusion and triphenyltetrazolium chloride staining. Controls underwent 30 min of global ischemia at 37 °C, followed by 10 min of simulated low- or high-quality CPR reperfusion and 90 min of reperfusion at 75 mmHg. The IH groups underwent IH at 34 °C during reperfusion. The U0126 group received U0126 (60 μM)-an extracellular signal-regulated kinase inhibitor-during reperfusion at 34 °C. The L-NIO (N-(1-iminoethyl)-L-ornithine dihydrochloride) group received L-NIO (2 μM)-an endothelial nitric oxide synthase inhibitor-5 min before global ischemia at 37 °C to the end of reperfusion at 34 °C. Infarct size did not significantly differ between the control and IH groups receiving low-quality CPR. However, IH with high-quality CPR reduced the infarct size from 47.2% ± 10.2% to 26.0% ± 9.4% (P = 0.005). U0126 reversed the IH-induced cardioprotection (45.9% ± 9.4%, P = 0.010), whereas L-NIO had no significant effect. Cardiopulmonary resuscitation quality affects IH-induced cardioprotection. Extracellular signal-regulated kinase may mediate IH-induced cardioprotection.

  1. Stress-Induced Evolution of Heat Resistance and Resuscitation Speed in Escherichia coli O157:H7 ATCC 43888.

    PubMed

    Gayán, Elisa; Cambré, Alexander; Michiels, Chris W; Aertsen, Abram

    2016-11-15

    The development of resistance in foodborne pathogens to food preservation techniques is an issue of increasing concern, especially in minimally processed foods where safety relies on hurdle technology. In this context, mild heat can be used in combination with so-called nonthermal processes, such as high hydrostatic pressure (HHP), at lower individual intensities to better retain the quality of the food. However, mild stresses may increase the risk of (cross-)resistance development in the surviving population, which in turn might compromise food safety. In this investigation, we examined the evolution of Escherichia coli O157:H7 strain ATCC 43888 after recurrent exposure to progressively intensifying mild heat shocks (from 54.0°C to 60.0°C in 0.5°C increments) with intermittent resuscitation and growth of survivors. As such, mutant strains were obtained after 10 cycles of selection with ca. 10(6)-fold higher heat resistance than that for the parental strain at 58.0°C, although this resistance did not extend to temperatures exceeding 60.0°C. Moreover, these mutant strains typically displayed cross-resistance against HHP shock and displayed signs of enhanced RpoS and RpoH activity. Interestingly, additional cycles of selection maintaining the intensity of the heat shock constant (58.5°C) selected for mutant strains in which resuscitation speed, rather than resistance, appeared to be increased. Therefore, it seems that resistance and resuscitation speed are rapidly evolvable traits in E. coli ATCC 43888 that can compromise food safety.

  2. Bronchoalveolar lavage in talc induced lung disease.

    PubMed Central

    Redondo, A A; Ettensohn, D B; Khan, M; Kessimian, N

    1988-01-01

    A 65 year old woman with a history of occupational talc inhalation presented with hypoxaemia, cough, and dyspnoea with a normal chest radiograph. Bronchoalveolar lavage showed considerable lymphocytosis, with a predominance of T8+ T lymphocytes, and open lung biopsy showed peribronchiolar granulomas containing talc crystals. Corticosteroid treatment resulted in dramatic improvement. Bronchoalveolar lavage may aid in the diagnosis of talc related lung injury. Images PMID:3238633

  3. Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Itoh, Takefumi; Obata, Hiroaki; Murakami, Shinsuke; Hamada, Kaoru; Kangawa, Kenji; Kimura, Hiroshi; Nagaya, Noritoshi

    2007-08-01

    Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 microg x kg(-1) x min(-1)) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-alpha and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

  4. Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice.

    PubMed

    Abraham, E; Bursten, S; Shenkar, R; Allbee, J; Tuder, R; Woodson, P; Guidot, D M; Rice, G; Singer, J W; Repine, J E

    1995-02-01

    Because phosphatidic acid (PA) pathway signaling may mediate many basic reactions involving cytokine-dependent responses, we investigated the effects of CT1501R, a functional inhibitor of the enzyme lysophosphatidic acid acyltransferase (LPAAT) which converts lysophosphatidic acid (Lyso-PA) to PA. We found that CT1501R treatment not only prevented hypoxia-induced PA increases and lyso-PA consumption in human neutrophils, but also prevented neutrophil chemotaxis and adherence in vitro, and lung injury and lung neutrophil accumulation in mice subjected to hemorrhage and resuscitation. In addition, CT1501R treatment prevented increases in mRNA levels and protein production of a variety of proinflammatory cytokines in multiple lung cell populations after blood loss and resuscitation. Our results indicate the fundamental role of PA metabolism in the development of acute inflammatory lung injury after blood loss.

  5. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury.

    PubMed

    Rey-Parra, G J; Vadivel, A; Coltan, L; Hall, A; Eaton, F; Schuster, M; Loibner, H; Penninger, J M; Kassiri, Z; Oudit, G Y; Thébaud, B

    2012-06-01

    Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin-angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice-male (ACE2(-/y)) and female (ACE2(-/-))-and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2(-/y) BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes α-smooth muscle actin (α-SMA) and Transforming Growth Factor ß1. Compared with ACE2(-/y) exposed to BLM, ACE2(-/-) exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS.

  6. Chemically-induced Mouse Lung Tumors: Applications to ...

    EPA Pesticide Factsheets

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to better understand the mouse lung tumor data’s role in human health assessments. Three environmental chemicals - naphthalene, styrene, and ethylbenzene were chosen for the analysis due to the commonality of mouse lung tumors in all three chemicals. The goals of the workshop were to: identify the evidence, from multiple scientific disciplines, regarding formation of chemically-induced lung tumors in mice; discuss analysis and interpretation of the evidence; discuss how such evidence informs human health assessments; and identify commonalities, linkages, or differences between the evidence from various disciplines and across the chemicals. Evidence informing the association between occupational exposure to styrene, ethylbenzene, or naphthalene and lung cancer; comparative biology of mouse lung tumors, associated pathologic effects, issues related to tissue and species concordance; mode of action analysis and biological mechanisms including pharmacokinetics and pharmacodynamics; and evidence from cellular, genetic and molecular toxicity was discussed. In summary, although consensus was not sought, the panelists agreed that available mouse lung tumor data should be considered for human health risk evaluation on an individual chemical basis. Key data gaps were identified that would assist in further understanding the mechanism and relevan

  7. Radiation-induced heart disease in lung cancer radiotherapy

    PubMed Central

    Ming, Xin; Feng, Yuanming; Yang, Chengwen; Wang, Wei; Wang, Ping; Deng, Jun

    2016-01-01

    Abstract Background: Radiation-induced heart disease (RIHD), which affects the patients’ prognosis with both acute and late side effects, has been published extensively in the radiotherapy of breast cancer, lymphoma and other benign diseases. Studies on RIHD in lung cancer radiotherapy, however, are less extensive and clear even though the patients with lung cancer are delivered with higher doses to the heart during radiation treatment. Methods: In this article, after extensive literature search and analysis, we reviewed the current evidence on RIHD in lung cancer patients after their radiation treatments and investigated the potential risk factors for RIHD as compared to other types of cancers. Result: Cardiac toxicity has been found highly relevant in lung cancer radiotherapy. So far, the crude incidence of cardiac complications in the lung cancer patients after radiotherapy has been up to 33%. Conclusion: The dose to the heart, the lobar location of tumor, the treatment modality, the history of heart and pulmonary disease and smoking were considered as potential risk factors for RIHD in lung cancer radiotherapy. As treatment techniques improve over the time with better prognosis for lung cancer survivors, an improved prediction model can be established to further reduce the cardiac toxicity in lung cancer radiotherapy. PMID:27741117

  8. Teamwork during resuscitation.

    PubMed

    Weinstock, Peter; Halamek, Louis P

    2008-08-01

    Effective resuscitation requires the integration of several cognitive, technical, and behavioral skills. Because resuscitation is performed by teams of health care professionals, these individuals must be able to work together in a coordinated and efficient manner, making teamwork a critical skill for care of patients in distress. Despite the importance of teamwork in health care, little consensus exists as to what it is, how it can most effectively be learned, and how it should be assessed. This article reviews current knowledge on the measurement, training, and importance of teamwork in pediatric resuscitation.

  9. Ventilator-induced lung injury in preterm infants

    PubMed Central

    Carvalho, Clarissa Gutierrez; Silveira, Rita C; Procianoy, Renato Soibelmann

    2013-01-01

    In preterm infants, the need for intubation and mechanical ventilation is associated with ventilator-induced lung injuries and subsequent bronchopulmonary dysplasia. The aim of the present review was to improve the understanding of the mechanisms of injury that involve cytokine-mediated inflammation to contribute to the development of new preventive strategies. Relevant articles were retrieved from the PubMed database using the search terms "ventilator-induced lung injury preterm", "continuous positive airway pressure", "preterm", and "bronchopulmonary dysplasia". The resulting data and other relevant information were divided into several topics to ensure a thorough, critical view of ventilation-induced lung injury and its consequences in preterm infants. The role of pro-inflammatory cytokines (particularly interleukins 6 and 8 and tumor necrosis factor alpha) as mediators of lung injury was assessed. Evidence from studies conducted with animals and human newborns is described. This evidence shows that brief periods of mechanical ventilation is sufficient to induce the release of pro-inflammatory cytokines. Other forms of mechanical and non-invasive ventilation were also analyzed as protective alternatives to conventional mechanical ventilation. It was concluded that non-invasive ventilation, intubation followed by early surfactant administration and quick extubation for nasal continuous positive airway pressure, and strategies that regulate tidal volume and avoid volutrauma (such as volume guarantee ventilation) protect against ventilator-induced lung injury in preterm infants. PMID:24553514

  10. Suspended animation for delayed resuscitation.

    PubMed

    Bellamy, R; Safar, P; Tisherman, S A; Basford, R; Bruttig, S P; Capone, A; Dubick, M A; Ernster, L; Hattler, B G; Hochachka, P; Klain, M; Kochanek, P M; Kofke, W A; Lancaster, J R; McGowan, F X; Oeltgen, P R; Severinghaus, J W; Taylor, M J; Zar, H

    1996-02-01

    Suspended animation is defined as the therapeutic induction of a state of tolerance to temporary complete systemic ischemia, i.w., protection-preservation of the whole organism during prolonged circulatory arrest ( > or = 1 hr), followed by resuscitation to survival without brain damage. The objectives of suspended animation include: a) helping to save victims of temporarily uncontrollable (internal) traumatic (e.g., combat casualties) or nontraumatic (e.g., ruptured aortic aneurysm) exsanguination, without severe brain trauma, by enabling evacuation and resuscitative surgery during circulatory arrest, followed by delayed resuscitation; b) helping to save some nontraumatic cases of sudden death, seemingly unresuscitable before definite repair; and c) enabling selected (elective) surgical procedures to be performed which are only feasible during a state of no blood flow. In the discussion session, investigators with suspended animation-relevant research interests brainstorm on present knowledge, future research potentials, and the advisability of a major research effort concerning this subject. The following topics are addressed: the epidemiologic facts of sudden death in combat casualties, which require a totally new resuscitative approach; the limits and potentials of reanimation research; complete reversibility of circulatory arrest of 1 hr in dogs under profound hypothermia ( < 10 degrees C), induced and reversed by portable cardiopulmonary bypass; the need for a still elusive pharmacologic or chemical induction of suspended animation in the field; asanguinous profound hypothermic low-flow with cardiopulmonary bypass; electric anesthesia; opiate therapy; lessons learned by hypoxia tolerant vertebrate animals, hibernators, and freeze-tolerant animals (cryobiology); myocardial preservation during open-heart surgery; organ preservation for transplantation; and reperfusion-reoxygenation injury in vital organs, including the roles of nitric oxide and free radicals

  11. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.

    PubMed

    Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

    2015-09-29

    Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

  12. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

    PubMed Central

    Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

    2015-01-01

    Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model. Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells. PMID:26396176

  13. Development of an In Vitro Assay for Detection of Drug-Induced Resuscitation-Promoting-Factor-Dependent Mycobacteria

    PubMed Central

    Loraine, Jessica; Pu, Feifei; Turapov, Obolbek

    2016-01-01

    Tuberculosis is a major infectious disease that requires prolonged chemotherapy with a combination of four drugs. Here we present data suggesting that treatment of Mycobacterium tuberculosis, the causative agent of tuberculosis, and Mycobacterium smegmatis, a model organism widely used for the screening of antituberculosis agents, with first-line drugs resulted in the generation of substantial populations that could be recovered only by the addition of a culture supernatant from growing mycobacteria. These bacilli failed to grow in standard media, resulting in significant underestimation of the numbers of viable mycobacteria in treated samples. We generated M. smegmatis strains overexpressing M. tuberculosis resuscitation-promoting factors (Rpfs) and demonstrated their application for the detection of Rpf-dependent mycobacteria generated after drug exposure. Our data offer novel opportunities for validation of the sterilizing activity of antituberculosis agents. PMID:27503641

  14. Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury

    PubMed Central

    Lee, Sang-Min; McLaughlin, Joseph N.; Frederick, Daniel R.; Zhu, Lin; Thambiayya, Kalidasan; Wasserloos, Karla J.; Kaminski, Iris; Pearce, Linda L.; Peterson, Jim; Li, Jin; Latoche, Joseph D.; Peck Palmer, Octavia M.; Stolz, Donna Beer; Fattman, Cheryl L.; Alcorn, John F.; Oury, Tim D.; Angus, Derek C.; Pitt, Bruce R.

    2013-01-01

    Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ∼4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury. PMID:23275622

  15. [German resuscitation registry : science and resuscitation research].

    PubMed

    Gräsner, J-T; Seewald, S; Bohn, A; Fischer, M; Messelken, M; Jantzen, T; Wnent, J

    2014-06-01

    Sudden death due to cardiac arrest represents one of the greatest challenges facing modern medicine, not only because of the massive number of cases involved but also because of its tremendous social and economic impact. For many years, the magic figure of 1 per 1000 inhabitants per year was generally accepted as an estimate of the annual incidence of sudden death in the industrialized world, with a survival rate of 6 %. This estimate was based on large numbers of published reports of local, regional, national and multinational experience in the management of cardiac arrest. Measuring the global incidence of cardiac arrest is challenging as many different definitions of patient populations are used. Randomized controlled trials (RCT) provide insights into the value of specific treatments or treatment strategies in a well-defined section of a population. Registries do not compete with clinical studies, but represent a useful supplement to them. Surveys and registries provide insights into the ways in which scientific findings and guidelines are being implemented in clinical practice. However, as with clinical studies, comprehensive preparations are needed in order to establish a registry. This is all the more decisive because not all of the questions that may arise are known at the time when the registry is established. The German resuscitation registry started in May 2007 and currently more than 230 paramedic services and hospitals take part. More than 45,000 cases of out-of-hospital cardiac arrest and in-hospital cardiac arrest are included. With this background the German resuscitation registry is one of the largest databases in emergency medicine in Germany. After 5 years of running the preclinical care dataset was revised in 2012. Data variables that reflect current or new treatment were added to the registry. The postresuscitation basic care and telephone cardiopulmonary resuscitation (CPR) datasets were developed in 2012 and 2013 as well. The German

  16. [Cardiopulmonary resuscitation through centuries].

    PubMed

    Gajić, Vladimir

    2011-01-01

    THE ANCIENT TIMES: Many early civilisations left testimonies about ancient times and resuscitation, as well. Some of them did it successfully and some of them did it less successfully; however, all of them wished to help a dying person and to bring him back to life. The first trustworthy note can be found in the Bible--Old Testament as a very realistic description of resuscitation of a child. THE MIDDLE AGES: The medieval scientists, Paracelsus and Vesalius, described first successful resuscitation attempts in the 15th and 16th century. These two men successfully applied ventilation methods by air inflation with blacksmith bellows. THE MODERN ERA: The first defibrillation was recorded in the 18th century in England, which was conducted by one of the volunteer society members. With the development of mechanics and techniques, the first precursors of modern respirators were introduced in the 19th century. The age of modern cardiopulmonary resuscitation began in the middle of 20th century, when Dr Peter Safar brought in the combination of artificial ventilation and chest compressions as the standard for implementing resuscitation. Adrenalin and defibrillation were introduced into the resuscitation techniques by Dr Redding and Dr Kouwenhaven, respectively; thus beginning the advance life support administration, which has been applied, with minor changes, until today.

  17. IL-17 induces EMT via Stat3 in lung adenocarcinoma

    PubMed Central

    Huang, Qi; Han, Jieli; Fan, Jinshuo; Duan, Limin; Guo, Mengfei; Lv, Zhilei; Hu, Guorong; Chen, Lian; Wu, Feng; Tao, Xiaonan; Xu, Juanjuan; Jin, Yang

    2016-01-01

    Epithelial-mesenchymal transition (EMT) plays a vital role in lung inflammatory diseases, including lung cancer. However, the role and mechanism of action of the proinflammatory cytokine IL-17 in EMT in lung adenocarcinoma remain unresolved. In our study, we discovered that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively correlated with IL-17 expression, while E-cadherin expression was negatively correlated with IL-17 expression in human lung adenocarcinoma tissues. Moreover, we confirmed that IL-17 promoted EMT in A549 and Lewis lung carcinoma (LLC) cells in vitro by upregulating N-cadherin, Vimentin, Snail1, Snail2, and Twist1 expression and downregulating E-cadherin expression. Stat3 was activated in IL-17-treated A549 and LLC cells, and Stat3 inhibition or siRNA knockdown notably reduced IL-17-induced EMT in A549 and LLC cells. Thus, IL-17 promotes EMT in lung adenocarcinoma via Stat3 signaling; these observations suggest that targeting IL-17 and EMT are potential novel therapeutic strategies for lung cancer. PMID:27186414

  18. Inflammation-induced preterm lung maturation: lessons from animal experimentation.

    PubMed

    Moss, Timothy J M; Westover, Alana J

    2016-10-20

    Intrauterine inflammation, or chorioamnionitis, is a major contributor to preterm birth. Prematurity per se is associated with considerable morbidity and mortality resulting from lung immaturity but exposure to chorioamnionitis reduces the risk of neonatal respiratory distress syndrome (RDS) in preterm infants. Animal experiments have identified that an increase in pulmonary surfactant production by the preterm lungs likely underlies this decreased risk of RDS in infants exposed to chorioamnionitis. Further animal experimentation has shown that infectious or inflammatory agents in amniotic fluid exert their effects on lung development by direct effects within the developing respiratory tract, and probably not by systemic pathways. Differences in the effects of intrauterine inflammation and glucocorticoids demonstrate that canonical glucocorticoid-mediated lung maturation is not responsible for inflammation-induced changes in lung development. Animal experimentation is identifying alternative lung maturational pathways, and transgenic animals and cell culture techniques will allow identification of novel mechanisms of lung maturation that may lead to new treatments for the prevention of RDS.

  19. Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

    SciTech Connect

    El-Agamy, Dina S.

    2011-06-01

    The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO{sub 2}{sup -}/NO{sub 3}{sup -}) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-{alpha} (TNF-{alpha}), transforming growth factor-{beta}{sub 1} (TGF-{beta}{sub 1}) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO{sub 2}{sup -}/NO{sub 3}{sup -} levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-{alpha}, TGF-{beta}{sub 1} and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells

  20. Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

    PubMed

    Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M; Feghali-Bostwick, Carol; Pardo, Annie; Selman, Moisés; Lagares, David; Tager, Andrew M

    2016-06-01

    Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

  1. Ozone therapy ameliorates paraquat-induced lung injury in rats.

    PubMed

    Kaldirim, Umit; Uysal, Bulent; Yuksel, Ramazan; Macit, Enis; Eyi, Yusuf E; Toygar, Mehmet; Tuncer, Salim K; Ardic, Sukru; Arziman, Ibrahim; Aydin, Ibrahim; Oztas, Yesim; Karslioglu, Yildirim; Topal, Turgut

    2014-12-01

    Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-β1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (P<0.05, PQ vs. PQ+OT). Total antioxidant capacity in PQ+OT group was significantly higher than PQ group (P < 0.05, PQ+OT vs. PQ). These findings suggest that outcome in PQ-induced lung injury may be improved by using OT as an adjuvant therapy.

  2. Apigenin protects against bleomycin-induced lung fibrosis in rats.

    PubMed

    Chen, Ling; Zhao, Wei

    2016-01-01

    Apigenin is a non-toxic and non-mutagenic flavone that exists abundantly in numerous herbs and vegetables. Apigenin exerts anti-proliferative and anti-inflammatory properties. The aim of the present study was to investigate the effects of apigenin on bleomycin-induced lung fibrosis in rats. A single intratracheal instillation of bleomycin (5 mg/kg) was administered and rats were sacrificed on 7 and 28 days post bleomycin instillation. The instillation of bleomycin resulted in decreased body weight and an increase in the lung index. In addition, bleomycin administration increased the hydroxyproline content, myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β levels and decreased the superoxide dismutase (SOD) activity in the rat lung tissues. Excessive collagen deposits were detected in the lung tissues in bleomycin-treated rats compared with normal control rats. Notably, the oral administration of apigenin (10, 15 and 20 mg/kg/day) appeared to prevent the fibrotic process. The treatment suppressed the increases in hydroxyproline content, MPO activity, TNF-α and TGF-β levels and attenuated the reduction of SOD activity that were induced by bleomycin. Furthermore, excessive collagen deposition was inhibited by the apigenin treatment. Collectively, these results suggest that apigenin may function as a potent anti-inflammatory and anti-fibrotic agent against bleomycin-induced lung fibrosis.

  3. Galangin dampens mice lipopolysaccharide-induced acute lung injury.

    PubMed

    Shu, Yu-Sheng; Tao, Wei; Miao, Qian-Bing; Lu, Shi-Chun; Zhu, Ya-Bing

    2014-10-01

    Galangin, an active ingredient of Alpinia galangal, has been shown to possess anti-inflammatory and antioxidant activities. Inflammation and oxidative stress are known to play vital effect in the pathogenesis of acute lung injury (ALI). In this study, we determined whether galangin exerts lung protection in lipopolysaccharide (LPS)-induced ALI. Male BALB/c mice were randomized to receive galangin or vehicle intraperitoneal injection 3 h after LPS challenge. Samples were harvested 24 h post LPS administration. Galangin administration decreased biochemical parameters of oxidative stress and inflammation, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of galangin were associated with inhibition of nuclear factor (NF)-κB and upregulation of heme oxygenase (HO)-1. Galangin reduces LPS-induced ALI by inhibition of inflammation and oxidative stress.

  4. SIRT1 in B[a]P-induced lung tumorigenesis

    PubMed Central

    Sun, Sufang; Zhang, Yongliang; Zhang, Lei; Peng, Lirong; Ma, Ailing; Ji, Pan; Dai, Jia; Cui, Tong; Liu, Heping; Gao, Jimin

    2015-01-01

    Benzo[a]pyrene (B[a]P) is a carcinogen in cigarette smoke. We found that B[a]P induced SIRT1 in human bronchial epithelial BEAS-2B cell. SIRT1 was overexpressed in the lung of B[a]P-exposed mice and in human lung cancer biopsies. SIRT1 up-regulated TNF-α and β-catenin and down-regulated the membrane fraction of E-cadherin. In addition, SIRT1 promoted invasion, migration and tumorigenesis of BEAS-2B cells in nude mice upon B[a]P exposure. Thus, SIRT1 is involved in B[a]P-induced transformation associated with activation of the TNF-α/β-catenin axis and is as a potential therapeutic target for lung cancer. PMID:26318035

  5. SIRT1 in B[a]P-induced lung tumorigenesis.

    PubMed

    Lu, Jianyi; Zhang, Min; Huang, Zhiyong; Sun, Sufang; Zhang, Yongliang; Zhang, Lei; Peng, Lirong; Ma, Ailing; Ji, Pan; Dai, Jia; Cui, Tong; Liu, Heping; Gao, Jimin

    2015-09-29

    Benzo[a]pyrene (B[a]P) is a carcinogen in cigarette smoke. We found that B[a]P induced SIRT1 in human bronchial epithelial BEAS-2B cell. SIRT1 was overexpressed in the lung of B[a]P-exposed mice and in human lung cancer biopsies. SIRT1 up-regulated TNF-α and β-catenin and down-regulated the membrane fraction of E-cadherin. In addition, SIRT1 promoted invasion, migration and tumorigenesis of BEAS-2B cells in nude mice upon B[a]P exposure. Thus, SIRT1 is involved in B[a]P-induced transformation associated with activation of the TNF-α/β-catenin axis and is as a potential therapeutic target for lung cancer.

  6. Alterations of lung microbiota in a mouse model of LPS-induced lung injury

    PubMed Central

    Meng, Fanyong; Meliton, Angelo; Afonyushkin, Taras; Ulanov, Alexander; Semenyuk, Ekaterina; Latif, Omar; Tesic, Vera; Birukova, Anna A.; Birukov, Konstantin G.

    2015-01-01

    Acute lung injury (ALI) and the more severe acute respiratory distress syndrome are common responses to a variety of infectious and noninfectious insults. We used a mouse model of ALI induced by intratracheal administration of sterile bacterial wall lipopolysaccharide (LPS) to investigate the changes in innate lung microbiota and study microbial community reaction to lung inflammation and barrier dysfunction induced by endotoxin insult. One group of C57BL/6J mice received LPS via intratracheal injection (n = 6), and another received sterile water (n = 7). Bronchoalveolar lavage (BAL) was performed at 72 h after treatment. Bacterial DNA was extracted and used for qPCR and 16S rRNA gene-tag (V3–V4) sequencing (Illumina). The bacterial load in BAL from ALI mice was increased fivefold (P = 0.03). The community complexity remained unchanged (Simpson index, P = 0.7); the Shannon diversity index indicated the increase of community evenness in response to ALI (P = 0.07). Principal coordinate analysis and analysis of similarity (ANOSIM) test (P = 0.005) revealed a significant difference between microbiota of control and ALI groups. Bacteria from families Xanthomonadaceae and Brucellaceae increased their abundance in the ALI group as determined by Metastats test (P < 0.02). In concordance with the 16s-tag data, Stenotrohomonas maltophilia (Xanthomonadaceae) and Ochrobactrum anthropi (Brucellaceae) were isolated from lungs of mice from both groups. Metabolic profiling of BAL detected the presence of bacterial substrates suitable for both isolates. Additionally, microbiota from LPS-treated mice intensified IL-6-induced lung inflammation in naive mice. We conclude that the morbid transformation of ALI microbiota was attributed to the set of inborn opportunistic pathogens thriving in the environment of inflamed lung, rather than the external infectious agents. PMID:25957290

  7. Alterations of lung microbiota in a mouse model of LPS-induced lung injury.

    PubMed

    Poroyko, Valeriy; Meng, Fanyong; Meliton, Angelo; Afonyushkin, Taras; Ulanov, Alexander; Semenyuk, Ekaterina; Latif, Omar; Tesic, Vera; Birukova, Anna A; Birukov, Konstantin G

    2015-07-01

    Acute lung injury (ALI) and the more severe acute respiratory distress syndrome are common responses to a variety of infectious and noninfectious insults. We used a mouse model of ALI induced by intratracheal administration of sterile bacterial wall lipopolysaccharide (LPS) to investigate the changes in innate lung microbiota and study microbial community reaction to lung inflammation and barrier dysfunction induced by endotoxin insult. One group of C57BL/6J mice received LPS via intratracheal injection (n = 6), and another received sterile water (n = 7). Bronchoalveolar lavage (BAL) was performed at 72 h after treatment. Bacterial DNA was extracted and used for qPCR and 16S rRNA gene-tag (V3-V4) sequencing (Illumina). The bacterial load in BAL from ALI mice was increased fivefold (P = 0.03). The community complexity remained unchanged (Simpson index, P = 0.7); the Shannon diversity index indicated the increase of community evenness in response to ALI (P = 0.07). Principal coordinate analysis and analysis of similarity (ANOSIM) test (P = 0.005) revealed a significant difference between microbiota of control and ALI groups. Bacteria from families Xanthomonadaceae and Brucellaceae increased their abundance in the ALI group as determined by Metastats test (P < 0.02). In concordance with the 16s-tag data, Stenotrohomonas maltophilia (Xanthomonadaceae) and Ochrobactrum anthropi (Brucellaceae) were isolated from lungs of mice from both groups. Metabolic profiling of BAL detected the presence of bacterial substrates suitable for both isolates. Additionally, microbiota from LPS-treated mice intensified IL-6-induced lung inflammation in naive mice. We conclude that the morbid transformation of ALI microbiota was attributed to the set of inborn opportunistic pathogens thriving in the environment of inflamed lung, rather than the external infectious agents.

  8. Pulmonary mass and multiple lung nodules mimicking a lung neoplasm as amiodarone-induced pulmonary toxicity.

    PubMed

    Rodríguez-García, J L.; García-Nieto, J C.; Ballesta, F; Prieto, E; Villanueva, M A.; Gallardo, J

    2001-07-01

    Amiodarone is an effective anti-arrhythmic agent. However, during long-term therapy, patients can develop severe adverse pulmonary reactions that are potentially life-threatening. A case of amiodarone-induced pulmonary toxicity is presented in a 78-year-old woman. She developed dyspnea and a pulmonary mass with associated multiple lung nodules mimicking a lung cancer following 5 years of treatment with amiodarone for atrial fibrillation. After drug withdrawal, and without any additional treatment, clinical and radiological improvement was observed, and radiological findings resolved completely within 6 months.

  9. OXIDATIVE STRESS PARTICIPATES IN PARTICULATE MATTER (PM) INDUCED LUNG INJURY

    EPA Science Inventory

    Oxidative stress participates in particulate matter (PM) induced acute lung injury.
    Elizabeth S. Roberts1, Judy L. Richards2, Kevin L. Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC, 2US Environmental Protection Agency, NHEERL, RTP, NC.
    Epidemiol...

  10. Preventive Effects of Carnosine on Lipopolysaccharide-induced Lung Injury

    PubMed Central

    Tanaka, Ken-Ichiro; Sugizaki, Toshifumi; Kanda, Yuki; Tamura, Fumiya; Niino, Tomomi; Kawahara, Masahiro

    2017-01-01

    Acute respiratory distress syndrome (ARDS) is a potentially devastating form of acute lung injury, which involves neutrophilic inflammation and pulmonary cell death. Reactive oxygen species (ROS) play important roles in ARDS development. New compounds for inhibiting the onset and progression of ARDS are required. Carnosine (β-alanyl-L-histidine) is a small di-peptide with numerous activities, including antioxidant effects, metal chelation, proton buffering capacity and the inhibition of protein carbonylation and glycoxidation. We have examined the preventive effects of carnosine on tissue injury, oedema and inflammation in a murine model for ARDS. Oral administration of carnosine suppressed lipopolysaccharide (LPS)-induced vascular permeability, tissue injury and inflammation in the lung. In vivo imaging analysis revealed that LPS administration increased the level of ROS and that this increase was inhibited by carnosine administration. Carnosine also suppressed LPS-induced neutrophilic inflammation (evaluated by activation of myeloperoxidase in the lung and increased extracellular DNA in bronchoalveolar lavage fluid). Furthermore, carnosine administration suppressed the LPS-induced endoplasmic reticulum stress response in vivo. These results suggest that the oral administration of carnosine suppresses LPS-induced lung injury via carnosine’s ROS-reducing activity. Therefore, carnosine may be beneficial for suppressing the onset and progression of ARDS. PMID:28205623

  11. A micro-CT analysis of murine lung recruitment in bleomycin-induced lung injury

    PubMed Central

    Shofer, Scott; Badea, Cristian; Qi, Yi; Potts, Erin; Foster, W. Michael; Johnson, G. Allan

    2008-01-01

    The effects of lung injury on pulmonary recruitment are incompletely understood. X-ray computed tomography (CT) has been a valuable tool in assessing changes in recruitment during lung injury. With the development of preclinical CT scanners designed for thoracic imaging in rodents, it is possible to acquire high-resolution images during the evolution of a pulmonary injury in living mice. We quantitatively assessed changes in recruitment caused by intratracheal bleomycin at 1 and 3 wk after administration using micro-CT in 129S6/SvEvTac mice. Twenty female mice were administered 2.5 U of bleomycin or saline and imaged with micro-CT at end inspiration and end expiration. Mice were extubated and allowed to recover from anesthesia and then reevaluated in vivo for quasi-static compliance measurements, followed by harvesting of the lungs for collagen analysis and histology. CT images were converted to histograms and analyzed for mean lung attenuation (MLA). MLA was significantly greater for bleomycin-exposed mice at week 1 for both inspiration (P < 0.0047) and exhalation (P < 0.0377) but was not significantly different for week 3 bleomycin-exposed mice. However, week 3 bleomycin-exposed mice did display significant increases in MLA shift from expiration to inspiration compared with either group of control mice (P < 0.005), suggesting increased lung recruitment at this time point. Week 1 bleomycin-exposed mice displayed normal shifts in MLA with inspiration, suggesting normal lung recruitment despite significant radiographic and histological changes. Lung alveolar recruitment is preserved in a mouse model of bleomycin-induced parenchymal injury despite significant changes in radiographic and physiological parameters. PMID:18566189

  12. Nitrogen dioxide-induced acute lung injury in sheep.

    PubMed

    Januszkiewicz, A J; Mayorga, M A

    1994-05-20

    Lung mechanics, hemodynamics and blood chemistries were assessed in sheep (Ovis aries) before, and up to 24 h following, a 15-20 min exposure to either air (control) or approximately 500 ppm nitrogen dioxide (NO2). Histopathologic examinations of lung tissues were performed 24 h after exposure. Nose-only and lung-only routes of exposure were compared for effects on NO2 pathogenesis. Bronchoalveolar lavage fluids from air- and NO2-exposed sheep were analyzed for biochemical and cellular signs of NO2 insult. The influence of breathing pattern on NO2 dose was also assessed. Five hundred ppm NO2 exposure of intubated sheep (lung-only exposure) was marked by a statistically significant, albeit small, blood methemoglobin increase. The exposure induced an immediate tidal volume decrease, and an increase in both breathing rate and inspired minute ventilation. Pulmonary function, indexed by lung resistance and dynamic lung compliance, progressively deteriorated after exposure. Maximal lung resistance and dynamic lung compliance changes occurred at 24 h post exposure, concomitant with arterial hypoxemia. Bronchoalveolar lavage fluid epithelial cell number and total protein were significantly increased while macrophage number was significantly decreased within the 24 h post-exposure period. Histopathologic examination of lung tissue 24 h after NO2 revealed patchy edema, mild hemorrhage and polymorphonuclear and mononuclear leukocyte infiltration. The NO2 toxicologic profile was significantly attenuated when sheep were exposed to the gas through a face mask (nose-only exposure). Respiratory pattern was not significantly altered, lung mechanics changes were minimal, hypoxemia did not occur, and pathologic evidence of exudation was not apparent in nose-only, NO2-exposed sheep. The qualitative responses of this large animal species to high-level NO2 supports the concept of size dependent species sensitivity to NO2. In addition, when inspired minute ventilation was used as a dose

  13. Stressed lungs: unveiling the role of circulating stress hormones in ozone-induced lung injury and inflammation.

    EPA Science Inventory

    Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction ...

  14. Extracorporeal cardiopulmonary resuscitation.

    PubMed

    Yam, Nicholson; McMullan, David Michael

    2017-02-01

    Extracorporeal life support (ECLS) is used for patients in isolated or combined cardiopulmonary failures. The use of ECLS to rescue patients with cardiac arrest that is refractory to conventional cardiopulmonary resuscitation has been shown to improve survival in many patient populations. Increasing recognition of the survival benefit associated with extracorporeal cardiopulmonary resuscitation (ECPR) has led to increased use of ECPR during the past decade. This review provides an overview of ECPR utilization; population-based clinical outcomes, resource utilization and costs associated this advanced form of life support therapy.

  15. Extracorporeal cardiopulmonary resuscitation

    PubMed Central

    Yam, Nicholson

    2017-01-01

    Extracorporeal life support (ECLS) is used for patients in isolated or combined cardiopulmonary failures. The use of ECLS to rescue patients with cardiac arrest that is refractory to conventional cardiopulmonary resuscitation has been shown to improve survival in many patient populations. Increasing recognition of the survival benefit associated with extracorporeal cardiopulmonary resuscitation (ECPR) has led to increased use of ECPR during the past decade. This review provides an overview of ECPR utilization; population-based clinical outcomes, resource utilization and costs associated this advanced form of life support therapy. PMID:28275617

  16. Teaching schoolchildren cardiopulmonary resuscitation.

    PubMed

    Lester, C; Donnelly, P; Weston, C; Morgan, M

    1996-02-01

    Forty-one children aged 11-12 years received tuition in cardiopulmonary resuscitation (CPR) and subsequently completed questionnaires to assess their theoretical knowledge and attitudes their likelihood of performing CPR. Although most children scored well on theoretical knowledge, this did not correlate with an assessment of practical ability using training manikins. In particular only one child correctly called for help after the casualty was found to be unresponsive, and none telephoned for an ambulance before starting resuscitation. These omissions have important implications for the teaching of CPR and the resulting effectiveness of community CPR programmes.

  17. Glycyrrhetinic acid alleviates radiation-induced lung injury in mice

    PubMed Central

    Chen, Jinmei; Zhang, Weijian; Zhang, Lurong; Zhang, Jiemin; Chen, Xiuying; Yang, Meichun; Chen, Ting; Hong, Jinsheng

    2017-01-01

    Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy, but efficacious therapy for RILI is lacking. This study ascertained whether glycyrrhetinic acid (GA; a functional hydrolyzed product of glycyrrhizic acid, which is extracted from herb licorice) can protect against RILI and investigated its relationship to the transforming growth factor (TGF)-β1/Smads signaling pathway. C57BL/6 mice were divided into four groups: a control group, a GA group and two irradiation (IR) groups. IR groups were exposed to a single fraction of X-rays (12 Gy) to the thorax and administered normal saline (IR + NS group) or GA (IR + GA group). Two days and 17 days after irradiation, histologic analyses were performed to assess the degree of lung injury, and the expression of TGF-β1, Smad2, Smad3 and Smad7 was recorded. GA administration mitigated the histologic changes of lung injury 2 days and 17 days after irradiation. Protein and mRNA expression of TGF-β1, Smad2 and Smad3, and the mRNA level of Smad7, in lung tissue were significantly elevated after irradiation. GA decreased expression of TGF-β1, Smad2 and Smad3 in lung tissue, but did not increase Smad7 expression. GA can protect against early-stage RILI. This protective effect may be associated with inhibition of the TGF-β1/Smads signaling pathway. PMID:27672101

  18. Molecular Mechanisms and Treatment of Radiation-Induced Lung Fibrosis

    PubMed Central

    Ding, Nian-Hua; Li, Jian Jian; Sun, Lun-Quan

    2014-01-01

    Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients. PMID:23909719

  19. [Cardiopulmonary resuscitation: risks and benefits of ventilation].

    PubMed

    Cordioli, Ricardo Luiz; Garelli, Valentina; Lyazidi, Aissam; Suppan, Laurent; Savary, Dominique; Brochard, Laurent; Richard, Jean-Christophe M

    2013-12-11

    Knowledge of the physiological mechanisms that govern cardiopulmonary interactions during cardiopulmonary resuscitation (CPR) allows to better assess risks and benefits of ventilation. Ventilation is required to maintain gas exchange, particularly when CPR is prolonged. Nevertheless, conventional ventilation (bag mask or mechanical ventilation) may be harmful when excessive or when chest compressions are interrupted. In fact large tidal volume and/or rapid respiratory rate may adversely compromise hemodynamic effects of chest compressions. In this regard, international recommendations that give the priority to chest compressions, are meaningful. Continuous flow insufflation with oxygen that generates a moderate positive airway pressure avoids any interruption of chest compressions and prevents the risk of lung injury associated with prolonged resuscitation.

  20. [Cardiopulmonary resuscitation and do not resuscitate orders].

    PubMed

    2007-05-01

    In medical practice, the different scenarios in which cardio respiratory resuscitation (CPR) may be applied must be taken into account. CPR is crucial in subjects that arrive in emergency rooms or suffer a cardiac arrest in public places or at their homes. It is also critical in hospitalized patients with potentially reversible diseases, who suffer cardiac arrest as an unexpected event during their evolution. In intensive care units, the decision is particularly complex. The concepts of therapeutic proportionality, treatment futility and therapeutic tenacity can help physicians in their decision making about when CPR is technically and morally mandatory. The do not resuscitate (DNR) decision in taken when a patient is bearing an irreversible disease and his life is coming to an end. DNR decisions are clearly indicated in intensive care units to limit the therapeutic effort and in other hospital facilities, when death is foreseeable and therapeutic tenacity must be avoided. DNR orders must be renewed and reconsidered on a daily basis. It does not mean that other treatment should be discontinued and by no means should the patient be abandoned. DNR and previous directives, DNR and quality of life and DNR communication are also commented in the present article.

  1. Arctigenin attenuates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Shi, Xianbao; Sun, Hongzhi; Zhou, Dun; Xi, Huanjiu; Shan, Lina

    2015-04-01

    Arctigenin (ATG) has been reported to possess anti-inflammatory properties. However, the effects of ATG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. In the present study, our investigation was designed to reveal the effect of ATG on LPS-induced ALI in rats. We found that ATG pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-1 (IL-6) in the bronchoalveolar lavage fluid. Furthermore, ATG downregulated the expression of nuclear factor kappa B (NF-κB) p65, promoted the phosphorylation of inhibitor of nuclear factor-κB-α (IκBα) and activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPKα) in the lung tissues. Our results suggested that ATG attenuates the LPS-induced ALI via activation of AMPK and suppression of NF-κB signaling pathway.

  2. Inhibition of soluble epoxide hydrolase after cardiac arrest/cardiopulmonary resuscitation induces a neuroprotective phenotype in activated microglia and improves neuronal survival.

    PubMed

    Wang, Jianming; Fujiyoshi, Tetsuhiro; Kosaka, Yasuharu; Raybuck, Jonathan D; Lattal, K Matthew; Ikeda, Mizuko; Herson, Paco S; Koerner, Ines P

    2013-10-01

    Cardiac arrest (CA) causes hippocampal neuronal death that frequently leads to severe loss of memory function in survivors. No specific treatment is available to reduce neuronal death and improve functional outcome. The brain's inflammatory response to ischemia can exacerbate injury and provides a potential treatment target. We hypothesized that microglia are activated by CA and contribute to neuronal loss. We used a mouse model to determine whether pharmacologic inhibition of the proinflammatory microglial enzyme soluble epoxide hydrolase (sEH) after CA alters microglial activation and neuronal death. The sEH inhibitor 4-phenylchalcone oxide (4-PCO) was administered after successful cardiopulmonary resuscitation (CPR). The 4-PCO treatment significantly reduced neuronal death and improved memory function after CA/CPR. We found early activation of microglia and increased expression of inflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the hippocampus after CA/CPR, which was unchanged after 4-PCO treatment, while expression of antiinflammatory IL-10 increased significantly. We conclude that sEH inhibition after CA/CPR can alter the transcription profile in activated microglia to selectively induce antiinflammatory and neuroprotective IL-10 and reduce subsequent neuronal death. Switching microglial gene expression toward a neuroprotective phenotype is a promising new therapeutic approach for ischemic brain injury.

  3. [Recommendations in neonatal resuscitation].

    PubMed

    2004-01-01

    The recommendations for neonatal resuscitation are not always based on sufficient scientific evidence and thus expert consensus based on current research, knowledge, and experience are useful for formulating practical protocols that are easy to follow. The latest recommendations, in 2000, modified previously published recommendations and are included in the present text.

  4. Hypotensive Resuscitation among Trauma Patients

    PubMed Central

    Carrick, Matthew M.; Leonard, Jan; Slone, Denetta S.; Mains, Charles W.

    2016-01-01

    Hemorrhagic shock is a principal cause of death among trauma patients within the first 24 hours after injury. Optimal fluid resuscitation strategies have been examined for nearly a century, more recently with several randomized controlled trials. Hypotensive resuscitation, also called permissive hypotension, is a resuscitation strategy that uses limited fluids and blood products during the early stages of treatment for hemorrhagic shock. A lower-than-normal blood pressure is maintained until operative control of the bleeding can occur. The randomized controlled trials examining restricted fluid resuscitation have demonstrated that aggressive fluid resuscitation in the prehospital and hospital setting leads to more complications than hypotensive resuscitation, with disparate findings on the survival benefit. Since the populations studied in each randomized controlled trial are slightly different, as is the timing of intervention and targeted vitals, there is still a need for a large, multicenter trial that can examine the benefit of hypotensive resuscitation in both blunt and penetrating trauma patients. PMID:27595109

  5. A3 adenosine receptor inhibition improves the efficacy of hypertonic saline resuscitation

    PubMed Central

    Inoue, Yoshiaki; Tanaka, Hiroshi; Sumi, Yuka; Woehrle, Tobias; Chen, Yu; Hirsh, Mark I.; Junger, Wolfgang G.

    2011-01-01

    We reported previously that hypertonic saline (HS) treatment can prevent or upregulate the function of polymorphonuclear neutrophils (PMN) via A2a adenosine receptors (A2aR) or A3 adenosine receptors (A3R), respectively. A3R translocate to the cell surface upon PMN stimulation and thus HS promotes PMN responses under conditions of delayed HS treatment. Here we investigated if inhibition of A3R improves the protective effects of HS resuscitation in a mouse sepsis model. We found that HS nearly triples extracellular adenosine concentrations in whole blood and that inhibition of A3R with the selective antagonist MRS-1191 dose-dependently improves the inhibitory effect of HS. MRS-1191 at a concentration of 1 nM enhanced the inhibitory effect of HS and reduced stimulatory effects of delayed HS treatment. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found that MRS-1191 reduces acute lung injury and PMN accumulation in lung tissue. While delayed HS treatment (4 ml/kg of 7.5 % NaCl) of mice 1 h after CLP aggravated PMN accumulation, lung tissue damage, and mortality 24 h after CLP, infusion of MRS-1191 (2 ng/kg body weight) combined with HS reduced these detrimental effects of delayed HS treatment. Our data thus show that A3 receptor antagonists can strengthen the beneficial effects of HS resuscitation by avoiding stimulatory side effects that result from delayed HS administration. PMID:20661181

  6. Stem cell factor improves lung recovery in rats following neonatal hyperoxia-induced lung injury

    PubMed Central

    Miranda, Luis F.; Rodrigues, Claudia O.; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Klim, Jammie; Hehre, Dorothy; McNiece, Ian; Hare, Joshua M.; Suguihara, Cleide Y.; Young, Karen C.

    2016-01-01

    BACKGROUND Stem cell factor (SCF) and its receptor, c-kit, are modulators of angiogenesis. Neonatal hyperoxia-induced lung injury (HILI) is characterized by disordered angiogenesis. The objective of this study was to determine whether exogenous SCF improves recovery from neonatal HILI by improving angiogenesis. METHODS Newborn rats assigned to normoxia (RA: 20.9% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to 15, received daily injections of SCF 100 µg/kg or placebo (PL) from P15 to P21. Lung morphometry was performed at P28. Capillary tube formation in SCF-treated hyperoxia-exposed pulmonary microvascular endothelial cells (HPMECs) was determined by Matrigel assay. RESULTS As compared with RA, hyperoxic-PL pups had decrease in alveolarization and in lung vascular density, and this was associated with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and vascular remodeling. In contrast, SCF-treated hyperoxic pups had increased angiogenesis, improved alveolarization, and attenuation of pulmonary hypertension as evidenced by decreased RVSP, right ventricular hypertrophy, and vascular remodeling. Moreover, in an in vitro model, SCF increased capillary tube formation in hyperoxia-exposed HPMECs. CONCLUSION Exogenous SCF restores alveolar and vascular structure in neonatal rats with HILI by promoting neoangiogenesis. These findings suggest a new strategy to treat lung diseases characterized by dysangiogenesis. PMID:24153399

  7. [Drug-induced interstitial lung disease].

    PubMed

    Gemma, Akihiko

    2008-10-01

    There was limited knowledge about drug-induced ILD(DILD), when safety reports of acute ILD-type events in gefitinib-treated patients appeared in Japan. There is a need to better understand DILD including event incidence on different treatments and risk factors for developing DILD. Some studies using recent advances in imaging, molecular examination, and pathology are designed and conducted by an independent academic team to define the risk and increase understanding of ILD of various agents in a postmarketing surveillance. These studies may help to shed light on the underlying mechanisms of DILD and appropriate strategies for such events.

  8. AKT1E¹⁷K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer.

    PubMed

    Malanga, Donatella; Belmonte, Stefania; Colelli, Fabiana; Scarfò, Marzia; De Marco, Carmela; Oliveira, Duarte Mendes; Mirante, Teresa; Camastra, Caterina; Gagliardi, Monica; Rizzuto, Antonia; Mignogna, Chiara; Paciello, Orlando; Papparella, Serenella; Fagman, Henrik; Viglietto, Giuseppe

    2016-01-01

    The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6-2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26) locus (R26-AKT1E17K mice) we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype.

  9. Hepatic cryoablation-induced acute lung injury: histopathologic findings.

    PubMed

    Washington, K; Debelak, J P; Gobbell, C; Sztipanovits, D R; Shyr, Y; Olson, S; Chapman, W C

    2001-01-01

    We have previously shown that hepatic cryoablation (cryo), but not partial hepatectomy, induces a systemic inflammatory response, with distant organ injury and overproduction of NF-kappaB-dependent cytokines. Serum tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2) levels are markedly increased 1 h and beyond after cryo compared with partial hepatectomy where no elevation occurs. NF-kappaB activation (by electrophoretic mobility shift assay) is strikingly increased in the noncryo liver (but not in the lung) at 30 min and in both the liver and lung tissue 1 h after cryo, returning to the baseline by 2 h and beyond. The current study investigated the histopathologic changes associated with cryoablation-induced acute lung injury. Animals underwent 35% hepatic resection or a similar volume hepatic cryo and were sacrificed at 1, 2, 6, and 24 h. Pulmonary histologic features were assessed using hematoxylin and eosin and immunoperoxidase staining with a macrophage-specific antibody (anti-lysozyme, 1:200 dilution, Dako, Carpinteria, CA). The following features were graded semiquantitatively (0-3): perivascular lymphoid cuffs, airspace edema and hemorrhage, margination of neutrophils within pulmonary vasculature, and the presence of macrophages with foamy cytoplasm in the pulmonary interstitium. Hepatic resection (n = 21) resulted in slight perivascular edema at 1, 2, 6, and 24 h post-resection, but there were no other significant changes. Pulmonary findings after hepatic cryo (n = 22) included prominent perivascular lymphoid cuffs 1 and 2 h following hepatic injury that were not present at any other time point (P 0.01). Marginating PMNs and foamy macrophages were more common after cryo at all time points (P<0.05, cryo vs resection). Severe lung injury, as evidenced by airspace edema and parenchymal hemorrhage, was present in four of six (67%) animals at 24 h (P 0.03). In follow-up studies immediate resection (n = 15) of the cryo

  10. End Points of Sepsis Resuscitation.

    PubMed

    Greenwood, John C; Orloski, Clinton J

    2017-02-01

    Resuscitation goals for the patient with sepsis and septic shock are to return the patient to a physiologic state that promotes adequate end-organ perfusion along with matching metabolic supply and demand. Ideal resuscitation end points should assess the adequacy of tissue oxygen delivery and oxygen consumption, and be quantifiable and reproducible. Despite years of research, a single resuscitation end point to assess adequacy of resuscitation has yet to be found. Thus, the clinician must rely on multiple end points to assess the patient's overall response to therapy. This review will discuss the role and limitations of central venous pressure (CVP), mean arterial pressure (MAP), and cardiac output/index as macrocirculatory resuscitation targets along with lactate, central venous oxygen saturation (ScvO2), central venous-arterial CO2 gradient, urine output, and capillary refill time as microcirculatory resuscitation endpoints in patients with sepsis.

  11. Budesonide inhalation ameliorates endotoxin-induced lung injury in rabbits

    PubMed Central

    Gao, Wei

    2015-01-01

    Acute respiratory distress syndrome (ARDS) is a serious clinical problem that has a 30–50% mortality rate. Budesonide has been used to reduce lung injury. This study aims to investigate the effects of nebulized budesonide on endotoxin-induced ARDS in a rabbit model. Twenty-four rabbits were randomized into three groups. Rabbits in the control and budesonide groups were injected with endotoxin. Thereafter, budesonide or saline was instilled, ventilated for four hours, and recovered spontaneous respiratory. Peak pressure, compliance, and PaO2/FiO2 were monitored for 4 h. After seven days, PaO2/FiO2 ratios were measured. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells, and percentage of neutrophils in BALF were evaluated. TNF-α, IL-1β, IL-8, and IL-10 in BALF were detected. Lung histopathologic injury and seven-day survival rate of the three groups were recorded. Peak pressure was downregulated, but compliance and PaO2/FiO2 were upregulated by budesonide. PaO2/FiO2 ratios significantly increased due to budesonide. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells and percentage of neutrophils in BALF decreased in the budesonide group. TNF-α, IL-1β, and IL-8 levels decreased in BALF, while IL-10 levels increased in the budesonide group. Lung injuries were reduced and survival rate was upregulated by budesonide. Budesonide effectively ameliorated respiratory function, attenuated endotoxin-induced lung injury, and improved the seven-day survival rate. PMID:25956681

  12. Lung deformations and radiation-induced regional lung collapse in patients treated with stereotactic body radiation therapy

    SciTech Connect

    Diot, Quentin Kavanagh, Brian; Vinogradskiy, Yevgeniy; Gaspar, Laurie; Miften, Moyed; Garg, Kavita

    2015-11-15

    Purpose: To differentiate radiation-induced fibrosis from regional lung collapse outside of the high dose region in patients treated with stereotactic body radiation therapy (SBRT) for lung tumors. Methods: Lung deformation maps were computed from pre-treatment and post-treatment computed tomography (CT) scans using a point-to-point translation method. Fifty anatomical landmarks inside the lung (vessel or airway branches) were matched on planning and follow-up scans for the computation process. Two methods using the deformation maps were developed to differentiate regional lung collapse from fibrosis: vector field and Jacobian methods. A total of 40 planning and follow-ups CT scans were analyzed for 20 lung SBRT patients. Results: Regional lung collapse was detected in 15 patients (75%) using the vector field method, in ten patients (50%) using the Jacobian method, and in 12 patients (60%) by radiologists. In terms of sensitivity and specificity the Jacobian method performed better. Only weak correlations were observed between the dose to the proximal airways and the occurrence of regional lung collapse. Conclusions: The authors presented and evaluated two novel methods using anatomical lung deformations to investigate lung collapse and fibrosis caused by SBRT treatment. Differentiation of these distinct physiological mechanisms beyond what is usually labeled “fibrosis” is necessary for accurate modeling of lung SBRT-induced injuries. With the help of better models, it becomes possible to expand the therapeutic benefits of SBRT to a larger population of lung patients with large or centrally located tumors that were previously considered ineligible.

  13. Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury.

    PubMed

    Acosta-Herrera, Marialbert; Lorenzo-Diaz, Fabian; Pino-Yanes, Maria; Corrales, Almudena; Valladares, Francisco; Klassert, Tilman E; Valladares, Basilio; Slevogt, Hortense; Ma, Shwu-Fan; Villar, Jesus; Flores, Carlos

    2015-01-01

    Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The 'response to microorganisms' was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection morphogenesis

  14. Afatinib-Induced Acute Fatal Pneumonitis in Metastatic Lung Adenocarcinoma

    PubMed Central

    Yoo, Sang Hoon; Ryu, Jin Ah; Kim, Seo Ree; Oh, Su Yun; Jung, Gu Sung; Lee, Dong Jae; Kwak, Bong Gyu; Nam, Yu Hyun; Kim, Kyung Hyun

    2016-01-01

    Afatinib is an oral tyrosine kinase inhibitor (TKI) that inhibit Endothelial Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. The common side effects of EGFR TKI are rash, acne, diarrhea, stomatitis, pruritus, nausea, and loss of appetite. Drug induced pneumonitis is the less common adverse effects of EGFR TKI. Afatinib, 2nd generation EGFR TKI is anticipated to overcome drug resistance from 1st generation EGFR TKI according to preclinical study, and several studies are being conducted to compare clinical efficacy between 1st and 2nd EGFR TKI. Several cases of rug induced acute fatal pneumonitis were reported after use of erlotinib or gefitinib. However, a case of acute fatal pneumonitis associated with afatinib was note reported except drug induced pneumonitis in other clinical study. Here, we present a cases of acute severe pneumonitis related with afatinib in metastatic lung adenocarcinoma with literature review. PMID:27900074

  15. Hypoxia-Induced Epithelial-Mesenchymal Transition Is Involved in Bleomycin-Induced Lung Fibrosis.

    PubMed

    Guo, Liang; Xu, Jun-mei; Liu, Lei; Liu, Su-mei; Zhu, Rong

    2015-01-01

    Pulmonary fibrosis is a severe disease that contributes to the morbidity and mortality of a number of lung diseases. However, the molecular and cellular mechanisms leading to lung fibrosis are poorly understood. This study investigated the roles of epithelial-mesenchymal transition (EMT) and the associated molecular mechanisms in bleomycin-induced lung fibrosis. The bleomycin-induced fibrosis animal model was established by intratracheal injection of a single dose of bleomycin. Protein expression was measured by Western blot, immunohistochemistry, and immunofluorescence. Typical lesions of lung fibrosis were observed 1 week after bleomycin injection. A progressive increase in MMP-2, S100A4, α-SMA, HIF-1α, ZEB1, CD44, phospho-p44/42 (p-p44/42), and phospho-p38 MAPK (p-p38) protein levels as well as activation of EMT was observed in the lung tissues of bleomycin mice. Hypoxia increased HIF-1α and ZEB1 expression and activated EMT in H358 cells. Also, continuous incubation of cells under mild hypoxic conditions increased CD44, p-p44/42, and p-p38 protein levels in H358 cells, which correlated with the increase in S100A4 expression. In conclusion, bleomycin induces progressive lung fibrosis, which may be associated with activation of EMT. The fibrosis-induced hypoxia may further activate EMT in distal alveoli through a hypoxia-HIF-1α-ZEB1 pathway and promote the differentiation of lung epithelial cells into fibroblasts through phosphorylation of p38 MAPK and Erk1/2 proteins.

  16. Resuscitation therapy for traumatic brain injury-induced coma in rats: mechanisms of median nerve electrical stimulation

    PubMed Central

    Feng, Zhen; Zhong, Ying-jun; Wang, Liang; Wei, Tian-qi

    2015-01-01

    In this study, rats were put into traumatic brain injury-induced coma and treated with median nerve electrical stimulation. We explored the wake-promoting effect, and possible mechanisms, of median nerve electrical stimulation. Electrical stimulation upregulated the expression levels of orexin-A and its receptor OX1R in the rat prefrontal cortex. Orexin-A expression gradually increased with increasing stimulation, while OX1R expression reached a peak at 12 hours and then decreased. In addition, after the OX1R antagonist, SB334867, was injected into the brain of rats after traumatic brain injury, fewer rats were restored to consciousness, and orexin-A and OXIR expression in the prefrontal cortex was downregulated. Our findings indicate that median nerve electrical stimulation induced an up-regulation of orexin-A and OX1R expression in the prefrontal cortex of traumatic brain injury-induced coma rats, which may be a potential mechanism involved in the wake-promoting effects of median nerve electrical stimulation. PMID:26170820

  17. When should resuscitation at birth cease?

    PubMed

    McGrath, J S; Roehr, C C; Wilkinson, D J C

    2016-11-01

    It is rare for newborn infants to require prolonged resuscitation at birth. While there are detailed national and international guidelines on when and how to provide resuscitation to newborns, there is little existing guidance on when newborn resuscitation should be stopped. In this paper we review current guidance surrounding adult, paediatric and neonatal resuscitation as well as recent evidence of outcome for newborn infants requiring prolonged resuscitation. We discuss the ethical principles that can potentially guide decisions surrounding resuscitation and post-resuscitation care. We also propose a structured approach to stopping resuscitation.

  18. Branching geometry induced by lung self-regulated growth

    NASA Astrophysics Data System (ADS)

    Clément, Raphaël; Douady, Stéphane; Mauroy, Benjamin

    2012-12-01

    Branching morphogenesis is a widely spread phenomenon in nature. In organogenesis, it results from the inhomogeneous growth of the epithelial sheet, leading to its repeated branching into surrounding mesoderm. Lung morphogenesis is an emblematic example of tree-like organogenesis common to most mammals. The core signalling network is well identified, notably the Fgf10/Shh couple, required to initiate and maintain branching. In a previous study, we showed that the restriction by SHH of Fgf10 expression domain to distal mesenchyme spontaneously induces differential epithelial proliferation leading to branching. A simple Laplacian model qualitatively reproduced FGF10 dynamics in the mesenchyme and the spontaneous self-avoiding branching morphogenesis. However, early lung geometry has several striking features that remain to be addressed. In this paper, we investigate, through simulations and data analysis, if the FGF10-diffusion scenario accounts for the following aspects of lung morphology: size dispersion, asymmetry of branching events, and distal epithelium-mesothelium equilibrium. We report that they emerge spontaneously in the model, and that most of the underlying mechanisms can be understood as dynamical interactions between gradients and shape. This suggests that specific regulation may not be required for the emergence of these striking geometrical features.

  19. Molecular Basis of Asbestos-Induced Lung Disease

    PubMed Central

    Liu, Gang; Cheresh, Paul; Kamp, David W.

    2013-01-01

    Asbestos causes asbestosis and malignancies by molecular mechanisms that are not fully understood. The modes of action underlying asbestosis, lung cancer, and mesothelioma appear to differ depending on the fiber type, lung clearance, and genetics. After reviewing the key pathologic changes following asbestos exposure, we examine recently identified pathogenic pathways, with a focus on oxidative stress. Alveolar epithelial cell apoptosis, which is an important early event in asbestosis, is mediated by mitochondria- and p53-regulated death pathways and may be modulated by the endoplasmic reticulum. We review mitochondrial DNA (mtDNA)-damage and -repair mechanisms, focusing on 8-oxoguanine DNA glycosylase, as well as cross talk between reactive oxygen species production, mtDNA damage, p53, OGG1, and mitochondrial aconitase. These new insights into the molecular basis of asbestos-induced lung diseases may foster the development of novel therapeutic targets for managing degenerative diseases (e.g., asbestosis and idiopathic pulmonary fibrosis), tumors, and aging, for which effective management is lacking. PMID:23347351

  20. Low Volume Resuscitation with Cell Impermeants

    DTIC Science & Technology

    2013-10-01

    mixture doubled the LVR time and significantly improved cardiovascular, hepatic, renal , and metabolic function during the LVR period and 24 hrs after...after full resuscitation. This lessens end organ failure and improves survival since distribution of the limited oxygen availability is enhanced...ischemia-induced loss of ATP dependent volume control mechanisms (Na/K ATPase or sodium pump failure ). An important attribute of cell impermeant

  1. Discovery of 2'-hydroxychalcones as autophagy inducer in A549 lung cancer cells.

    PubMed

    Wang, Fang-Wu; Wang, Sheng-Qing; Zhao, Bao-Xiang; Miao, Jun-Ying

    2014-05-21

    A series of 2'-hydroxychalcone derivatives was synthesized and the effects of all the compounds on growth of A549 lung cancer cell were investigated. The results showed that all compounds had inhibitory effects on the growth of A549 lung cancer cells and compound possessed the highest growth inhibitory effect and induced autophagy of A549 lung cancer cells.

  2. Exercise-induced haemoptysis as a rare presentation of a rare lung disease.

    PubMed

    Mihalek, Andrew D; Haney, Carissa; Merino, Maria; Roy-Chowdhuri, Sinchita; Moss, Joel; Olivier, Kenneth N

    2016-09-01

    Amyloid primarily affecting the lungs is a seldom seen clinical entity. This case discusses the work-up of a patient presenting with exercise-induced haemoptysis and diffuse cystic lung disease on radiographic imaging. The common clinical and radiographic findings of diffuse cystic lung diseases as well as a brief overview of pulmonary amyloid are presented.

  3. Effects of Pentoxifylline on TNF-Alpha and Lung Histopathology in HCl-Induced Lung Injury

    PubMed Central

    de Oliveira-Júnior, Itamar Souza; Maganhin, Carla Cristina; Carbonel, Adriana Aparecida Ferraz; Monteiro, Cristina Maria Rodrigues; Cavassani, Sâmia Santos; Oliveira-Filho, Ricardo Martins

    2008-01-01

    OBJECTIVE To evaluate the effects of pentoxifylline on hydrochloric acid-induced lung lesions in rats subjected to mechanical ventilation. METHODS Twenty male, adult Wistar-EPM-1 rats were anesthetized and randomly grouped (n=5 animals per group) as follows: control-MV (mechanical ventilation, MV group); bilateral instillation of HCl (HCl group); bilateral instillation of HCl followed by pentoxifylline (50 mg/kg bw) infusion (HCl+PTX group) and pentoxifylline infusion followed by bilateral instillation of HCl (PTX+HCl group). At 20, 30, 90 and 180 min after treatments, the blood partial pressures of CO2 and O2 were measured. The animals were euthanized, and bronchoalveolar lavages were taken to determine the contents of total proteins, corticosterone and TNF-α. Samples of lung tissue were used for histomorphometric studies and determining the wet-to-dry (W/D) lung weight ratio. RESULTS In the MV group, rats had alveolar septal congestion, and, in the HCl group, a remarkable recruitment of neutrophils and macrophages into the alveoli was noticed; these events were reduced in the animals with PTX+HCl. The partial pressure of oxygen increased in PTX+HCl animals (121±5 mmHg) as compared with the HCl (62±6 mmHg) and HCl+PTX (67±3 mmHg) groups within 30 minutes. TNF-α levels in bronchoalveolar lavage were significantly higher in the HCl group (458±50 pg/mL), reduced in the HCl+PTX group (329±45 pg/mL) and lowest in the PTX+HCl group (229±41 pg/mL). The levels of corticosterone in bronchoalveolar lavage were significantly lower in the HCl (8±1.3 ng/mL) and HCl+PTX group (16±2 ng/mL) and were highest in the PTX+HCl (27±1.9 ng/mL). CONCLUSION Pretreatment with PTX improves oxygenation, reduces TNF-α concentration and increases the concentration of corticosterone in bronchoalveolar lavage upon lung lesion induced by HCl. PMID:18297211

  4. The ethics of newborn resuscitation.

    PubMed

    Mercurio, Mark R

    2009-12-01

    It is widely believed in neonatology and obstetrics that there are situations in which it is inappropriate to attempt newborn resuscitation, and other times when newborn resuscitation is obligatory despite parental refusal. In each case, an ethical justification for the decision needs to be identified. This essay is intended to provide guidance in deciding when resuscitation should be attempted, and in identifying ethical considerations that should be taken into account. It specifically addresses the issue of extreme prematurity, including an analysis of current recommendations, the data, relevant rights of patient and parents, and a discussion of the relative merits of withholding resuscitation vs providing resuscitation and possibly withdrawing intensive care later. In addition to extreme prematurity, the considerations presented are also relevant to a wider spectrum of newborn problems, including Trisomy 13, Trisomy 18, and severe congenital anomalies.

  5. Amelioration of superoxide dismutase on ventilator-induced lung injury by suppressing leukocyte in the lungs and systemic circulation.

    PubMed

    Su, Chien-Ling; Du, Wen-Yuan; Chiang, Ling-Ling; Lin, Yen-Kuang; Lee, Hui-Ling; Chen, Kuan-Hao; Wang, Jiun-; Wang, David

    2013-08-31

    Superoxide dismutase (SOD) is a free radical scavenger and a broad-spectrum antioxidant. Its anti-inflammatory and immunomodulatory effects have recently been noted. We studied the effects of this antioxidant on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Sprange-Dawley rats (n = 40). Animals were randomized and evenly divided into two experimental groups, low tidal volume (V(T)) ventilation (V(T) = 9 ml/kg) and high V(T) ventilation (V(T) = 28 ml/kg). Each group was evenly divided into two subgroups: ten animals were treated with superoxide dismutase (SOD; 10,000 U/kg i.v., 2 h prior to the ventilation) and the rests were treated with vehicle. Lung injury was evaluated by histological examination, and cells counts of red blood cells (RBC) and white blood cells (WBC) in the alveoli and the septal wall thickness in lung tissues and serum lactate dehydrogenase (LDH). The lung permeability was assessed by the wet-to-dry weight ratio (W/D), lung weight to body weight ratio (LW/BW) and protein concentration in broncholavage fluid (BALF). Levels of oxidative stress and lipid peroxidation in the lungs were evaluated by tissue malondialdehyde (MDA) and methylguanidine (MG) in BALF, respectively. SOD pretreatment significantly decreased WBC counts in systemic circulation and in alveoli, and effectively attenuated high V(T) ventilation induced lung injury by reducing hyaline membrane development, septal wall thickness, lung W/D and LW/BW and serum LDH in relation to those of the control. In addition, lung tissues MDA and MG in BALF were also notably reduced.

  6. Inhaled Carbon Monoxide Protects against the Development of Shock and Mitochondrial Injury following Hemorrhage and Resuscitation

    PubMed Central

    Gomez, Hernando; Kautza, Benjamin; Escobar, Daniel; Nassour, Ibrahim; Luciano, Jason; Botero, Ana Maria; Gordon, Lisa; Martinez, Silvia; Holder, Andre; Ogundele, Olufunmilayo; Loughran, Patricia; Rosengart, Matthew R.; Pinsky, Michael; Shiva, Sruti; Zuckerbraun, Brian S.

    2015-01-01

    Aims Currently, there is no effective resuscitative adjunct to fluid and blood products to limit tissue injury for traumatic hemorrhagic shock. The objective of this study was to investigate the role of inhaled carbon monoxide (CO) to limit inflammation and tissue injury, and specifically mitochondrial damage, in experimental models of hemorrhage and resuscitation. Results Inhaled CO (250 ppm for 30 minutes) protected against mortality in severe murine hemorrhagic shock and resuscitation (HS/R) (20% vs. 80%; P<0.01). Additionally, CO limited the development of shock as determined by arterial blood pH (7.25±0.06 vs. 7.05±0.05; P<0.05), lactate levels (7.2±5.1 vs 13.3±6.0; P<0.05), and base deficit (13±3.0 vs 24±3.1; P<0.05). A dose response of CO (25–500 ppm) demonstrated protection against HS/R lung and liver injury as determined by MPO activity and serum ALT, respectively. CO limited HS/R-induced increases in serum tumor necrosis factor-α and interleukin-6 levels as determined by ELISA (P<0.05 for doses of 100–500ppm). Furthermore, inhaled CO limited HS/R induced oxidative stress as determined by hepatic oxidized glutathione:reduced glutathione levels and lipid peroxidation. In porcine HS/R, CO did not influence hemodynamics. However, CO limited HS/R-induced skeletal muscle and platelet mitochondrial injury as determined by respiratory control ratio (muscle) and ATP-linked respiration and mitochondrial reserve capacity (platelets). Conclusion These preclinical studies suggest that inhaled CO can be a protective therapy in HS/R; however, further clinical studies are warranted. PMID:26366865

  7. Carboxyhaemoglobin dissociation in the cadaver following attempted resuscitation.

    PubMed Central

    Rice, H M

    1976-01-01

    A series of 300 cases of fatal carbon-monoxide poisoning showed wide variations in carboxyhaemoglobin saturation. Levels below 50% in 24 subjects under the age of 70 were probably falsely low following attempted resuscitation on the way to hospital. Artificial respiration, especially with oxygen-rich gas, causes dissociation of carboxyhaemoglobin in the lungs of the cadaver while movement of blood into and out of the lungs, with mixing, lowers the saturation levels in the neighbouring large veins. In four cases subclavian blood showed saturation levels much lower than blood from sites further from the lungs. Blood should be taken from the femoral vein to get true readings. PMID:1249248

  8. Genome‑wide analysis of DNA methylation in rat lungs with lipopolysaccharide‑induced acute lung injury.

    PubMed

    Zhang, Xiao-Qiang; Lv, Chang-Jun; Liu, Xiang-Yong; Hao, Dong; Qin, Jing; Tian, Huan-Huan; Li, Yan; Wang, Xiao-Zhi

    2013-05-01

    Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are associated with high morbidity and mortality in patients, however, the precise pathogenesis of ALI/ARDS remains unknown. Lipopolysaccharide (LPS) exhibits a number of critical functions and may be associated with the DNA methylation of genes in the lungs. In the present study a genome‑wide analysis of DNA methylation was performed in rat lungs with LPS‑induced ALI/ARDS. Normal and LPS‑induced lung tissues with ALI were analyzed using methylated DNA immunoprecipitation and a rat DNA methylation promoter plus CpG island microarray and the candidate genes were validated by quantitative reverse transcriptase polymerase chain reaction (qRT‑PCR). Aberrant DNA methylation of the promoter regions of 1,721 genes and the CpG islands of 990 genes was identified when normal lung tissues and lung tissues with LPS‑induced ALI/ARDS were compared. These genes were commonly located on chromosomes 1, 3, 5, 7 and 10 (P<0.01). Methylation level and CpG density were compared and it was found that genes associated with high CpG density promoters had a high ratio of methylation. Furthermore, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In addition, three genes (Mapk3, Pak1 and Rac2) were validated in the control and lung tissues with ALI by RT‑PCR. The results indicate that aberrant DNA methylation of lung tissues may be involved in the pathophysiology of LPS‑induced ALI/ARDS. Future studies are required to evaluate the therapeutic and prognostic value of the current novel observations in ALI/ARDS.

  9. Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration

    PubMed Central

    Jones, Heather D.; Yoo, Jeena; Crother, Timothy R.; Kyme, Pierre; Ben-Shlomo, Anat; Khalafi, Ramtin; Tseng, Ching W.; Parks, William C.; Arditi, Moshe

    2015-01-01

    Background Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury. Methods We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε. Results Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice. Conclusions Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but

  10. Behaviour of three resuscitators under hyperbaric conditions.

    PubMed

    Ross, J A; Manson, H J

    1977-01-01

    Three portable resuscitators were tested under hyperbaric conditions--the Pneupac Ventilator/Resuscitator, the Motivus Resuscitator (Type P.V.),and the Stephenson Minuteman Resuscitator. The first two delivered an inadequate tidal volume at 2 ATA. The third, while delivering a constant tidal volume, did so at an increasingly inadequate ventilatory frequency.

  11. Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis.

    PubMed

    Liu, Gang; Beri, Rohinee; Mueller, Amanda; Kamp, David W

    2010-11-05

    Asbestos causes pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully elucidated. Accumulating evidence show that alveolar epithelial cell (AEC) apoptosis is a crucial initiating and perpetuating event in the development of pulmonary fibrosis following exposure to a wide variety of noxious stimuli, including asbestos. We review the important molecular mechanisms underlying asbestos-induced AEC apoptosis. Specifically, we focus on the role of asbestos in augmenting AEC apoptosis by the mitochondria- and p53-regulated death pathways that result from the production of iron-derived reactive oxygen species (ROS) and DNA damage. We summarize emerging evidence implicating the endoplasmic reticulum (ER) stress response in AEC apoptosis in patients with idiopathic pulmonary fibrosis (IPF), a disease with similarities to asbestosis. Finally, we discuss a recent finding that a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) acts as a mitochondrial aconitase chaperone protein to prevent oxidant (asbestos and H(2)O(2))-induced AEC mitochondrial dysfunction and intrinsic apoptosis. The coupling of mitochondrial Ogg1 to mitochondrial aconitase is a novel mechanism linking metabolism to mitochondrial DNA that may be important in the pathophysiologic events resulting in oxidant-induced toxicity as seen in tumors, aging, and respiratory disorders (e.g. asbestosis, IPF). Collectively, these studies are illuminating the molecular basis of AEC apoptosis following asbestos exposure that may prove useful for developing novel therapeutic strategies. Importantly, the asbestos paradigm is elucidating pathophysiologic insights into other more common pulmonary diseases, such as IPF and lung cancer, for which better therapy is required.

  12. Elastase induces lung epithelial cell autophagy through placental growth factor

    PubMed Central

    Hou, Hsin-Han; Cheng, Shih-Lung; Chung, Kuei-Pin; Kuo, Mark Yen-Ping; Yeh, Cheng-Chang; Chang, Bei-En; Lu, Hsuan-Hsuan; Wang, Hao-Chien; Yu, Chong-Jen

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a devastating disease, which is associated with increasing mortality and morbidity. Therefore, there is a need to clearly define the COPD pathogenic mechanism and to explore effective therapies. Previous studies indicated that cigarette smoke (CS) induces autophagy and apoptosis in lung epithelial (LE) cells. Excessive ELANE/HNE (elastase, neutrophil elastase), a factor involved in protease-antiprotease imbalance and the pathogenesis of COPD, causes LE cell apoptosis and upregulates the expression of several stimulus-responsive genes. However, whether or not elastase induces autophagy in LE cell remains unknown. The level of PGF (placental growth factor) is higher in COPD patients than non-COPD controls. We hypothesize that elastase induces PGF expression and causes autophagy in LE cells. In this study, we demonstrated that porcine pancreatic elastase (PPE) induced PGF expression and secretion in LE cells in vitro and in vivo. The activation of MAPK8/JNK1 (mitogen-activated protein kinase 8) and MAPK14/p38alpha MAPK signaling pathways was involved in the PGF mediated regulation of the TSC (tuberous sclerosis complex) pathway and autophagy in LE cells. Notably, PGF-induced MAPK8 and MAPK14 signaling pathways mediated the inactivation of MTOR (mechanistic target of rapamycin), the upregulation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β) and the increase of autophagosome formation in mice. Furthermore, the PPE-induced autophagy promotes further apoptosis in vitro and in vivo. In summary, elastase-induced autophagy promotes LE cell apoptosis and pulmonary emphysema through the upregulation of PGF. PGF and its downstream MAPK8 and MAPK14 signaling pathways are potential therapeutic targets for the treatment of emphysema and COPD. PMID:24988221

  13. Expression of inducible nitric oxide in human lung epithelial cells.

    PubMed

    Robbins, R A; Barnes, P J; Springall, D R; Warren, J B; Kwon, O J; Buttery, L D; Wilson, A J; Geller, D A; Polak, J M

    1994-08-30

    Nitric oxide (NO) is increased in the exhaled air of subjects with several airway disorders. To determine if cytokines could stimulate epithelial cells accounting for the increased NO, the capacity of the proinflammatory cytokines (cytomix: tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma) to increase inducible nitric oxide synthase (iNOS) was investigated in A549 and primary cultures of human bronchial epithelial cells. Cytomix induced a time-dependent increase in nitrite levels in culture supernatant fluids (p < 0.05). Increased numbers of cells stained for iNOS and increased iNOS mRNA was detected in the cytokine-stimulated cells compared to control (p < 0.05). Dexamethasone diminished the cytokine-induced increase in nitrite, iNOS by immunocytochemistry, and iNOS mRNA. These data demonstrate that cytokines, such as those released by mononuclear cells, can induce lung epithelial iNOS expression and NO release, and that this is attenuated by dexamethasone.

  14. Oxidative Stress Mediates Radiation Lung Injury by Inducing Apoptosis

    SciTech Connect

    Zhang Yu; Zhang Xiuwu; Rabbani, Zahid N.; Jackson, Isabel L.; Vujaskovic, Zeljko

    2012-06-01

    Purpose: Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown. Methods and Materials: C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species. Results: Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-{beta}1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells. Conclusion: Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.

  15. Bitumen fume-induced gene expression profile in rat lung

    SciTech Connect

    Gate, Laurent . E-mail: laurent.gate@inrs.fr; Langlais, Cristina; Micillino, Jean-Claude; Nunge, Herve; Bottin, Marie-Claire; Wrobel, Richard; Binet, Stephane

    2006-08-15

    Exposure to bitumen fumes during paving and roofing activities may represent an occupational health risk. To date, most of the studies performed on the biological effect of asphalt fumes have been done with regard to their content in carcinogenic polycyclic aromatic hydrocarbons (PAH). In order to gain an additional insight into the mechanisms of action of bitumen fumes, we studied their pulmonary effects in rodents following inhalation using the microarray technology. Fisher 344 rats were exposed for 5 days, 6 h/day to bitumen fumes generated at road paving temperature (170 {sup o}C) using a nose-only exposition device. With the intention of studying the early transcriptional events induced by asphalt fumes, lung tissues were collected immediately following exposure and gene expression profiles in control and exposed rats were determined by using oligonucleotide microarrays. Data analysis revealed that genes involved in lung inflammatory response as well as genes associated with PAH metabolization and detoxification were highly expressed in bitumen-exposed animals. In addition, the expression of genes related to elastase activity and its inhibition which are associated with emphysema was also modulated. More interestingly genes coding for monoamine oxidases A and B involved in the metabolism of neurotransmitters and xenobiotics were downregulated in exposed rats. Altogether, these data give additional information concerning the bitumen fumes biological effects and would allow to better review the health effects of occupational asphalt fumes exposure.

  16. Bitumen fume-induced gene expression profile in rat lung.

    PubMed

    Gate, Laurent; Langlais, Cristina; Micillino, Jean-Claude; Nunge, Hervé; Bottin, Marie-Claire; Wrobel, Richard; Binet, Stéphane

    2006-08-15

    Exposure to bitumen fumes during paving and roofing activities may represent an occupational health risk. To date, most of the studies performed on the biological effect of asphalt fumes have been done with regard to their content in carcinogenic polycyclic aromatic hydrocarbons (PAH). In order to gain an additional insight into the mechanisms of action of bitumen fumes, we studied their pulmonary effects in rodents following inhalation using the microarray technology. Fisher 344 rats were exposed for 5 days, 6 h/day to bitumen fumes generated at road paving temperature (170 degrees C) using a nose-only exposition device. With the intention of studying the early transcriptional events induced by asphalt fumes, lung tissues were collected immediately following exposure and gene expression profiles in control and exposed rats were determined by using oligonucleotide microarrays. Data analysis revealed that genes involved in lung inflammatory response as well as genes associated with PAH metabolization and detoxification were highly expressed in bitumen-exposed animals. In addition, the expression of genes related to elastase activity and its inhibition which are associated with emphysema was also modulated. More interestingly genes coding for monoamine oxidases A and B involved in the metabolism of neurotransmitters and xenobiotics were downregulated in exposed rats. Altogether, these data give additional information concerning the bitumen fumes biological effects and would allow to better review the health effects of occupational asphalt fumes exposure.

  17. Endotoxin-induced maturation of monocytes in preterm fetal sheep lung.

    PubMed

    Kramer, Boris W; Joshi, Shubhada N; Moss, Timothy J M; Newnham, John P; Sindelar, Richard; Jobe, Alan H; Kallapur, Suhas G

    2007-08-01

    The fetal lung normally contains immature monocytes and very few mature macrophages. The chorioamnionitis frequently associated with preterm birth induces monocyte influx into the fetal lung. Previous studies demonstrated that monocytes in the developing lung can mediate lung injury responses that resemble BPD in humans. We hypothesized that chorioamnionitis would induce maturation of immature monocytes in the fetal lung. Groups of three to seven time-mated ewes received saline or 10 mg of endotoxin (Escherichia coli 055:B5) in saline by intra-amniotic injection for intervals from 1 to 14 days before operative delivery at 124 days of gestational age. Monocytic cells from lung tissue were recovered using Percoll gradients. Monocytic cells consistent with macrophages were identified morphologically and by myosin heavy chain class II expression. An increase in macrophages was preceded by induction of granulocyte-macrophage colony-stimulating factor in the lung and subsequent activation of the transcription factor PU.1. The production of IL-6 by monocytes/macrophages in response to endotoxin challenge in vitro increased 7 and 14 days after exposure to intra-amniotic endotoxin. Recombinant TNF-alpha induced IL-6 production by lung monocytic cells exposed to intra-amniotic endotoxin but not in control cells. Monocytic phagocytosis of apoptotic neutrophils also increased 7 and 14 days after exposure to intra-amniotic endotoxin. Intra-amniotic endotoxin induced lung monocytes to develop into functionally mature cells consistent with macrophages. These findings have implications for lung immune responses after exposure to chorioamnionitis.

  18. Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

    PubMed Central

    Prado-Garcia, Heriberto; Romero-Garcia, Susana; Aguilar-Cazares, Dolores; Meneses-Flores, Manuel; Lopez-Gonzalez, Jose Sullivan

    2012-01-01

    Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer. PMID:23118782

  19. Tumor-induced CD8+ T-cell dysfunction in lung cancer patients.

    PubMed

    Prado-Garcia, Heriberto; Romero-Garcia, Susana; Aguilar-Cazares, Dolores; Meneses-Flores, Manuel; Lopez-Gonzalez, Jose Sullivan

    2012-01-01

    Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

  20. Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs.

    PubMed

    Allison, Beth J; Hooper, Stuart B; Coia, Elise; Zahra, Valerie A; Jenkin, Graham; Malhotra, Atul; Sehgal, Arvind; Kluckow, Martin; Gill, Andrew W; Sozo, Foula; Miller, Suzanne L; Polglase, Graeme R

    2016-02-01

    Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation.

  1. Effects of aminoguanidine and antioxidant erdosteine on bleomycin-induced lung fibrosis in rats.

    PubMed

    Yildirim, Zeki; Turkoz, Yusuf; Kotuk, Mahir; Armutcu, Ferah; Gurel, Ahmet; Iraz, Mustafa; Ozen, Suleyman; Aydogdu, Ismet; Akyol, Omer

    2004-09-01

    Reactive oxygen and nitrogen species have been implicated in the pathogenesis of bleomycin-induced lung fibrosis. The effects of aminoguanidine and erdosteine on the bleomycin-induced lung fibrosis were evaluated in rats. The animals were placed into five groups: Vehicle + vehicle, vehicle + bleomycin (2.5 U/kg), bleomycin + aminoguanidine (200 mg/kg), bleomycin + erdosteine (10 mg/kg), and bleomycin + erdosteine + aminoguanidine. Bleomycin administration resulted in prominent lung fibrosis as measured by lung hydroxyproline content and lung histology, which is completely prevented by erdosteine and aminoguanidine. A strong staining for nitro tyrosine antibody in lung tissue and increased levels of lung NO were found in bleomycin group, that were significantly reduced by aminoguanidine and erdosteine. Aminoguanidine and erdosteine significantly prevented depletion of superoxide dismutase and glutathione peroxidase and elevated myeloperoxidase activities, malondialdehyde level in lung tissue produced by bleomycin. Data presented here indicate that aminoguanidine and erdosteine prevented bleomycin-induced lung fibrosis and that nitric oxide mediated tyrosine nitration of proteins plays a significant role in the pathogenesis of bleomycin-induced lung fibrosis. Also our data suggest that antifibrotic affect of antioxidants may be due to their inhibitory effect on nitric oxide generation in this model.

  2. [Courses in neonatal cardiopulmonary resuscitation].

    PubMed

    2003-03-01

    The optimal management of newborns with asphyxia is closely associated with improved survival and a better quality of life without neuromotor handicaps. Therefore, the training of health professionals who are present at the time of birth in neonatal resuscitation should be a priority. In the present article, we present a program of training courses in neonatal resuscitation. This program has been designed for the training of health care providers and instructors in technical aspects of neonatal resuscitation. The type of courses, their contents and methodology are described.

  3. Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation.

    PubMed

    Cheng, Tao; Liu, Qingbo; Zhang, Rui; Zhang, Ying; Chen, Jianfeng; Yu, Ronghuan; Ge, Gaoxiang

    2014-12-01

    Enzymes involved in collagen biosynthesis, including lysyl oxidase (LOX), have been proposed as potential therapeutic targets for idiopathic pulmonary fibrosis. LOX expression is significantly upregulated in bleomycin (BLM)-induced lung fibrosis, and knockdown of LOX expression or inhibition of LOX activity alleviates the lung fibrosis. Unexpectedly, treatment of the mice with LOX inhibitor at the inflammatory stage, but not the fibrogenic stage, efficiently reduces collagen deposition and normalizes lung architecture. Inhibition of LOX impairs inflammatory cell infiltration, TGF-β signaling, and myofibroblast accumulation. Furthermore, ectopic expression of LOX sensitizes the fibrosis-resistant Balb/c mice to BLM-induced inflammation and lung fibrosis. These results suggest that LOX is indispensable for the progression of BLM-induced experimental lung fibrosis by aggravating the inflammatory response and subsequent fibrosis process after lung injury.

  4. Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair

    PubMed Central

    MacKenzie, BreAnne; Henneke, Ingrid; Hezel, Stefanie; Al Alam, Denise; El Agha, Elie; Chao, Cho-Ming; Quantius, Jennifer; Wilhelm, Jochen; Jones, Matthew; Goth, Kerstin; Li, Xiaokun; Seeger, Werner; Königshoff, Melanie; Herold, Susanne; Rizvanov, Albert A.; Günther, Andreas

    2015-01-01

    Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26rtTA/+;tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0–11; days 0–28) or during later stages (days 6–28 and 14–28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice. PMID:25820524

  5. Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair.

    PubMed

    MacKenzie, BreAnne; Henneke, Ingrid; Hezel, Stefanie; Al Alam, Denise; El Agha, Elie; Chao, Cho-Ming; Quantius, Jennifer; Wilhelm, Jochen; Jones, Matthew; Goth, Kerstin; Li, Xiaokun; Seeger, Werner; Königshoff, Melanie; Herold, Susanne; Rizvanov, Albert A; Günther, Andreas; Bellusci, Saverio

    2015-05-15

    Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26(rtTA/+);tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0-11; days 0-28) or during later stages (days 6-28 and 14-28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice.

  6. Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Chen, Xueyu; Walther, Frans J.; Laghmani, El H.; Hoogeboom, Annemarie M.; Hogen-Esch, Anne C. B.; van Ark, Ingrid; Folkerts, Gert; Wagenaar, Gerry T. M.

    2017-01-01

    Aim: Survivors of neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) suffer from compromised lung function and are at high risk for developing lung injury by multiple insults later in life. Because neonatal lysophosphatidic acid receptor-1 (LPAR1)-deficient rats are protected against hyperoxia-induced lung injury, we hypothesize that LPAR1-deficiency may protect adult survivors of BPD from a second hit response against lipopolysaccharides (LPS)-induced lung injury. Methods: Directly after birth, Wistar control and LPAR1-deficient rat pups were exposed to hyperoxia (90%) for 8 days followed by recovery in room air. After 7 weeks, male rats received either LPS (2 mg kg−1) or 0.9% NaCl by intraperitoneal injection. Alveolar development and lung inflammation were investigated by morphometric analysis, IL-6 production, and mRNA expression of cytokines, chemokines, coagulation factors, and an indicator of oxidative stress. Results: LPAR1-deficient and control rats developed hyperoxia-induced neonatal emphysema, which persisted into adulthood, as demonstrated by alveolar enlargement and decreased vessel density. LPAR1-deficiency protected against LPS-induced lung injury. Adult controls with BPD exhibited an exacerbated response toward LPS with an increased expression of pro-inflammatory mRNAs, whereas LPAR1-deficient rats with BPD were less sensitive to this “second hit” with a decreased pulmonary influx of macrophages and neutrophils, interleukin-6 (IL-6) production, and mRNA expression of IL-6, monocyte chemoattractant protein-1, cytokine-induced neutrophil chemoattractant 1, plasminogen activator inhibitor-1, and tissue factor. Conclusion: LPAR1-deficient rats have increased hyperoxia-induced BPD survival rates and, despite the presence of neonatal emphysema, are less sensitive to an aggravated “second hit” than Wistar controls with BPD. Intervening in LPA-LPAR1-dependent signaling may not only have therapeutic potential for neonatal chronic

  7. Biochemical and connective tissue changes in cyclophosphamide-induced lung fibrosis in rats.

    PubMed

    Venkatesan, N; Punithavathi, D; Chandrakasan, G

    1998-10-01

    The present investigation was designed to characterize the biochemical and connective tissue components and to correlate the significance of morphological and biochemical perturbations in cyclophosphamide (CP)-induced lung fibrosis in rats. Lung fibrosis was induced in male Wistar rats by intraperitoneal injection of 20 mg/100 g body weight of CP, and their pneumotoxic derangements were characterized during an early destructive phase followed by a proliferative and synthetic phase. Serum angiotensin-converting enzyme (ACE) activity was higher in CP-treated rats at days 2, 3, 5, 7, and 11, but there was a significant decrease in lung ACE activity during the same time period. Elevated levels of beta-glucuronidase activity were observed in the lung lavage fluid of CP-administered rats days 2, 3, 5, and 7. Lung myeloperoxidase activity was higher in CP rats. Of significance was the presence of collagenase and collagenolytic cathepsin in the lavage fluid of CP rats, when compared with the barely detectable levels in controls. A similar increase in these enzyme activities was also noticed in the lung tissue of CP rats during the same experimental period. Lavage fluid hydroxyproline content was higher in CP rats when compared with controls. Similarly, lung protein and DNA levels were elevated significantly after treatment with CP. The pulmonary histamine and serotonin contents were significantly higher in CP rats. The incorporation of [3H]thymidine into lung total DNA, [3H]proline into lung hydroxyproline, and [35S]sulphate into lung glycosaminoglycan, measured as indicators of lung DNA, collagen, and glycosaminoglycan synthesis, respectively, was also higher in CP groups. Increased levels of hydroxyproline, elastin, hexosamine, total hexose, fucose, sialic acid, and uronic acid in the lungs of rats 14, 28, and 42 days after CP insult were characterized as biomarkers of CP-induced interstitial changes. These findings indicate that CP-induced lung fibrosis results in

  8. Caerulein-induced acute pancreatitis results in mild lung inflammation and altered respiratory mechanics.

    PubMed

    Elder, Alison S F; Saccone, Gino T P; Bersten, Andrew D; Dixon, Dani-Louise

    2011-03-01

    Acute lung injury is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths. Although some aspects of AP-induced lung inflammation have been demonstrated, investigation of resultant changes in lung function is limited. The aim of this study was to characterize lung injury in caerulein-induced AP. Male Sprague Dawley rats (n = 7-8/group) received 7 injections of caerulein (50 μg/kg) at 12, 24, 48, 72, 96, or 120 hours before measurement of lung impedance mechanics. Bronchoalveolar lavage (BAL), plasma, pancreatic, and lung tissue were collected to determine pancreatic and lung measures of acute inflammation. AP developed between 12 and 24 hours, as indicated by increased plasma amylase activity and pancreatic myeloperoxidase (MPO) activity, edema, and abnormal acinar cells, before beginning to resolve by 48 hours. In the lung, MPO activity peaked at 12 and 96 hours, with BAL cytokine concentrations peaking at 12 hours, followed by lung edema at 24 hours, and BAL cell count at 48 hours. Importantly, no significant changes in BAL protein concentration or arterial blood gas-pH levels were evident over the same period, and only modest changes were observed in respiratory mechanics. Caerulein-induced AP results in minor lung injury, which is not sufficient to allow protein permeability and substantially alter respiratory mechanics.

  9. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    SciTech Connect

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  10. AKT1E17K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer

    PubMed Central

    Malanga, Donatella; Belmonte, Stefania; Colelli, Fabiana; Scarfò, Marzia; De Marco, Carmela; Oliveira, Duarte Mendes; Mirante, Teresa; Camastra, Caterina; Gagliardi, Monica; Rizzuto, Antonia; Mignogna, Chiara; Paciello, Orlando; Papparella, Serenella; Fagman, Henrik; Viglietto, Giuseppe

    2016-01-01

    The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6–2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26) locus (R26-AKT1E17K mice) we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype. PMID:26859676

  11. Relevance of particle-induced rat lung tumors for assessing lung carcinogenic hazard and human lung cancer risk.

    PubMed Central

    Mauderly, J L

    1997-01-01

    Rats and other rodents are exposed by inhalation to identify agents that might present hazards for lung cancer in humans exposed by inhalation. In some cases, the results are used in attempts to develop quantitative estimates of human lung cancer risk. This report reviews evidence for the usefulness of the rat for evaluation of lung cancer hazards from inhaled particles. With the exception of nickel sulfate, particulate agents thought to be human lung carcinogens cause lung tumors in rats exposed by inhalation. The rat is more sensitive to carcinogenesis from nonfibrous particles than mice or Syrian hamsters, which have both produced false negatives. However, rats differ from mice and nonhuman primates in both the pattern of particle retention in the lung and alveolar epithelial hyperplastic responses to chronic particle exposure. Present evidence warrants caution in extrapolation from the lung tumor response of rats to inhaled particles to human lung cancer hazard, and there is considerable uncertainty in estimating unit risks for humans from rat data. It seems appropriate to continue using rats in inhalation carcinogenesis assays of inhaled particles, but the upper limit of exposure concentrations must be set carefully to avoid false-positive results. A positive finding in both rats and mice would give greater confidence that an agent presents a carcinogenic hazard to man, and both rats and mice should be used if the agent is a gas or vapor. There is little justification for including Syrian hamsters in assays of the intrapulmonary carcinogenicity of inhaled agents. PMID:9400748

  12. Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27

    SciTech Connect

    Leung, Kin Chung; Hsin, Michael K.Y.; Chan, Joey S.Y.; Yip, Johnson H.Y.; Li, Mingyue; Leung, Billy C.S.; Mok, Tony S.K.; Warner, Timothy D.; Underwood, Malcolm J.; Chen, George G.

    2009-10-15

    The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB{sub 2}) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB{sub 2} but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

  13. Loss of hypoxia-inducible factor 2 alpha in the lung alveolar epithelium of mice leads to enhanced eosinophilic inflammation in cobalt-induced lung injury.

    PubMed

    Proper, Steven P; Saini, Yogesh; Greenwood, Krista K; Bramble, Lori A; Downing, Nathaniel J; Harkema, Jack R; Lapres, John J

    2014-02-01

    Hard metal lung disease (HMLD) is an occupational lung disease specific to inhalation of cobalt-containing particles whose mechanism is largely unknown. Cobalt is a known hypoxia mimic and stabilizer of the alpha subunits of hypoxia-inducible factors (HIFs). Previous work revealed that though HIF1α contrib utes to cobalt toxicity in vitro, loss of HIF1α in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. HIF1α and HIF2α show unique tissue expression profiles, and HIF2α is known to be the predominant HIF mRNA isoform in the adult lung. Thus, if HIF2α activation by cobalt contributes to pathophysiology of HMLD, we hypothesized that loss of HIF2α in lung epithelium would provide protection from cobalt-induced inflammation. Mice with HIF2α-deficiency in Club and alveolar type II epithelial cells (ATIIs) (HIF2α(Δ/Δ)) were exposed to cobalt (60 µg/day) or saline using a subacute occupational exposure model. Bronchoalveolar lavage cellularity, cytokines, qRT-PCR, and histopathology were analyzed. Results show that loss of HIF2α leads to enhanced eosinophilic inflammation and increased goblet cell metaplasia. Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2α(Δ/Δ) mice, suggesting a role for epithelial HIF2α in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2α(Δ/Δ) and control mice were compared. In summary, our data suggest that although loss of HIF2α does not afford protection from cobalt-induced lung inflammation, epithelial HIF2α signaling does play an important role in modulating the inflammatory and repair response in the lung.

  14. Curcumin inhibits B[a]PDE-induced procarcinogenic signals in lung cancer cells, and curbs B[a]P-induced mutagenesis and lung carcinogenesis.

    PubMed

    Puliyappadamba, Vineshkumar T; Thulasidasan, Arun Kumar T; Vijayakurup, Vinod; Antony, Jayesh; Bava, Smitha V; Anwar, Shabna; Sundaram, Sankar; Anto, Ruby John

    2015-01-01

    Benzo[a]pyrene is a procarcinogen present in environment and cigarette smoke, which could be bio-transformed in vivo to B[a]PDE, a potent carcinogen known to form DNA adducts and induce mutations. We observed that curcumin, a known chemopreventive, could significantly inhibit the survival of lung cancer cells exposed to B[a]PDE. It also downregulates B[a]PDE-induced nuclear translocation of NF-κB as assessed by Electrophoretic Mobility Shift Assay (EMSA) and NF-κB-dependent reporter gene assay. Ames assay demonstrated its ability to revert the mutagenic property of benzo[a]pyrene. These observations prompted us to evaluate the efficacy of curcumin in preventing B[a]P-induced lung carcinogenesis in vivo and to explore the molecular mechanism associated with it. The average number of tumor nodules present in the lungs of the Swiss albino mice, which received benzo[a]pyrene, was significantly high compared to that received curcumin as 2% diet along with B[a]P. Curcumin treatment significantly reverted histopathological deviations in the lung tissues due to benzo[a]pyrene ingestion. Moreover, curcumin diet reduced benzo[a]pyrene-induced activation of NF-κB and MAPK signaling and Cox-2 transcription in lung tissues of mice. Taken together, this study illustrates multifaceted efficacy of curcumin in preventing lung cancer.

  15. [The latest in paediatric resuscitation recommendations].

    PubMed

    López-Herce, Jesús; Rodríguez, Antonio; Carrillo, Angel; de Lucas, Nieves; Calvo, Custodio; Civantos, Eva; Suárez, Eva; Pons, Sara; Manrique, Ignacio

    2017-04-01

    Cardiac arrest has a high mortality in children. To improve the performance of cardiopulmonary resuscitation, it is essential to disseminate the international recommendations and the training of health professionals and the general population in resuscitation. This article summarises the 2015 European Paediatric Cardiopulmonary Resuscitation recommendations, which are based on a review of the advances in cardiopulmonary resuscitation and consensus in the science and treatment by the International Council on Resuscitation. The Spanish Paediatric Cardiopulmonary Resuscitation recommendations, developed by the Spanish Group of Paediatric and Neonatal Resuscitation, are an adaptation of the European recommendations, and will be used for training health professionals and the general population in resuscitation. This article highlights the main changes from the previous 2010 recommendations on prevention of cardiac arrest, the diagnosis of cardiac arrest, basic life support, advanced life support and post-resuscitation care, as well as reviewing the algorithms of treatment of basic life support, obstruction of the airway and advanced life support.

  16. Protective effects of imipramine in murine endotoxin-induced acute lung injury.

    PubMed

    Yang, Jin; Qu, Jie-ming; Summah, Hanssa; Zhang, Jin; Zhu, Ying-gang; Jiang, Hong-ni

    2010-07-25

    The tricyclic antidepressant imipramine has recently emerged as a cytoprotective agent, exerting beneficial effects in inflammatory tissue injury. The present study aimed to investigate therapeutic effects of imipramine in murine model of endotoxin-induced acute lung injury. Mice were administrated intraperitoneally with LPS (lipopolysaccharide) from Escherichia coli or vehicle. Imipramine was administrated intraperitoneally 30 min before LPS challenge. Pretreatment of mice with imipramine reduced lethality. Impramine also significantly attenuated lung inflammation, lung edema, MPO (myeloperoxidase) activity, lung tissue pathological changes and nuclear factor-kappaB DNA binding activity. The results of this study suggest that imipramine can exert protective effects in endotoxin-induced acute lung injury by suppressing nuclear factor-kappaB-mediated expression of inflammatory genes. Thus, imipramine could be a potential novel therapeutic agent for the treatment for acute lung injury.

  17. Mustard vesicant-induced lung injury: Advances in therapy.

    PubMed

    Weinberger, Barry; Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro; Heck, Diane E; Laskin, Jeffrey D; Laskin, Debra L

    2016-08-15

    Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and, in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.

  18. Oral administration of aflatoxin G₁ induces chronic alveolar inflammation associated with lung tumorigenesis.

    PubMed

    Liu, Chunping; Shen, Haitao; Yi, Li; Shao, Peilu; Soulika, Athena M; Meng, Xinxing; Xing, Lingxiao; Yan, Xia; Zhang, Xianghong

    2015-02-03

    Our previous studies showed oral gavage of aflatoxin G₁ (AFG₁) induced lung adenocarcinoma in NIH mice. We recently found that a single intratracheal administration of AFG₁ caused chronic inflammatory changes in rat alveolar septum. Here, we examine whether oral gavage of AFG₁ induces chronic lung inflammation and how it contributes to carcinogenesis. We evaluated chronic lung inflammatory responses in Balb/c mice after oral gavage of AFG₁ for 1, 3 and 6 months. Inflammatory responses were heightened in the lung alveolar septum, 3 and 6 months after AFG₁ treatment, evidenced by increased macrophages and lymphocytes infiltration, up-regulation of NF-κB and p-STAT3, and cytokines production. High expression levels of superoxide dismutase (SOD-2) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, were detected in alveolar epithelium of AFG₁-treated mice. Promoted alveolar type II cell (AT-II) proliferation in alveolar epithelium and angiogenesis, as well as increased COX-2 expression were also observed in lung tissues of AFG₁-treated mice. Furthermore, we prolonged survival of the mice in the above model for another 6 months to examine the contribution of AFG₁-induced chronic inflammation to lung tumorigenesis. Twelve months later, we observed that AFG₁ induced alveolar epithelial hyperplasia and adenocarcinoma in Balb/c mice. Up-regulation of NF-κB, p-STAT3, and COX-2 was also induced in lung adenocarcinoma, thus establishing a link between AFG₁-induced chronic inflammation and lung tumorigenesis. This is the first study to show that oral administration of AFG₁ could induce chronic lung inflammation, which may provide a pro-tumor microenvironment to contribute to lung tumorigenesis.

  19. Protective effect of sodium aescinate on lung injury induced by methyl parathion.

    PubMed

    Du, Yuan; Wang, Tian; Jiang, Na; Ren, Ru-Tong; Zhao, De-Lu; Li, Chong; Fu, Feng-Hua

    2011-10-01

    Methyl parathion (MP) is a high venenosus insecticide. It has been used in pest control of agriculture for several years. The present study is performed to investigate the protective effect of sodium aescinate (SA) on lung injury induced by MP. Forty male Sprague-Dawley rats are randomly divided into five groups, with 8 animals in each group: control group, MP administration group, MP plus SA at doses of 0.45 mg/kg, 0.9 mg/kg and 1.8 mg/kg groups. Acetylcholinesterase (AChE) activity and nitric oxide (NO) level in plasma, myeloperoxidase (MPO) activity, NO level, and antioxidative parameters in lung tissue are assayed. Histopathological examination of lung is also performed. The results show that SA has no effect on AChE. Treatment with SA decreases the activity of MPO in lung and the level of NO in plasma and lung. The level of malondialdehyde in lung is decreased after SA treatments. SA increases the activities of superoxide dismutase, glutathione peroxidase and the content of glutathione in lung. SA administration also ameliorates lung injury induced by MP. The findings indicate that SA could protect lung injury induced by MP and the mechanism of action is related to the anti-inflammatory and anti-oxidative effect of SA.

  20. CXCR4 Blockade Attenuates Hyperoxia Induced Lung Injury in Neonatal Rats

    PubMed Central

    Drummond, Shelley; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Suguihara, Cleide; Young, Karen C.

    2015-01-01

    Background Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. Whether antagonism of CXCR4 will alleviate lung inflammation in neonatal hyperoxia-induced lung injury is unknown. Objective To determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods Newborn rats exposed to normoxia (RA) or hyperoxia (FiO2=0.9) from postnatal day 2 (P2)-P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis, and inflammation were evaluated at P16. Results As compared to RA, hyperoxic-PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in bronchoalveolar lavage fluid macrophage and neutrophil count and reduced lung myeloperoxidase activity. Conclusion CXCR4 antagonism decreases lung inflammation and improves alveolar as well as vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD. PMID:25825119

  1. c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis.

    PubMed

    Hattar, K; Oppermann, S; Ankele, C; Weissmann, N; Schermuly, R T; Bohle, R M; Moritz, R; Krögel, B; Seeger, W; Grimminger, F; Sibelius, U; Grandel, U

    2010-07-01

    Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.

  2. Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema.

    PubMed

    Yu, Jinyan; Ma, Zhongsen; Shetty, Sreerama; Ma, Mengshi; Fu, Jian

    2016-07-01

    Lung endothelial damage contributes to the pathogenesis of acute lung injury. New strategies against lung endothelial barrier dysfunction may provide therapeutic benefits against lung vascular injury. Cell-cell junctions and microtubule cytoskeleton are basic components in maintaining endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate nonnuclear protein function through deacetylation. Both α-tubulin and β-catenin are substrates for HDAC6. Here, we examined the effects of tubastatin A, a highly selective HDAC6 inhibitor, on TNF-α induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Selective HDAC6 inhibition by tubastatin A blocked TNF-α-induced lung endothelial cell hyperpermeability, which was associated with increased α-tubulin acetylation and microtubule stability. Tubastatin A pretreatment inhibited TNF-α-induced endothelial cell contraction and actin stress fiber formation with reduced myosin light chain phosphorylation. Selective HDAC6 inhibition by tubastatin A also induced β-catenin acetylation in human lung endothelial cells, which was associated with increased membrane localization of β-catenin and stabilization of adherens junctions. HDAC6 knockdown by small interfering RNA also prevented TNF-α-induced barrier dysfunction and increased α-tubulin and β-catenin acetylation in endothelial cells. Furthermore, in a mouse model of endotoxemia, tubastatin A was able to prevent endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues, which was associated with reduced pulmonary edema. Collectively, our data indicate that selective HDAC6 inhibition by tubastatin A is a potent approach against lung endothelial barrier dysfunction.

  3. A new CT-based method to quantify radiation-induced lung damage in patients.

    PubMed

    Ghobadi, Ghazaleh; Wiegman, Erwin M; Langendijk, Johannes A; Widder, Joachim; Coppes, Robert P; van Luijk, Peter

    2015-10-01

    A new method to assess radiation-induced lung toxicity (RILT) using CT-scans was developed. It is more sensitive in detecting damage and corresponds better to physician-rated radiation pneumonitis than routinely-used methods. Use of this method may improve lung toxicity assessment and thereby facilitate development of more accurate predictive models for RILT.

  4. Multimodality imaging for resuscitated sudden cardiac death.

    PubMed

    Chen, Yingming Amy; Deva, Djeven; Kirpalani, Anish; Prabhudesai, Vikram; Marcuzzi, Danny W; Graham, John J; Verma, Subodh; Jimenez-Juan, Laura; Yan, Andrew T

    2015-01-01

    We present a case that elegantly illustrates the utility of two novel noninvasive imaging techniques, computed tomography (CT) coronary angiography and cardiac MRI, in the diagnosis and management of a 27-year-old man with exertion-induced cardiac arrest caused by an anomalous right coronary artery. CT coronary angiography with 3D reformatting delineated the interarterial course of an anomalous right coronary artery compressed between the aorta and pulmonary artery, whereas cardiac MRI showed a small myocardial infarction in the right coronary artery territory not detected on echocardiography. This case highlights the value of novel multimodality imaging techniques in the risk stratification and management of patients with resuscitated cardiac arrest.

  5. Cerium-144-induced lung gumors in two strains of mice

    SciTech Connect

    Hahn, F.F.; Griffith, W.C.

    1995-12-01

    A major problem in the extrapolation of radiation cancer risk factors from one species or population to another is the choice of the risk model to use, either absolute or relative. The purpose of this study was to compare absolute and relative risk models in predicting the lung-tumor risks between a low lung-tumor incidence strain of mice and a high-incidence strain of mice. The conclusion from this study is that absolute risk is more accurate than relative risk for predicting lung tumor risk from high to low lung-tumor incidence strains of mice.

  6. Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms.

    PubMed

    Ge, Guang-Zhe; Xu, Tian-Rui; Chen, Ceshi

    2015-07-01

    Tobacco usage is a major risk factor in the development, progression, and outcomes for lung cancer. Of the carcinogens associated with lung cancer, tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is among the most potent ones. The oncogenic mechanisms of NNK are not entirely understood, hindering the development of effective strategies for preventing and treating smoking-associated lung cancers. Here, we introduce the NNK-induced lung cancer animal models in different species and its potential mechanisms. Finally, we summarize several chemopreventive agents developed from these animal models.

  7. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    SciTech Connect

    Salama, Samir A.; Omar, Hany A.; Maghrabi, Ibrahim A.; AlSaeed, Mohammed S.; EL-Tarras, Adel E.

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  8. TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment.

    PubMed

    Degryse, Amber L; Tanjore, Harikrishna; Xu, Xiaochuan C; Polosukhin, Vasiliy V; Jones, Brittany R; Boomershine, Chad S; Ortiz, Camila; Sherrill, Taylor P; McMahon, Frank B; Gleaves, Linda A; Blackwell, Timothy S; Lawson, William E

    2011-06-01

    The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice that express β-galactosidase (β-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFβR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFβR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/β-gal(+)) fibroblasts. Attenuation of TGFβ signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine.

  9. Comparison of lung alveolar and tissue cells in silica-induced inflammation.

    PubMed

    Sjöstrand, M; Absher, P M; Hemenway, D R; Trombley, L; Baldor, L C

    1991-01-01

    The silicon dioxide mineral, cristobalite (CRS) induces inflammation involving both alveolar cells and connective tissue compartments. In this study, we compared lung cells recovered by whole lung lavage and by digestion of lung tissue from rats at varying times after 8 days of exposure to aerosolized CRS. Control and exposed rats were examined between 2 and 36 wk after exposure. Lavaged cells were obtained by bronchoalveolar lavage with phosphate-buffered saline. Lung wall cells were prepared via collagenase digestion of lung tissue slices. Cells from lavage and lung wall were separated by Percoll density centrifugation. The three upper fractions, containing mostly macrophages, were cultured, and the conditioned medium was assayed for effect on lung fibroblast growth and for activity of the lysosomal enzyme, N-acetyl-beta-D-glucosaminidase. Results demonstrated that the cells separated from the lung walls exhibited different reaction patterns compared with those cells recovered by lavage. The lung wall cells exhibited a progressive increase in the number of macrophages and lymphocytes compared with a steady state in cells of the lung lavage. This increase in macrophages apparently was due to low density cells, which showed features of silica exposure. Secretion of a fibroblast-stimulating factor was consistently high by lung wall macrophages, whereas lung lavage macrophages showed inconsistent variations. The secretion of NAG was increased in lung lavage macrophages, but decreased at most observation times in lung wall macrophages. No differences were found among cells in the different density fractions regarding fibroblast stimulation and enzyme secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Supplementary catechins attenuate cooking-oil-fumes-induced oxidative stress in rat lung.

    PubMed

    Yang, Chao-Huei; Lin, Chun-Yao; Yang, Joan-Hwa; Liou, Shaw-Yih; Li, Ping-Chia; Chien, Chiang-Ting

    2009-06-30

    Cooking-oil-fumes containing toxic components may induce reactive oxygen species (ROS) to oxidize macromolecules and lead to acute lung injury. Our previous study showed that a decaffineated green tea extract containing (+)-catechin, (-)-epicatechin, (+)-gallocatechin, (-)-epigallocatechin, (-)-epicatechin gallate, and (-)-epigallocatechin gallate can inhibit oxidation, inflammation, and apoptosis. We determined whether the catechins supplement may reduce cooking-oil-fumes-induced acute lung injury in rat. In the urethane-anesthetized Wistar rat subjected to 30-120 min of cooking-oil-fumes exposure, blood ROS significantly increased in the recovery stage. After 30-min cooking-oil-fumes exposure, the enhanced blood ROS level further increased in a time-dependent manner during the recovery stage (321 +/- 69 counts/10 s after 1 h, 540 +/- 89 counts/10 s after 2 h, and 873 +/- 112 counts/10 s after 4 h). Four hours after 30-min cooking-oil-fumes exposure, lung lavage neutrophils and ROS as well as lung tissue dityrosine and 4-hydroxy-2-nonenal increased significantly. Two weeks of catechins supplememnt significantly reduced the enhanced lavage ROS, lung dityrosine and 4-hydroxy-2-nonenal level. Cooking-oil-fumes-induced oxidative stress decreased lung Bcl-2/Bax ratio and HSP70 expression, but catechins treatment preserved the downregulation of Bcl-2/Bax ratio and HSP70 expression. We conclude that catechins supplement attenuates cooking-oil-fumes-induced acute lung injury via the preservation of oil-smoke induced downregulation of antioxidant, antiapoptosis, and chaperone protein expression.

  11. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Tsurumaki, Hiroaki; Mogi, Chihiro; Aoki-Saito, Haruka; Tobo, Masayuki; Kamide, Yosuke; Yatomi, Masakiyo; Sato, Koichi; Dobashi, Kunio; Ishizuka, Tamotsu; Hisada, Takeshi; Yamada, Masanobu; Okajima, Fumikazu

    2015-01-01

    Acute lung injury is characterized by the infiltration of neutrophils into lungs and the subsequent impairment of lung function. Here we explored the role of TDAG8 in lung injury induced by lipopolysaccharide (LPS) administrated intratracheally. In this model, cytokines and chemokines released from resident macrophages are shown to cause neutrophilic inflammation in the lungs. We found that LPS treatment increased TDAG8 expression in the lungs and confirmed its expression in resident macrophages in bronchoalveolar lavage (BAL) fluids. LPS administration remarkably increased neutrophil accumulation without appreciable change in the resident macrophages, which was associated with increased penetration of blood proteins into BAL fluids, interstitial accumulation of inflammatory cells, and damage of the alveolar architecture. The LPS-induced neutrophil accumulation and the associated lung damage were enhanced in TDAG8-deficient mice as compared with those in wild-type mice. LPS also increased several mRNA and protein expressions of inflammatory cytokines and chemokines in the lungs or BAL fluids. Among these inflammatory mediators, mRNA and protein expression of KC (also known as CXCL1), a chemokine of neutrophils, were significantly enhanced by TDAG8 deficiency. We conclude that TDAG8 is a negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production. PMID:26690120

  12. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury.

    PubMed

    Tsurumaki, Hiroaki; Mogi, Chihiro; Aoki-Saito, Haruka; Tobo, Masayuki; Kamide, Yosuke; Yatomi, Masakiyo; Sato, Koichi; Dobashi, Kunio; Ishizuka, Tamotsu; Hisada, Takeshi; Yamada, Masanobu; Okajima, Fumikazu

    2015-12-04

    Acute lung injury is characterized by the infiltration of neutrophils into lungs and the subsequent impairment of lung function. Here we explored the role of TDAG8 in lung injury induced by lipopolysaccharide (LPS) administrated intratracheally. In this model, cytokines and chemokines released from resident macrophages are shown to cause neutrophilic inflammation in the lungs. We found that LPS treatment increased TDAG8 expression in the lungs and confirmed its expression in resident macrophages in bronchoalveolar lavage (BAL) fluids. LPS administration remarkably increased neutrophil accumulation without appreciable change in the resident macrophages, which was associated with increased penetration of blood proteins into BAL fluids, interstitial accumulation of inflammatory cells, and damage of the alveolar architecture. The LPS-induced neutrophil accumulation and the associated lung damage were enhanced in TDAG8-deficient mice as compared with those in wild-type mice. LPS also increased several mRNA and protein expressions of inflammatory cytokines and chemokines in the lungs or BAL fluids. Among these inflammatory mediators, mRNA and protein expression of KC (also known as CXCL1), a chemokine of neutrophils, were significantly enhanced by TDAG8 deficiency. We conclude that TDAG8 is a negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production.

  13. Beetroot red (betanin) inhibits vinyl carbamate- and benzo(a)pyrene-induced lung tumorigenesis through apoptosis.

    PubMed

    Zhang, Qi; Pan, Jing; Wang, Yian; Lubet, Ronald; You, Ming

    2013-09-01

    Betanin, also called beetroot red, has been extensively used as a food colorant. In this study, the chemopreventive activity of betanin by oral consumption was investigated in two mouse lung tumor models. Vinyl carbamate (VC) and benzo(a)pyrene (B(a)P) were used to induce lung tumors, and female A/J mice were treated with betanin in drinking water. Betanin significantly decreased tumor multiplicity and tumor load induced by both carcinogens. Tumor multiplicity and tumor load were decreased by 20% and 39% in the VC lung model, and by 46% and 65% in the B(a)P lung model, respectively. Betanin reduced the number of CD31+ endothelial microvessels and increased the expression of caspase-3, suggesting that the lung tumor inhibitory effects were through induction of apoptosis and inhibition of angiogenesis. Betanin also induced apoptosis through activated caspase-3, -7, -9, and PARP in human lung cancer cell lines. Our data show that betanin significantly inhibits lung tumorigenesis in A/J mice and merits investigation as a chemopreventive agent for human lung cancer.

  14. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury.

    PubMed

    Abraham, E; Carmody, A; Shenkar, R; Arcaroli, J

    2000-12-01

    Acute lung injury is characterized by accumulation of neutrophils in the lungs, accompanied by the development of interstitial edema and an intense inflammatory response. To assess the role of neutrophils as early immune effectors in hemorrhage- or endotoxemia-induced lung injury, mice were made neutropenic with cyclophosphamide or anti-neutrophil antibodies. Endotoxemia- or hemorrhage-induced lung edema was significantly reduced in neutropenic animals. Activation of the transcriptional regulatory factor nuclear factor-kappaB after hemorrhage or endotoxemia was diminished in the lungs of neutropenic mice compared with nonneutropenic controls. Hemorrhage or endotoxemia was followed by increases in pulmonary mRNA and protein levels for interleukin-1beta (IL-1beta), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-alpha (TNF-alpha). Endotoxin-induced increases in proinflammatory cytokine expression were greater than those found after hemorrhage. The amounts of mRNA or protein for IL-1beta, MIP-2, and TNF-alpha were significantly lower after hemorrhage in the lungs of neutropenic versus nonneutropenic mice. Neutropenia was associated with significant reductions in IL-1beta and MIP-2 but not in TNF-alpha expression in the lungs after endotoxemia. These experiments show that neutrophils play a central role in initiating acute inflammatory responses and causing injury in the lungs after hemorrhage or endotoxemia.

  15. Right turn resuscitation: frequently asked questions.

    PubMed

    Tai, N R M; Russell, R

    2011-09-01

    In this article the process of operating room resuscitation - commonly known as Right Turn Resuscitation (RTR) when conducted in the medical treatment facility at Camp Bastion - is described. The place of RTR within the concepts of damage control resuscitation and surgery is discussed along with activation criteria and protocols. The medical leadership, team roles, advantages and disadvantages are reviewed. Finally, studies describing the impact of RTR and operating room resuscitation are briefly described.

  16. TU-G-BRA-01: Assessing Radiation-Induced Reductions in Regional Lung Perfusion Following Stereotactic Radiotherapy for Lung Cancer

    SciTech Connect

    McGurk, R; Green, R; Lawrence, M; Schreiber, E; Das, S; Zagar, T; Marks, L; Sheikh, A; McCartney, W; Rivera, P

    2015-06-15

    Purpose: The dose-dependent nature of radiation therapy (RT)-induced lung injury following hypo-fractionated stereotactic RT is unclear. We herein report preliminary results of a prospective study assessing the magnitude of RT-induced reductions in regional lung perfusion following hypo-fractionated stereotactic RT. Methods: Four patients undergoing hypo-fractionated stereotactic lung RT (SBRT: 12 Gy x 4 fractions or 10 Gy x 5 fractions) had a pre-treatment SPECT (single-photon emission computed tomography) perfusion scan providing a 3D map of regional lung perfusion. Scans were repeated 3–6 months post-treatment. Pre- and post SPECT scans were registered to the planning CT scan (and hence the 3D dose data). Changes in regional perfusion (counts per cc on the pre-post scans) were computed in regions of the lung exposed to different doses of radiation (in 5 Gy intervals), thus defining a dose-response function. SPECT scans were internally normalized to the regions receiving <5 Gy. Results: At 3 months post-RT, the changes in perfusion are highly variable. At 6 months, there is a consistent dose-dependent reduction in regional perfusion. The average percent decline in regional perfusion was 10% at 15–20 Gy, 20% at 20–25 Gy, and 30% at 25–30 Gy representing a relatively linear dose response with an approximate 2% reduction per Gray for doses in excess of 10 Gy. There was a subtle increase in perfusion in the lung receiving <10 Gy. Conclusion: Hypo-fractionated stereotactic RT appears to cause a dose-dependent reduction in regional lung perfusion. There appears to be a threshold effect with no apparent perfusion loss at doses <10 Gy, though this might be in part due to the normalization technique used. Additional data is needed from a larger number of patients to better assess this issue. This sort of data can be used to assist optimizing RT treatment plans that minimize the risk of lung injury. Partly supported by the NIH (CA69579) and the Lance Armstrong

  17. Fluid Resuscitation in Severe Sepsis.

    PubMed

    Loflin, Rob; Winters, Michael E

    2017-02-01

    Since its original description in 1832, fluid resuscitation has become the cornerstone of early and aggressive treatment of severe sepsis and septic shock. However, questions remain about optimal fluid composition, dose, and rate of administration for critically ill patients. This article reviews pertinent physiology of the circulatory system, pathogenesis of septic shock, and phases of sepsis resuscitation, and then focuses on the type, rate, and amount of fluid administration for severe sepsis and septic shock, so providers can choose the right fluid, for the right patient, at the right time.

  18. Prostaglandin E₂ protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction.

    PubMed

    Dackor, Ryan T; Cheng, Jennifer; Voltz, James W; Card, Jeffrey W; Ferguson, Catherine D; Garrett, Ryan C; Bradbury, J Alyce; DeGraff, Laura M; Lih, Fred B; Tomer, Kenneth B; Flake, Gordon P; Travlos, Gregory S; Ramsey, Randle W; Edin, Matthew L; Morgan, Daniel L; Zeldin, Darryl C

    2011-11-01

    Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P < 0.05). When administered 7 days before bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and

  19. Asbestos-induced lung disease in small-scale clutch manufacturing workers

    PubMed Central

    Gothi, Dipti; Gahlot, Tanushree; Sah, Ram B.; Saxena, Mayank; Ojha, U. C.; Verma, Anand K.; Spalgais, Sonam

    2016-01-01

    Background: The crocidolite variety of asbestos is banned. However, chrysotile, which is not prohibited, is still used in developing countries in making products such as clutch plate. Fourteen workers from a small-scale clutch plate-manufacturing factory were analyzed for asbestos-induced lung disease as one of their colleagues had expired due to asbestosis. Aims: This study was conducted to evaluate the awareness of workers, the prevalence and type of asbestos-induced lung disease, and the sensitivity and specificity of diffusion test. Materials and Methods: History, examination, chest radiograph, spirometry with diffusion, and high resolution computed tomography (HRCT) thorax was performed in all the workers. The diagnosis of asbestos-induced lung disease was suspected on the basis of HRCT. This was subsequently confirmed on transbronchial lung biopsy (TBLB). Results: None of the workers had detailed information about asbestos and its ill effects. Eleven out of 14 (71.42%) workers had asbestos-induced lung disease. All 11 had small airway disease (SAD). Three had SAD alone, 6 had additional interstitial lung disease (ILD), and 2 patients had additional ILD and chronic obstructive pulmonary disease. Sensitivity and specificity of residual volume (RV) or total lung capacity (TLC) for detecting SAD was 90% and 100%, respectively, and that of diffusion capacity of lung for carbon monoxide (DLCO) for detecting ILD was 100%. Conclusion: The awareness about asbestos in small-scale clutch-plate manufacturing industry is poor. The usage of chrysotile should be strictly regulated as morbidity and mortality is high. DLCO and RV/TLC are sensitive and specific in detecting nonmalignant asbestos induced lung disease. PMID:28194083

  20. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    SciTech Connect

    Sunil, Vasanthi R.; Shen, Jianliang; Patel-Vayas, Kinal; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-05-15

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  1. N-acetylcysteine alleviates the meconium-induced acute lung injury.

    PubMed

    Mokra, D; Drgova, A; Petras, M; Mokry, J; Antosova, M; Calkovska, A

    2015-01-01

    Meconium aspiration in newborns causes lung inflammation and injury, which may lead to meconium aspiration syndrome (MAS). In this study, the effect of the antioxidant N-acetylcysteine on respiratory and inflammatory parameters were studied in a model of MAS. Oxygen-ventilated rabbits were intratracheally given 4 mL/kg of meconium (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were administered N-acetylcysteine (10 mg/kg; i.v.), or were left without treatment. The animals were oxygen-ventilated for additional 5 h. Ventilatory pressures, oxygenation, right-to-left pulmonary shunts, and leukocyte count were measured. At the end of experiment, trachea and lung were excised. The left lung was saline-lavaged and a total and differential count of cells in bronchoalveolar lavage fluid (BAL) was determined. Right lung tissue strips were used for detection of lung edema (expressed as wet/dry weight ratio) and peroxidation (expressed by thiobarbituric acid-reactive substances, TBARS). In lung and tracheal strips, airway reactivity to acetylcholine was measured. In addition, TBARS and total antioxidant status were determined in the plasma. Meconium instillation induced polymorphonuclear-derived inflammation and oxidative stress. N-acetylcysteine improved oxygenation, reduced lung edema, decreased polymorphonuclears in BAL fluid, and diminished peroxidation and meconium-induced airway hyperreactivity compared with untreated animals. In conclusion, N-acetylcysteine effectively improved lung functions in an animal model of MAS.

  2. Protective effect of hydrogen sulfide on hyperbaric hyperoxia-induced lung injury in a rat model.

    PubMed

    Liu, Wenwu; Liu, Kehuan; Ma, Chunqing; Yu, Jiangang; Peng, Zhaoyun; Huang, Guoyang; Cai, Zhiyu; Li, Runping; Xu, Weigang; Sun, Xuejun; Liu, Kan; Zheng, Juan

    2014-01-01

    Hyperbaric oxygen therapy is one of the most widely used clinical interventions to counteract insufficient pulmonary oxygen delivery in patients with severe lung injury. However, prolonged exposure to hyperoxia leads to inflammation and acute lung injury. This study aimed to investigate the protective effect of hydrogen sulfide on hyperbaric hyperoxia-induced lung injury. Rats were intraperitoneally treated with sodium hydrosulphide (NaHS) at 28 μmol/kg immediately before hyperoxia exposure and then exposed to pure oxygen at 2.5 atmospheres absolute (atm abs) with continuous ventilation for six hours, Immediately after hyperoxia exposure, rats were sacrificed via anesthesia. The bronchoalveolar lavage fluid (BALF) was harvested for the detection of protein concentration and IL-1 content, and the lungs were collected for HE staining, TUNEL staining and detection of wet/dry weight ratio. Our results showed hyperbaric hyperoixa exposure could significantly damage the lung (HE staining), increase the protein and IL-13 in the BALF, elevate the wet/dry Weight ratio and raise the TUNEL positive cells. However, pre-treatment with hydrogen sulfide improved the lung morphology, reduced the TUNEL positive cells and attenuated the lung inflammation (reduction in IL-13 of BALF and HE staining). Taken together, our findings indicate that hydrogen sulfide pretreatment may exert protective effects on hyperbaric hyperoxia-induced lung injury.

  3. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  4. Selective phosphodiesterase 3 inhibitor olprinone attenuates meconium-induced oxidative lung injury.

    PubMed

    Mokra, Daniela; Drgova, Anna; Pullmann, Rudolf; Calkovska, Andrea

    2012-06-01

    Since inflammation and oxidation play a key role in the pathophysiology of neonatal meconium aspiration syndrome, various anti-inflammatory drugs have been tested in the treatment. This study evaluated whether the phosphodiesterase (PDE) 3 inhibitor olprinone can alleviate meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated rabbits intratracheally received 4 ml/kg of meconium (25 mg/ml) or saline. Thirty minutes after meconium/saline instillation, meconium-instilled animals were treated by intravenous olprinone (0.2 mg/kg) or were left without treatment. All animals were oxygen-ventilated for an additional 5 h. A bronchoalveolar lavage (BAL) of the left lungs was performed and differential leukocyte count in the sediment was estimated. The right lungs were used to determine lung edema by wet/dry weight ratio, as well as to detect oxidative damage to the lungs. In the lung tissue homogenate, total antioxidant status (TAS) was determined. In isolated lung mitochondria, the thiol group content, conjugated dienes, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation products, and activity of cytochrome c oxidase (COX) were estimated. To evaluate the effects of meconium instillation and olprinone treatment on the systemic level, TBARS and TAS were determined in the blood plasma, as well. Meconium instillation increased the relative numbers of neutrophils and eosinophils in the BAL fluid, increased edema formation and concentrations of oxidation markers, and decreased TAS. Treatment with olprinone reduced the numbers of polymorphonuclears in the BAL fluid, decreased the formation of most oxidation markers in the lungs, reduced lung edema and prevented a decrease in TAS in the lung homogenate compared to non-treated animals. In the blood plasma, olprinone decreased TBARS and increased TAS compared to the non-treated group. Conclusion, the selective PDE3 inhibitor olprinone has shown potent antioxidative and anti

  5. RAGE/NF-κB signaling mediates lipopolysaccharide induced acute lung injury in neonate rat model.

    PubMed

    Li, Yuhong; Wu, Rong; Tian, Yian; Yu, Min; Tang, Yun; Cheng, Huaipin; Tian, Zhaofang

    2015-01-01

    Lipopolysaccharide (LPS) is known to induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Accumulating data suggest the crucial role of RAGE in the pathogenesis of ALI/ARDS. However, the mechanism by which RAGE mediates inflammatory lung injury in the neonates remains elusive. In this study we established LPS-induced ALI model in neonate rats, and investigated the role of RAGE/NF-κB signaling in mediating ALI. We found that RAGE antibody or bortezomib reduced LPS-induced histopathological abnormalities in the lung and lung damage score. RAGE antibody or bortezomib also reduced TNF-α level in both serum and BALF of the rats. Furthermore, RAGE antibody or bortezomib significantly reduced LPS-induced upregulation of RAGE and NF-κB expression in the lung. In conclusion, we established ALI model in neonate rats to demonstrate that LPS induced inflammatory lung injury via RAGE/NF-κB signaling. Interference with RAGE/NF-κB signaling is a potential approach to prevent and treat sepsis-related ALI/ARDS.

  6. Nitrogen Dioxide-Induced Acute Lung Injury in Sheep

    DTIC Science & Technology

    1994-01-01

    subsequent to inhalation expo- sure. Non- cardiogenic pulmonary edema is produced by brief exposure and unlike hyperoxia (Newman et al., 1983; Fukushima...macrophage number significantly decreased within the 24-h post-exposure period. Examination of lung tissue 24 after NO2 revealed patchy edema , mild hemorrhage...examination of lung tissue 24 h after NO, revealed patchy edema , mild hemorrhage and polymorphonuclear c, and mononuclear leukocyte infiltration. The NO

  7. Emphysema and mechanical stress-induced lung remodeling.

    PubMed

    Suki, Béla; Sato, Susumu; Parameswaran, Harikrishnan; Szabari, Margit V; Takahashi, Ayuko; Bartolák-Suki, Erzsébet

    2013-11-01

    Transpulmonary pressure and the mechanical stresses of breathing modulate many essential cell functions in the lung via mechanotransduction. We review how mechanical factors could influence the pathogenesis of emphysema. Although the progression of emphysema has been linked to mechanical rupture, little is known about how these stresses alter lung remodeling. We present possible new directions and an integrated multiscale view that may prove useful in finding solutions for this disease.

  8. Prevention of tobacco carcinogen-induced lung cancer in female mice using antiestrogens.

    PubMed

    Stabile, Laura P; Rothstein, Mary E; Cunningham, Diana E; Land, Stephanie R; Dacic, Sanja; Keohavong, Phouthone; Siegfried, Jill M

    2012-11-01

    Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression, and most human lung tumors express estrogen receptor β (ERβ) as well as aromatase. To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen, alone or in combination with the ER antagonist fulvestrant, ovariectomized female mice received treatments with the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) along with daily supplements of androstenedione, the substrate for aromatase. Placebo, anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis. The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors (mean = 0.5) compared with placebo (mean = 4.6, P < 0.001), fulvestrant alone (mean = 3.4, P < 0.001) or anastrozole alone (mean = 2.8, P = 0.002). A significantly lower Ki67 cell proliferation index was also observed compared with single agent and control treatment groups. Beginning antiestrogen treatment after NNK exposure, when preneoplastic lesions had already formed, also yielded maximum antitumor effects with the combination. Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs, whereas ERβ was found in both macrophages and tumor cells. Antiestrogens, especially in combination, effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis and may have application for lung cancer prevention. An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens, beginning early in the carcinogenesis process. ERβ expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production.

  9. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure

    PubMed Central

    Miranda da Silva, Cristiane; Peres Leal, Mayara; Brochetti, Robson Alexandre; Braga, Tárcio; Vitoretti, Luana Beatriz; Saraiva Câmara, Niels Olsen; Damazo, Amílcar Sabino; Ligeiro-de-Oliveira, Ana Paula; Chavantes, Maria Cristina; Lino-dos-Santos-Franco, Adriana

    2015-01-01

    Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT) has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA), an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1%) or vehicle (distillated water) during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure). Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant. PMID:26569396

  10. Changes in breath sound power spectra during experimental oleic acid-induced lung injury in pigs.

    PubMed

    Räsänen, Jukka; Nemergut, Michael E; Gavriely, Noam

    2014-01-01

    To evaluate the effect of acute lung injury on the frequency spectra of breath sounds, we made serial acoustic recordings from nondependent, midlung and dependent regions of both lungs in ten 35- to 45-kg anesthetized, intubated, and mechanically ventilated pigs during development of acute lung injury induced with intravenous oleic acid in prone or supine position. Oleic acid injections rapidly produced severe derangements in the gas exchange and mechanical properties of the lung, with an average increase in venous admixture from 16 ± 12 to 62 ± 16% (P < 0.01), and a reduction in dynamic respiratory system compliance from 25 ± 4 to 14 ± 4 ml/cmH2O (P < 0.01). A concomitant increase in sound power was seen in all lung regions (P < 0.05), predominantly in frequencies 150-800 Hz. The deterioration in gas exchange and lung mechanics correlated best with concurrent spectral changes in the nondependent lung regions. Acute lung injury increases the power of breath sounds likely secondary to redistribution of ventilation from collapsed to aerated parts of the lung and improved sound transmission in dependent, consolidated areas.

  11. CD11b(+) Mononuclear Cells Mitigate Hyperoxia-Induced Lung Injury in Neonatal Mice.

    PubMed

    Eldredge, Laurie C; Treuting, Piper M; Manicone, Anne M; Ziegler, Steven F; Parks, William C; McGuire, John K

    2016-02-01

    Bronchopulmonary dysplasia (BPD) is a common consequence of life-saving interventions for infants born with immature lungs. Resident tissue myeloid cells regulate lung pathology, but their role in BPD is poorly understood. To determine the role of lung interstitial myeloid cells in neonatal responses to lung injury, we exposed newborn mice to hyperoxia, a neonatal mouse lung injury model with features of human BPD. In newborn mice raised in normoxia, we identified a CD45(+) F4/80(+) CD11b(+), Ly6G(lo-int) CD71(+) population of cells in lungs of neonatal mice present in significantly greater percentages than in adult mice. In response to hyperoxia, surface marker and gene expression in whole lung macrophages/monocytes was biased to an alternatively activated phenotype. Partial depletion of these CD11b(+) mononuclear cells using CD11b-diphtheria toxin (DT) receptor transgenic mice resulted in 60% mortality by 40 hours of hyperoxia exposure with more severe lung injury, perivascular edema, and alveolar hemorrhage compared with DT-treated CD11b-DT receptor-negative controls, which displayed no mortality. These results identify an antiinflammatory population of CD11b(+) mononuclear cells that are protective in hyperoxia-induced neonatal lung injury in mice, and suggest that enhancing their beneficial functions may be a treatment strategy in infants at risk for BPD.

  12. Resveratrol ameliorates LPS-induced acute lung injury via NLRP3 inflammasome modulation.

    PubMed

    Jiang, Lei; Zhang, Lei; Kang, Kai; Fei, Dongsheng; Gong, Rui; Cao, Yanhui; Pan, Shangha; Zhao, Mingran; Zhao, Mingyan

    2016-12-01

    NLRP3 inflammasome plays a pivotal role in the development of acute lung injury (ALI), accelerating IL-1β and IL-18 release and inducing lung inflammation. Resveratrol, a natural phytoalexin, has anti-inflammatory properties via inhibition of oxidation, leukocyte priming, and production of inflammatory mediators. In this study, we aimed to investigate the effect of resveratrol on NLRP3 inflammasome in lipopolysaccharide-induced ALI. Mice were intratracheally instilled with 3mg/kg lipopolysaccharide (LPS) to induce ALI. Resveratrol treatment alleviated the LPS-induced lung pathological damage, lung edema and neutrophil infiltration. In addition, resveratrol reversed the LPS-mediated elevation of IL-1β and IL-18 level in the BAL fluids. In lung tissue, resveratrol also inhibited the LPS-induced NLRP3, ASC, caspase-1 mRNA and protein expression, and NLRP3 inflammasome activation. Moreover, resveratrol administration not only suppressed the NF-κB p65 nuclear translocation, NF-κB activity and ROS production in the LPS-treated mice, but also inhibited the LPS-induced thioredoxin-interacting protein (TXNIP) protein expression and interaction of TXNIP-NLRP3 in lung tissue. Meanwhile, resveratrol obviously induced SIRT1 mRNA and protein expression in the LPS-challenged mice. Taken together, our study suggests that resveratrol protects against LPS-induced lung injury by NLRP3 inflammasome inhibition. These findings further suggest that resveratrol may be of great value in the treatment of ALI and a potential and an effective pharmacological agent for inflammasome-relevant diseases.

  13. Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation.

    PubMed

    Ma, Jianqun; Xu, Hai; Wu, Jun; Qu, Changfa; Sun, Fenglin; Xu, Shidong

    2015-12-01

    Linalool, a natural compound that exists in the essential oils of several aromatic plants species, has been reported to have anti-inflammatory effects. However, the effects of linalool on cigarette smoke (CS)-induced acute lung inflammation have not been reported. In the present study, we investigated the protective effects of linalool on CS-induced acute lung inflammation in mice. Linalool was given i.p. to mice 2h before CS exposure daily for five consecutive days. The numbers of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) were measured. The production of TNF-α, IL-6, IL-1β, IL-8 and MCP-1 were detected by ELISA. The expression of NF-κB was detected by Western blotting. Our results showed that treatment of linalool significantly attenuated CS-induced lung inflammation, coupled with inhibited the infiltration of inflammatory cells and TNF-α, IL-6, IL-1β, IL-8 and MCP-1 production. Meanwhile, treatment of linalool inhibited CS-induced lung MPO activity and pathological changes. Furthermore, linalool suppressed CS-induced NF-κB activation in a dose-dependent manner. In conclusion, our results demonstrated that linalool protected against CS-induced lung inflammation through inhibiting CS-induced NF-κB activation.

  14. Therapeutic Efficacy of Esomeprazole in Cotton Smoke-Induced Lung Injury Model

    PubMed Central

    Nelson, Christina; Lee, Jameisha; Ko, Kang; Sikora, Andrew G.; Bonnen, Mark D.; Enkhbaatar, Perenlei; Ghebre, Yohannes T.

    2017-01-01

    Proton pump inhibitors (PPIs) are well-known antacid drugs developed to treat gastric disorders. Emerging studies demonstrate that PPIs possess biological activities that extend beyond inhibition of H+/K+ ATPase (proton pumps) expressed in parietal cells of the stomach. Some of the extra-gastric activities of PPIs include modulation of epithelial, endothelial, and immune cell functions. Recently, we reported that PPIs suppress the expression of several proinflammatory and profibrotic molecules, as well as enhance antioxidant mechanisms in order to favorably regulate lung inflammation and fibrosis in an animal model of bleomycin-induced lung injury. In addition, several retrospective clinical studies report that the use of PPIs is associated with beneficial outcomes in chronic lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Based on these preclinical and clinical observations, we hypothesized that PPIs ameliorate smoke-induced lung injury. Accordingly, we evaluated the pharmacological efficacy of the PPI esomeprazole in a mouse model of cotton smoke-induced lung injury. The animals were exposed to cotton smoke for 3-weeks in the presence or absence of esomeprazole treatment. We found that therapeutic administration of esomeprazole significantly inhibited the progression of fibrosis throughout the lungs of the animals in this group compared to controls. In addition, esomeprazole also reduced circulating markers of inflammation and fibrosis. Overall, our work extends the emerging anti-inflammatory and antifibrotic potential of PPIs and their role in modulation of chronic lung diseases. PMID:28184197

  15. Curcumin Inhibits Transforming Growth Factor β Induced Differentiation of Mouse Lung Fibroblasts to Myofibroblasts

    PubMed Central

    Liu, Daishun; Gong, Ling; Zhu, Honglan; Pu, Shenglan; Wu, Yang; Zhang, Wei; Huang, Guichuan

    2016-01-01

    Transforming growth factor β (TGF-β) induced differentiation of lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. This study aimed to evaluate the effect of curcumin on TGF-β induced differentiation of lung fibroblasts to myofibroblasts and explore the underlying mechanism. Mouse lung fibroblasts were cultured and treated with TGF-β2 and curcumin or rosiglitazone. Cell vitality was examined by MTT assay. The secretion of collagen-1 was assessed by ELISA. α smooth muscle actin (α-SMA) was visualized by immunofluorescence technique. The expression of peroxisome proliferator activated receptor γ (PPAR-γ) and platelet derived growth factor R β (PDGFR-β) was detected by PCR and Western blot analysis. We found that curcumin and rosiglitazone inhibited the proliferation and TGF-β induced differentiation of mouse lung fibroblasts. In addition, curcumin and rosiglitazone inhibited collagen-1 secretion and α-SMA expression in mouse lung fibroblasts. Furthermore, curcumin and rosiglitazone upregulated PPAR-γ and downregulated PDGFR-β expression in mouse lung fibroblasts. In conclusion, our study reveals novel mechanism by which curcumin inhibits TGF-β2 driven differentiation of lung fibroblasts to myofibroblasts. Curcumin could potentially be used for effective treatment of pulmonary fibrosis. PMID:27877129

  16. Chlamydia pneumoniae Infection in Mice Induces Chronic Lung Inflammation, iBALT Formation, and Fibrosis

    PubMed Central

    Jupelli, Madhulika; Shimada, Kenichi; Chiba, Norika; Slepenkin, Anatoly; Alsabeh, Randa; Jones, Heather D.; Peterson, Ellena; Chen, Shuang

    2013-01-01

    Chlamydia pneumoniae (CP) lung infection can induce chronic lung inflammation and is associated with not only acute asthma but also COPD exacerbations. However, in mouse models of CP infection, most studies have investigated specifically the acute phase of the infection and not the longer-term chronic changes in the lungs. We infected C57BL/6 mice with 5×105 CP intratracheally and monitored inflammation, cellular infiltrates and cytokine levels over time to investigate the chronic inflammatory lung changes. While bacteria numbers declined by day 28, macrophage numbers remained high through day 35. Immune cell clusters were detected as early as day 14 and persisted through day 35, and stained positive for B, T, and follicular dendritic cells, indicating these clusters were inducible bronchus associated lymphoid tissues (iBALTs). Classically activated inflammatory M1 macrophages were the predominant subtype early on while alternatively activated M2 macrophages increased later during infection. Adoptive transfer of M1 but not M2 macrophages intratracheally 1 week after infection resulted in greater lung inflammation, severe fibrosis, and increased numbers of iBALTS 35 days after infection. In summary, we show that CP lung infection in mice induces chronic inflammatory changes including iBALT formations as well as fibrosis. These observations suggest that the M1 macrophages, which are part of the normal response to clear acute C. pneumoniae lung infection, result in an enhanced acute response when present in excess numbers, with greater inflammation, tissue injury, and severe fibrosis. PMID:24204830

  17. Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury.

    PubMed

    Mathew, Biji; Takekoshi, Daisuke; Sammani, Saad; Epshtein, Yulia; Sharma, Rajesh; Smith, Brett D; Mitra, Sumegha; Desai, Ankit A; Weichselbaum, Ralph R; Garcia, Joe G N; Jacobson, Jeffrey R

    2015-12-15

    We previously reported protective effects of GADD45a (growth arrest and DNA damage-inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in GADD45a (GADD45a(-/-)) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore, GADD45a(-/-) mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in both Akt(+/-) mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI-susceptibility in GADD45a(-/-) mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly increased in GADD45a(-/-) mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically.

  18. Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury

    PubMed Central

    Mathew, Biji; Takekoshi, Daisuke; Sammani, Saad; Epshtein, Yulia; Sharma, Rajesh; Smith, Brett D.; Mitra, Sumegha; Desai, Ankit A.; Weichselbaum, Ralph R.; Garcia, Joe G. N.

    2015-01-01

    We previously reported protective effects of GADD45a (growth arrest and DNA damage-inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in GADD45a (GADD45a−/−) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore, GADD45a−/− mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in both Akt+/− mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI-susceptibility in GADD45a−/− mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly increased in GADD45a−/− mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically. PMID:26498248

  19. Do-not-resuscitate order

    MedlinePlus

    ... order; DNR; DNR order; Advance care directive - DNR; Health care agent - DNR; Health care proxy - DNR; End-of-life - DNR; Living will - ... medical order written by a doctor. It instructs health care providers not to do cardiopulmonary resuscitation (CPR) if ...

  20. Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats.

    PubMed

    Wang, Wen; Liu, Zhi; Su, Jie; Chen, Wen-Sheng; Wang, Xiao-Wu; Bai, San-Xing; Zhang, Jin-Zhou; Yu, Shi-Qiang

    2016-08-01

    Micro-RNA (miR)-155 is a novel gene regulator with important roles in inflammation. Herein, our study aimed to explore the role of miR-155 in LPS-induced acute lung injury(ALI). ALI in mice was induced by intratracheally delivered LPS. Loss-of-function experiments performed on miR-155 knockout mice showed that miR-155 gene inactivation protected mice from LPS-induced ALI, as manifested by preserved lung permeability and reduced lung inflammation compared with wild-type controls. Bone marrow transplantation experiments identified leukocytes, but not lung parenchymal-derived miR-155-promoted acute lung inflammation. Real-time PCR analysis showed that the expression of miR-155 in lung tissue was greatly elevated in wild-type mice after LPS stimulation. In situ hybridization showed that miR-155 was mainly expressed in alveolar macrophages. In vitro experiments performed in isolated alveolar macrophages and polarized bone marrow-derived macrophages confirmed that miR-155 expression in macrophages was increased in response to LPS stimulation. Conversely, miR-155 gain-of-function in alveolar macrophages remarkably exaggerated LPS-induced acute lung injury. Molecular studies identified the inflammation repressor suppressor of cytokine signaling (SOCS-1) as the downstream target of miR-155. By binding to the 3'-UTR of the SOCS-1 mRNA, miR-155 downregulated SOCS-1 expression, thus, permitting the inflammatory response during lung injury. Finally, we generated a novel miR-155 knockout rat strain and showed that the proinflammatory role of miR-155 was conserved in rats. Our study identified miR-155 as a proinflammatory factor after LPS stimulation, and alveolar macrophages-derived miR-155 has an important role in LPS-induced ALI.

  1. Mild hypothermia reduces ventilator-induced lung injury, irrespective of reducing respiratory rate.

    PubMed

    Aslami, Hamid; Kuipers, Maria T; Beurskens, Charlotte J P; Roelofs, Joris J T H; Schultz, Marcus J; Juffermans, Nicole P

    2012-02-01

    In the era of lung-protective mechanical ventilation using limited tidal volumes, higher respiratory rates are applied to maintain adequate minute volume ventilation. However, higher respiratory rates may contribute to ventilator-induced lung injury (VILI). Induced hypothermia reduces carbon dioxide production and might allow for lower respiratory rates during mechanical ventilation. We hypothesized that hypothermia protects from VILI and investigated whether reducing respiratory rates enhance lung protection in an in vivo model of VILI. During 4 h of mechanical ventilation, VILI was induced by tidal volumes of 18 mL/kg in rats, with respiratory rates set at 15 or 10 breaths/min in combination with hypothermia (32°C) or normothermia (37°C). Hypothermia was induced by external cooling. A physiologic model was established. VILI was characterized by increased pulmonary neutrophil influx, protein leak, wet weights, histopathology score, and cytokine levels compared with lung protective mechanical ventilation. Hypothermia decreased neutrophil influx, pulmonary levels, systemic interleukin-6 levels, and histopathology score, and it tended to decrease the pulmonary protein leak. Reducing the respiratory rate in combination with hypothermia did not reduce the parameters of the lung injury. In conclusion, hypothermia protected from lung injury in a physiologic VILI model by reducing inflammation. Decreasing the respiratory rate mildly did not enhance protection.

  2. RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury.

    PubMed

    Zhang, Zhuo; Zhou, Jie; Liao, Changli; Li, Xiaobing; Liu, Minghua; Song, Daqiang; Jiang, Xian

    2017-04-01

    Lidocaine (Lido) is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of cecal ligation and puncture (CLP)-induced acute lung injury (ALI). The receptor for advanced glycation end product (RAGE) exerts pro-inflammatory effects by enhancing pro-inflammatory cytokine production. However, the precise mechanism by which Lido confers protection against ALI is not clear. ALI was induced in RAGE WT and RAGE knockout (KO) rats using cecal ligation and puncture (CLP) operations for 24 h. The results showed that Lido significantly inhibited CLP-induced lung inflammation and histopathological lung injury. Furthermore, Lido significantly reduced CLP-induced upregulation of HMGB1 and RAGE expression and activation of the NF-κB and MAPK signaling pathways. With the use of RAGE KO rats, we demonstrate here that RAGE deficiency attenuates the protective effect of Lido against CLP-induced lung inflammatory cell infiltration and histopathological lung injury. These results suggest that RAGE deficiency attenuates the protective effect of Lido against CLP-induced ALI by attenuating the pro-inflammatory cytokines production.

  3. VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice

    PubMed Central

    James, Masheika L.; Ross, A. Catharine; Nicola, Teodora; Steele, Chad

    2013-01-01

    We have recently shown that a combination of vitamin A (VA) and retinoic acid (RA) in a 10:1 molar ratio (VARA) synergistically increases lung retinoid content in newborn rodents, more than either VA or RA alone in equimolar amounts. We hypothesized that the increase in lung retinoids would reduce oxidative stress and proinflammatory cytokines, resulting in attenuation of alveolar simplification and abnormal lung function in hyperoxia-exposed newborn mice. Newborn C57BL/6 mice were exposed to 85% O2 (hyperoxia) or air (normoxia) for 7 or 14 days from birth and given vehicle or VARA every other day. Lung retinol content was measured by HPLC, function was assessed by flexiVent, and development was evaluated by radial alveolar counts, mean linear intercept, and secondary septal crest density. Mediators of oxidative stress, inflammation, and alveolar development were evaluated in lung homogenates. We observed that VARA increased lung retinol stores and attenuated hyperoxia-induced alveolar simplification while increasing lung compliance and lowering resistance. VARA attenuated hyperoxia-induced increases in DNA damage and protein oxidation accompanied with a reduction in nuclear factor (erythroid-derived 2)-like 2 protein but did not alter malondialdehyde adducts, nitrotyrosine, or myeloperoxidase concentrations. Interferon-γ and macrophage inflammatory protein-2α mRNA and protein increased with hyperoxia, and this increase was attenuated by VARA. Our study suggests that the VARA combination may be a potential therapeutic strategy in conditions characterized by VA deficiency and hyperoxia-induced lung injury during lung development, such as bronchopulmonary dysplasia in preterm infants. PMID:23585226

  4. Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

    PubMed

    Yu, Peng-Jiu; Li, Jing-Rong; Zhu, Zheng-Guang; Kong, Huan-Yu; Jin, Hong; Zhang, Jun-Yan; Tian, Yuan-Xin; Li, Zhong-Huang; Wu, Xiao-Yun; Zhang, Jia-Jie; Wu, Shu-Guang

    2013-06-15

    Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury.

  5. Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management.

    PubMed

    Mulshine, James L; Avila, Rick; Yankelevitz, David; Baer, Thomas M; Estépar, Raul San Jose; Ambrose, Laurie Fenton; Aldigé, Carolyn R

    2015-05-01

    The Prevent Cancer Foundation Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management was held in New York, NY on May 16 and 17, 2014. The two goals of the Workshop were to define strategies to drive innovation in precompetitive quantitative research on the use of imaging to assess new therapies for management of early lung cancer and to discuss a process to implement a national program to provide high quality computed tomography imaging for lung cancer and other tobacco-induced disease. With the central importance of computed tomography imaging for both early detection and volumetric lung cancer assessment, strategic issues around the development of imaging and ensuring its quality are critical to ensure continued progress against this most lethal cancer.

  6. Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation.

    PubMed

    Hoyle, Gary W; Chen, Jing; Schlueter, Connie F; Mo, Yiqun; Humphrey, David M; Rawson, Greg; Niño, Joe A; Carson, Kenneth H

    2016-05-01

    Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposed mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation.

  7. Association of Kidney Tissue Barrier Disrupture and Renal Dysfunction in Resuscitated Murine Septic Shock.

    PubMed

    Stenzel, Tatjana; Weidgang, Clair; Wagner, Katja; Wagner, Florian; Gröger, Michael; Weber, Sandra; Stahl, Bettina; Wachter, Ulrich; Vogt, Josef; Calzia, Enrico; Denk, Stephanie; Georgieff, Michael; Huber-Lang, Markus; Radermacher, Peter; McCook, Oscar

    2016-10-01

    Septic shock-related kidney failure is characterized by almost normal morphological appearance upon pathological examination. Endothelial barrier disrupture has been suggested to be of crucial importance for septic shock-induced organ dysfunction. Therefore, in murine resuscitated cecal ligation and puncture (CLP)-induced septic shock, we tested the hypothesis whether there is a direct relationship between the kidney endothelial barrier injury and renal dysfunction. Anesthetized mice underwent CLP, and 15 h later, were anesthetized again and surgically instrumented for a 5-h period of intensive care comprising lung-protective mechanical ventilation, fluid resuscitation, continuous i.v. norepinephrine to maintain target hemodynamics, and measurement of creatinine clearance (CrCl). Animals were stratified according to low or high CrCl. Nitrotyrosine formation, expression of the inducible isoform of the nitric oxide synthase, and blood cytokine (tumor necrosis factor, interleukin-6, interleukin-10) and chemokine (monocyte chemoattractant protein-1, keratinocyte-derived chemokine) levels were significantly higher in animals with low CrCl. When plotted against CrCl and neutrophil gelatinase-associated lipocalin levels, extravascular albumin accumulation, and tissue expression of the vascular endothelial growth factor and angiopoietin-1 showed significant mathematical relationships related to kidney (dys)function. Preservation of the constitutive expression of the hydrogen sulfide producing enzyme cystathione-γ-lyase was associated with maintenance of organ function. The direct quantitative relation between microvascular leakage and kidney (dys)function may provide a missing link between near-normal tissue morphology and septic shock-related renal failure, thus further highlighting the important role of vascular integrity in septic shock-related renal failure.

  8. Tobacco smoke induces production of chemokine CCL20 to promote lung cancer.

    PubMed

    Wang, Gui-Zhen; Cheng, Xin; Li, Xin-Chun; Liu, Yong-Qiang; Wang, Xian-Quan; Shi, Xu; Wang, Zai-Yong; Guo, Yong-Qing; Wen, Zhe-Sheng; Huang, Yun-Chao; Zhou, Guang-Biao

    2015-07-10

    Tobacco kills nearly 6 million people each year, and 90% of the annual 1.59 million lung cancer deaths worldwide are caused by cigarette smoke. Clinically, a long latency is required for individuals to develop lung cancer since they were first exposed to smoking. In this study, we aimed to identify clinical relevant inflammatory factors that are critical for carcinogenesis by treating normal human lung epithelial cells with tobacco carcinogen nicotine-derived nitrosaminoketone (NNK) for a long period (60 days) and systematic screening in 84 cytokines/chemokines. We found that a chemokine CCL20 was significantly up-regulated by NNK, and in 78/173 (45.1%) patients the expression of CCL20 was higher in tumor samples than their adjacent normal lung tissues. Interestingly, CCL20 was up-regulated in 48/92 (52.2%) smoker and 29/78 (37.2%) nonsmoker patients (p = 0.05), and high CCL20 was associated with poor prognosis. NNK induced the production of CCL20, which promoted lung cancer cell proliferation and migration. In addition, an anti-inflammation drug, dexamethasone, inhibited NNK-induced CCL20 production and suppressed lung cancer in vitro and in vivo. These results indicate that CCL20 is crucial for tobacco smoke-caused lung cancer, and anti-CCL20 could be a rational approach to fight against this deadly disease.

  9. Benzo(a)pyrene induced lung cancer: Role of dietary phytochemicals in chemoprevention.

    PubMed

    Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Barua, Chandana C; Sriram, Chandra Shekhar; Gogoi, Ranadeep

    2015-10-01

    Lung cancer is the major cause of overall cancer deaths, and chemoprevention is a promising strategy to control this disease. Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is one among the principal constituents of tobacco smoke that plays a key role in lung carcinogenesis. The B(a)P induced lung cancer in mice offers a relevant model to study the effect of natural products and has been widely used by many researchers and found considerable success in ameliorating the pathophysiological changes of lung cancer. Currently available synthetic drugs that constitute the pharmacological armamentarium are themselves effective in managing the condition but not without setbacks. These hunches have accelerated the requisite for natural products, which may be used as dietary supplement to prevent the progress of lung cancer. Besides, these agents also supplement the conventional treatment and offer better management of the condition with less side effects. In the context of soaring interest toward dietary phytochemicals as newer pharmacological interventions for lung cancer, in the present review, we are attempting to give a silhouette of mechanisms of B(a)P induced lung carcinogenesis and the role of dietary phytochemicals in chemoprevention.

  10. Aspirin, but Not Tirofiban Displays Protective Effects in Endotoxin Induced Lung Injury

    PubMed Central

    Gombert, Alexander; Jacobs, Michael J.; Drechsler, Maik; Döring, Yvonne; Soehnlein, Oliver; Grommes, Jochen

    2016-01-01

    Background Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. Recruitment of neutrophils into the lungs, regarded as a key mechanism in progression of ALI, depends on signaling between neutrophils and platelets. Consequently we explored the effect of platelet-targeted aspirin and tirofiban treatment in endotoxin induced acute lung injury Methods C57Bl/6 mice were exposed to aerosolized LPS (500μg/ml) for 30min and treated with Aspirin (100μg/g bodyweight via intraperitoneal injection, 30 min before or 1 hour after LPS inhalation) or Tirofiban (0.5μg/ g bodyweight via tail vein injection 30 min before or 1 hour after LPS inhalation). The count of alveolar, interstitial, and intravascular neutrophils was assessed 4h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and protein content in the BAL fluid. Results Aspirin both before and after LPS inhalation reduced neutrophil influx into the lung and lung permeability indicating the protective role of Aspirin in ALI. Tirofiban, however, did not alter neutrophil recruitment after LPS inhalation. Release of platelet-derived chemokines CCL5 and PF4 and neutrophil extracellular traps was reduced by Aspirin but not by Tirofiban. Conclusion Aspirin, but not Tirofiban reduces neutrophil recruitment and displays protective effects during endotoxin induced lung injury. PMID:27583400

  11. Eicosapentaenoic acid attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling

    PubMed Central

    Liu, Meng-Han; Lin, An-Hsuan; Lu, Shing-Hwa; Peng, Ruo-Yun; Lee, Tzong-Shyuan; Kou, Yu Ru

    2014-01-01

    Cigarette smoking causes chronic lung inflammation that is mainly regulated by redox-sensitive pathways. Our previous studies have demonstrated that cigarette smoke (CS) activates reactive oxygen species (ROS)-sensitive mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling resulting in induction of lung inflammation. Eicosapentaenoic acid (EPA), a major type of omega-3 polyunsaturated fatty acid, is present in significant amounts in marine-based fish and fish oil. EPA has been shown to possess antioxidant and anti-inflammatory properties in vitro and in vivo. However, whether EPA has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model, we show that subchronic CS exposure for 4 weeks caused pulmonary inflammatory infiltration (total cell count in bronchoalveolar lavage fluid (BALF), 11.0-fold increase), increased lung vascular permeability (protein level in BALF, 3.1-fold increase), elevated levels of chemokines (11.4–38.2-fold increase) and malondialdehyde (an oxidative stress biomarker; 2.0-fold increase) in the lungs, as well as lung inflammation; all of these CS-induced events were suppressed by daily supplementation with EPA. Using human bronchial epithelial cells, we further show that CS extract (CSE) sequentially activated NADPH oxidase (NADPH oxidase activity, 1.9-fold increase), increased intracellular levels of ROS (3.0-fold increase), activated both MAPKs and NF-κB, and induced interleukin-8 (IL-8; 8.2-fold increase); all these CSE-induced events were inhibited by pretreatment with EPA. Our findings suggest a novel role for EPA in alleviating the oxidative stress and lung inflammation induced by subchronic CS exposure in vivo and in suppressing the CSE-induced IL-8 in vitro via its antioxidant function and by inhibiting MAPKs/NF-κB signaling. PMID:25452730

  12. Proteomic Analysis of Serum in Lung Cancer Induced by 3-Methylcholanthrene

    PubMed Central

    Li, Minhua; Ye, Bo; Zhang, Yuxia; Chen, Honglei; Xia, Dong; Liu, Mingqiu; Yang, Fei

    2009-01-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide. Early detection of lung cancer is problematic due to the lack of a marker with high diagnosis sensitivity and specificity. To determine the differently expressed proteins in the serum of lung cancer and figure out the function of the proteins, two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were used to screen the serum proteins of lung cancer model induced by 3-methylcholanthrene (MCA). From optimized 2DE image, 455 spots in the normal sera and 716 spots in the lung cancers sera were detected. Among them, 141 protein spots were differentially expressed when comparing the serum from normal rat and serum from lung cancer model, including 82 overexpressed proteins and 59 underexpressed proteins. Changes of haptoglobin, transthyretin, and TNF superfamily member 8 (TNFRS8) were confirmed in sera from lung cancer by MALDI-TOF-MS. Proteomics technology leads to identify changes of haptoglobin, transthyretin, and TNFRS8 in serum of rat lung cancer model and represents a powerful tool in searching for candidate proteins as biomarkers. PMID:19794824

  13. Endothelial Semaphorin 7A Promotes Inflammation in Seawater Aspiration-Induced Acute Lung Injury

    PubMed Central

    Zhang, Minlong; Wang, Li; Dong, Mingqing; Li, Zhichao; Jin, Faguang

    2014-01-01

    Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have shown that Semaphorin 7A (SEMA7A) promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague–Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs) were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF)-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease. PMID:25353180

  14. Sesamin Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Inhibition of TLR4 Signaling Pathways.

    PubMed

    Qiang, Li; Yuan, Jiang; Shouyin, Jiang; Yulin, Li; Libing, Jiang; Jian-An, Wang

    2016-02-01

    Recent studies suggested that TLR4 signaling pathways played an important role in the development of LPS-induced acute lung injury (ALI). Sesamin, a sesame lignan exacted from sesame seeds, has been shown to exhibit significant anti-inflammatory activity. The purpose of this study was to investigate the anti-inflammatory effects of sesamin on LPS-induced ALI in mice. Mice ALI model was induced by intratracheal instillation of LPS. Sesamin was given 1 h after LPS challenge. Our results showed that sesamin inhibited LPS-induced lung pathological change, edema, and myeloperoxidase (MPO) activity. Sesamin suppressed LPS-induced inflammatory cytokines TNF-α, IL-6, and IL-1β production. Furthermore, sesamin inhibited LPS-induced TLR4 expression and NF-κB activation. In conclusion, the results of this study indicated that sesamin protected against LPS-induced ALI by inhibition of TLR4 signaling pathways.

  15. Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells

    PubMed Central

    Martino, Julieta; Holmes, Amie L.; Xie, Hong; Wise, Sandra S.; Wise, John Pierce

    2015-01-01

    Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. Lung tumors are characterized by structural and numerical chromosome instability. Centrosome amplification is a phenotype commonly found in solid tumors, including lung tumors, which strongly correlates with chromosome instability. Human lung cells exposed to Cr(VI) exhibit centrosome amplification but the underlying phenotypes and mechanisms remain unknown. In this study, we further characterize the phenotypes of Cr(VI)-induced centrosome abnormalities. We show that Cr(VI)-induced centrosome amplification correlates with numerical chromosome instability. We also show chronic exposure to particulate Cr(VI) induces centrosomes with supernumerary centrioles and acentriolar centrosomes in human lung cells. Moreover, chronic exposure to particulate Cr(VI) affects the timing of important centriolar events. Specifically, chronic exposure to particulate Cr(VI) causes premature centriole disengagement in S and G2 phase cells. It also induces premature centrosome separation in interphase. Altogether, our data suggest that chronic exposure to particulate Cr(VI) targets the protein linkers that hold centrioles together. These centriolar linkers are important for key events of the centrosome cycle and their premature disruption might underlie Cr(VI)-induced centrosome amplification. PMID:26293554

  16. Soluble transition metals mediate residual oil fly ash induced acute lung injury.

    PubMed

    Dreher, K L; Jaskot, R H; Lehmann, J R; Richards, J H; McGee, J K; Ghio, A J; Costa, D L

    1997-02-21

    Identification of constituents responsible for the pulmonary toxicity of fugitive combustion emission source particles may provide insight into the adverse health effects associated with exposure to these particles as well as ambient air particulate pollution. Herein, we describe results of studies conducted to identify constituents responsible for the acute lung injury induced by residual oil fly ash (ROFA) and to assess physical-chemical factors that influence the pulmonary toxicity of these constituents. Biochemical and cellular analyses performed on bronchoalveolar lavage fluid obtained from rats following intratracheal instillation of ROFA suspension demonstrated the presence of severe inflammation, an indicator of pulmonary injury, which included recruitment of neutrophils, eosinophils, and monocytes into the airway. A leachate prepared from ROFA, containing predominantly Fe, Ni, V, Ca, Mg, and sulfate, produced similar lung injury to that induced by ROFA suspension. Depletion of Fe, Ni, and V from the ROFA leachate abrogated its pulmonary toxicity. Correspondingly, minimal lung injury was observed in animals exposed to saline-washed ROFA particles. A surrogate transition metal sulfate solution containing Fe, V, and Ni largely reproduced the lung injury induced by ROFA. Metal interactions and pH were found to influence the severity and kinetics of lung injury induced by ROFA and soluble transition metals. These findings provide direct evidence for the role of soluble transition metals in the pulmonary injury induced by the combustion emission source particulate, ROFA.

  17. Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

    SciTech Connect

    Shin, Jung Ar; Chung, Jin Sil; Cho, Sang-Ho; Kim, Hyung Jung; Yoo, Young Do

    2013-09-20

    Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain. Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H{sub 2}O{sub 2}) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H{sub 2}O{sub 2} treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells.

  18. Multiwalled carbon nanotubes intratracheally instilled into the rat lung induce development of pleural malignant mesothelioma and lung tumors.

    PubMed

    Suzui, Masumi; Futakuchi, Mitsuru; Fukamachi, Katsumi; Numano, Takamasa; Abdelgied, Mohamed; Takahashi, Satoru; Ohnishi, Makoto; Omori, Toyonori; Tsuruoka, Shuji; Hirose, Akihiko; Kanno, Jun; Sakamoto, Yoshimitsu; Alexander, David B; Alexander, William T; Jiegou, Xu; Tsuda, Hiroyuki

    2016-07-01

    Multiwalled carbon nanotubes (MWCNT) have a fibrous structure and physical properties similar to asbestos and have been shown to induce malignant mesothelioma of the peritoneum after injection into the scrotum or peritoneal cavity in rats and mice. For human cancer risk assessment, however, data after administration of MWCNT via the airway, the exposure route that is most relevant to humans, is required. The present study was undertaken to investigate the carcinogenicity of MWCNT-N (NIKKISO) after administration to the rat lung. MWCNT-N was fractionated by passing it through a sieve with a pore size of 25 μm. The average lengths of the MWCNT were 4.2 μm before filtration and 2.6 μm in the flow-through fraction; the length of the retained MWCNT could not be determined. For the present study, 10-week-old F344/Crj male rats were divided into five groups: no treatment, vehicle control, MWCNT-N before filtration, MWCNT-N flow-through and MWCNT-N retained groups. Administration was by the trans-tracheal intrapulmonary spraying (TIPS) method. Rats were administered a total of 1 mg/rat during the initial 2 weeks of the experiment and then observed up to 109 weeks. The incidences of malignant mesothelioma and lung tumors (bronchiolo-alveolar adenomas and carcinomas) were 6/38 and 14/38, respectively, in the three groups administered MWCNT and 0/28 and 0/28, respectively, in the control groups. All malignant mesotheliomas were localized in the pericardial pleural cavity. The sieve fractions did not have a significant effect on tumor incidence. In conclusion, administration of MWCNT to the lung in the rat induces malignant mesothelioma and lung tumors.

  19. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    PubMed

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  20. Natural Antioxidant Betanin Protects Rats from Paraquat-Induced Acute Lung Injury Interstitial Pneumonia

    PubMed Central

    Ma, Deshun; Zhang, Miao; Yang, Xuelian; Tan, Dehong

    2015-01-01

    The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further. PMID:25861636

  1. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    NASA Astrophysics Data System (ADS)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  2. Nontypeable Haemophilus influenzae Induces Sustained Lung Oxidative Stress and Protease Expression

    PubMed Central

    King, Paul T.; Sharma, Roleen; O’Sullivan, Kim; Selemidis, Stavros; Lim, Steven; Radhakrishna, Naghmeh; Lo, Camden; Prasad, Jyotika; Callaghan, Judy; McLaughlin, Peter; Farmer, Michael; Steinfort, Daniel; Jennings, Barton; Ngui, James; Broughton, Bradley R. S.; Thomas, Belinda; Essilfie, Ama-Tawiah; Hickey, Michael; Holmes, Peter W.; Hansbro, Philip; Bardin, Philip G.; Holdsworth, Stephen R.

    2015-01-01

    Nontypeable Haemophilus influenzae (NTHi) is a prevalent bacterium found in a variety of chronic respiratory diseases. The role of this bacterium in the pathogenesis of lung inflammation is not well defined. In this study we examined the effect of NTHi on two important lung inflammatory processes 1), oxidative stress and 2), protease expression. Bronchoalveolar macrophages were obtained from 121 human subjects, blood neutrophils from 15 subjects, and human-lung fibroblast and epithelial cell lines from 16 subjects. Cells were stimulated with NTHi to measure the effect on reactive oxygen species (ROS) production and extracellular trap formation. We also measured the production of the oxidant, 3-nitrotyrosine (3-NT) in the lungs of mice infected with this bacterium. NTHi induced widespread production of 3-NT in mouse lungs. This bacterium induced significantly increased ROS production in human fibroblasts, epithelial cells, macrophages and neutrophils; with the highest levels in the phagocytic cells. In human macrophages NTHi caused a sustained, extracellular production of ROS that increased over time. The production of ROS was associated with the formation of macrophage extracellular trap-like structures which co-expressed the protease metalloproteinase-12. The formation of the macrophage extracellular trap-like structures was markedly inhibited by the addition of DNase. In this study we have demonstrated that NTHi induces lung oxidative stress with macrophage extracellular trap formation and associated protease expression. DNase inhibited the formation of extracellular traps. PMID:25793977

  3. Natural antioxidant betanin protects rats from paraquat-induced acute lung injury interstitial pneumonia.

    PubMed

    Han, Junyan; Ma, Deshun; Zhang, Miao; Yang, Xuelian; Tan, Dehong

    2015-01-01

    The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further.

  4. Neonatal resuscitation: advances in training and practice

    PubMed Central

    Sawyer, Taylor; Umoren, Rachel A; Gray, Megan M

    2017-01-01

    Each year in the US, some four hundred thousand newborns need help breathing when they are born. Due to the frequent need for resuscitation at birth, it is vital to have evidence-based care guidelines and to provide effective neonatal resuscitation training. Every five years, the International Liaison Committee on Resuscitation (ILCOR) reviews the science of neonatal resuscitation. In the US, the American Heart Association (AHA) develops treatment guidelines based on the ILCOR science review, and the Neonatal Resuscitation Program (NRP) translates the AHA guidelines into an educational curriculum. In this report, we review recent advances in neonatal resuscitation training and practice. We begin with a review of the new 7th edition NRP training curriculum. Then, we examine key changes to the 2015 AHA neonatal resuscitation guidelines. The four components of the NRP curriculum reviewed here include eSim®, Performance Skills Stations, Integrated Skills Station, and Simulation and Debriefing. The key changes to the AHA neonatal resuscitation guidelines reviewed include initial steps of newborn care, positive-pressure ventilation, endotracheal intubation and use of laryngeal mask, chest compressions, medications, resuscitation of preterm newborns, and ethics and end-of-life care. We hope this report provides a succinct review of recent advances in neonatal resuscitation. PMID:28096704

  5. Device induces lungs to maintain known constant pressure

    NASA Technical Reports Server (NTRS)

    Lippitt, M. W.; Reed, J. H.

    1964-01-01

    This device requires the use of thoracic muscles to maintain prescribed air pressure in the lungs for brief periods. It consists of a clear plastic hollow cylinder fitted with a mouthpiece, a spring-loaded piston, and a small vent for escaping air when exhalation into the mouthpiece displaces the piston.

  6. Biochemical and cellular mechanisms of dust-induced lung fibrosis.

    PubMed Central

    Richards, R J; Curtis, C G

    1984-01-01

    The sequence of cellular and biochemical events in response to the deposition of dust particles in lung tissue is described. Primary reactions at the lung surface include changes in the free cell population, the alveolar surface protein and in the quantity of pulmonary surfactant, a lipoprotein-rich material secreted by Type II cells. The relationship between these changes and lung fibrogenesis is discussed. It is suggested that such primary changes are protective mechanisms which may assist in the prevention of fibrogenesis rather than lead to an increase in collagen formation and deposition. If these primary defenses are overcome, then the interstitial fibroblastlike cell may have a prominent role in fibrogenesis. Therefore detailed observations of the interaction between lung fibroblasts and mineral dusts in vitro are described. As fibrogenesis may be arrested in vivo, or possibly reversed, and does not always progress to fibrosis, final consideration is given to the step from fibrogenesis to fibrosis. It is suggested that this step may involve other tissue proteins apart from collagen and that the irreversible nature of fibrosis can be explained by the formation of strong intermolecular crosslinks between different proteins. The types of crosslinks that may be involved are discussed. Emphasis is placed on the role of calcium-dependent transglutaminases in fibrosis, as these enzymes have hitherto received little attention. Images FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. FIGURE 10. FIGURE 11. FIGURE 12. FIGURE 20. FIGURE 21. FIGURE 22. FIGURE 23. PMID:6376109

  7. Risk assessment methodologies for passive smoking-induced lung cancer

    SciTech Connect

    Repace, J.L.; Lowrey, A.H. )

    1990-03-01

    Risk assessment methodologies have been successfully applied to control societal risk from outdoor air pollutants. They are now being applied to indoor air pollutants such as environmental tobacco smoke (ETS) and radon. Nonsmokers' exposures to ETS have been assessed based on dosimetry of nicotine, its metabolite, continine, and on exposure to the particulate phase of ETS. Lung cancer responses have been based on both the epidemiology of active and of passive smoking. Nine risk assessments of nonsmokers' lung cancer risk from exposure to ETS have been performed. Some have estimated risks for lifelong nonsmokers only; others have included ex-smokers; still others have estimated total deaths from all causes. To facilitate interstudy comparison, in some cases lung cancers had to be interpolated from a total, or the authors' original estimate had to be adjusted to include ex-smokers. Further, all estimates were adjusted to 1988. Excluding one study whose estimate differs from the mean of the others by two orders of magnitude, the remaining risk assessments are in remarkable agreement. The mean estimate is approximately 5000 +/- 2400 nonsmokers' lung cancer deaths (LCDSs) per year. This is a 25% greater risk to nonsmokers than is indoor radon, and is about 57 times greater than the combined estimated cancer risk from all the hazardous outdoor air pollutants currently regulated by the Environmental Protection Agency: airborne radionuclides, asbestos, arsenic, benzene, coke oven emissions, and vinyl chloride. 48 references.

  8. Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin).

    PubMed

    Pini, Alessandro; Boccalini, Giulia; Lucarini, Laura; Catarinicchia, Stefano; Guasti, Daniele; Masini, Emanuela; Bani, Daniele; Nistri, Silvia

    2016-06-01

    Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD), which is characterized by airway remodeling, lung inflammation and fibrosis, emphysema, and respiratory failure. The current therapies can improve COPD management but cannot arrest its progression and reduce mortality. Hence, there is a major interest in identifying molecules susceptible of development into new drugs to prevent or reduce CS-induced lung injury. Serelaxin (RLX), or recombinant human relaxin-2, is a promising candidate because of its anti-inflammatory and antifibrotic properties highlighted in lung disease models. Here, we used a guinea pig model of CS-induced lung inflammation, and remodeling reproducing some of the hallmarks of COPD. Animals exposed chronically to CS (8 weeks) were treated with vehicle or RLX, delivered by osmotic pumps (1 or 10 μg/day) or aerosol (10 μg/ml/day) during CS treatment. Controls were nonsmoking animals. RLX maintained airway compliance to a control-like pattern, likely because of its capability to counteract lung inflammation and bronchial remodeling. In fact, treatment of CS-exposed animals with RLX reduced the inflammatory recruitment of leukocytes, accompanied by a significant reduction of the release of proinflammatory cytokines (tumor necrosis factor α and interleukin-1β). Moreover, RLX was able to counteract the adverse bronchial remodeling and emphysema induced by CS exposure by reducing goblet cell hyperplasia, smooth muscle thickening, and fibrosis. Of note, RLX delivered by aerosol has shown a comparable efficacy to systemic administration in reducing CS-induced lung dysfunction and damage. In conclusion, RLX emerges as a new molecule to counteract CS-induced inflammatory lung diseases.

  9. Real-time imaging of inflation-induced ATP release in the ex vivo rat lung.

    PubMed

    Furuya, Kishio; Tan, Ju Jing; Boudreault, Francis; Sokabe, Masahiro; Berthiaume, Yves; Grygorczyk, Ryszard

    2016-11-01

    Extracellular ATP and other nucleotides are important autocrine/paracrine mediators that regulate diverse processes critical for lung function, including mucociliary clearance, surfactant secretion, and local blood flow. Cellular ATP release is mechanosensitive; however, the impact of physical stimuli on ATP release during breathing has never been tested in intact lungs in real time and remains elusive. In this pilot study, we investigated inflation-induced ATP release in rat lungs ex vivo by real-time luciferin-luciferase (LL) bioluminescence imaging coupled with simultaneous infrared tissue imaging to identify ATP-releasing sites. With LL solution introduced into air spaces, brief inflation of such edematous lung (1 s, ∼20 cmH2O) induced transient (<30 s) ATP release in a limited number of air-inflated alveolar sacs during their recruitment/opening. Released ATP reached concentrations of ∼10(-6) M, relevant for autocrine/paracrine signaling, but it remained spatially restricted to single alveolar sacs or their clusters. ATP release was stimulus dependent: prolonged (100 s) inflation evoked long-lasting ATP release that terminated upon alveoli deflation/derecruitment while cyclic inflation/suction produced cyclic ATP release. With LL introduced into blood vessels, inflation induced transient ATP release in many small patchlike areas the size of alveolar sacs. Findings suggest that inflation induces ATP release in both alveoli and the surrounding blood capillary network; the functional units of ATP release presumably consist of alveolar sacs or their clusters. Our study demonstrates the feasibility of real-time ATP release imaging in ex vivo lungs and provides the first direct evidence of inflation-induced ATP release in lung air spaces and in pulmonary blood capillaries, highlighting the importance of purinergic signaling in lung function.

  10. Oral kanglaite injection (KLTI) attenuates the lung cancer-promoting effect of high-fat diet (HFD)-induced obesity

    PubMed Central

    Guo, Zhenzhen; Zheng, Yaqiu; Geng, Shengnan; Meng, Mingjing; Du, Zhenhua; Lin, Haihong; Duan, Yongjian; Du, Gangjun

    2016-01-01

    Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC allograft model by increasing oxidative stress and cellular signaling molecules including JAK, STAT3, Akt, mTOR, NF-κB and cyclin D1. These changes resulted in increases in vascular disruption and the lung water content, thereby promoting lung epithelial proliferation and the epithelial-mesenchymal transition (EMT) during carcinogenesis. Chronic KLTI treatment substantially prevented the weight gain resulting from HFD consumption, thereby reversing the metabolic dysfunction-related physiological changes and reducing susceptibility to lung carcinogenesis. In vitro, KLTI significantly suppressed the proliferation and induced apoptosis and differentiation in 3T3-L1 preadipocyte cells and attenuated endothelial cell permeability in HUVECs. Our study indicates that there is a potential relationship between obesity and lung cancer. This is the first study to show that obesity can directly accelerate carcinogen-induced lung cancer progression and that KLTI can decrease the lung cancer-promoting effect of HFD-induced obesity. PMID:27528218

  11. Antibiotic drug levofloxacin inhibits proliferation and induces apoptosis of lung cancer cells through inducing mitochondrial dysfunction and oxidative damage.

    PubMed

    Song, Meijun; Wu, Hongcheng; Wu, Shibo; Ge, Ting; Wang, Guoan; Zhou, Yingyan; Sheng, Shimo; Jiang, Jingbo

    2016-12-01

    Lung cancer is the leading cause of cancer death worldwide and its clinical management remains challenge. Here, we repurposed antibiotic levofloxacin for lung cancer treatment. We show that levofloxacin is effectively against a panel of lung cancer cell lines via inhibiting proliferation and inducing apoptosis, regardless of cellular origin and genetic pattern, in in vitro cell culture system and in vivo xenograft lung tumor model. Mechanistically, levofloxacin inhibits activities of mitochondrial electron transport chain complex I and III, leading to inhibition of mitochondrial respiration and reduction of ATP production. In addition, levofloxacin significantly increases levels of ROS, mitochondrial superoxide and hydrogen peroxide in vitro and oxidative stress markers (HEL and 4-HNE) in vivo. Antioxidants, such as NAC and vitamin C, prevent the inhibitory effects of levofloxacin, confirming the induction of oxidative damage as the mechanism of its action in lung cancer cells. Our work demonstrates that levofloxacin is a useful addition to the treatment of lung cancer. Our work also suggests that targeting mitochondria may be an alternative therapeutic strategy for lung cancer treatment.

  12. Consecutive CT-guided core needle tissue biopsy of lung lesions in the same dog at different phases of radiation-induced lung injury

    PubMed Central

    Yin, Zhongyuan; Deng, Sisi; Liang, Zhiwen; Wang, Qiong

    2016-01-01

    This project aimed to set up a Beagle dog model of radiation-induced lung injury in order to supply fresh lung tissue samples in the different injury phases for gene and protein research. Three dogs received 18 Gy X-ray irradiation in one fraction, another three dogs received 8 Gy in each of three fractions at weekly intervals, and one control dog was not irradiated. Acute pneumonitis was observed during the first 3 months after radiation, and chronic lung fibrosis was found during the next 4–12 months in all the dogs exposed to radiation. CT-guided core needle lung lesion biopsies were extracted from each dog five times over the course of 1 year. The dogs remained healthy after each biopsy, and 50–100 mg fresh lung lesion tissues were collected in each operation. The incidence of pneumothorax and hemoptysis was 20% and 2.8%, respectively, in the 35 tissue biopsies. A successful and stable radiation-induced lung injury dog model was established. Lung lesion tissue samples from dogs in acute stage, recovery stage and fibrosis stage were found to be sufficient to support cytology, genomics and proteomics research. This model safely supplied fresh tissue samples that would allow future researchers to more easily explore and develop treatments for radiation-induced lung injury. PMID:27422930

  13. Cyclin D expression in plutonium-induced lung tumors in F344 rats

    SciTech Connect

    Hahn, F.F.; Kelly, G.

    1995-12-01

    The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

  14. Resuscitation and quantification of stressed Escherichia coli K12 NCTC8797 in water samples.

    PubMed

    Ozkanca, R; Saribiyik, F; Isik, K; Sahin, N; Kariptas, E; Flint, K P

    2009-01-01

    The aim of this study was to investigate the impact on numbers of using different media for the enumeration of Escherichia coli subjected to stress, and to evaluate the use of different resuscitation methods on bacterial numbers. E. coli was subjected to heat stress by exposure to 55 degrees C for 1h or to light-induced oxidative stress by exposure to artificial light for up to 8h in the presence of methylene blue. In both cases, the bacterial counts on selective media were below the limits of detection whereas on non-selective media colonies were still produced. After resuscitation in non-selective media, using a multi-well MPN resuscitation method or resuscitation on membrane filters, the bacterial counts on selective media matched those on non-selective media. Heat and light stress can affect the ability of E. coli to grow on selective media essential for the enumeration as indicator bacteria. A resuscitation method is essential for the recovery of these stressed bacteria in order to avoid underestimation of indicator bacteria numbers in water. There was no difference in resuscitation efficiency using the membrane filter and multi-well MPN methods. This study emphasises the need to use a resuscitation method if the numbers of indicator bacteria in water samples are not to be underestimated. False-negative results in the analysis of drinking water or natural bathing waters could have profound health effects.

  15. High-fat diet induces lung remodeling in ApoE-deficient mice: an association with an increase in circulatory and lung inflammatory factors.

    PubMed

    Naura, Amarjit S; Hans, Chetan P; Zerfaoui, Mourad; Errami, Youssef; Ju, Jihang; Kim, Hogyoung; Matrougui, Khalid; Kim, Jong G; Boulares, A Hamid

    2009-11-01

    Hypercholesterolemia is increasingly considered the basis for not only cardiovascular pathologies but also several complications affecting other organs such as lungs. In this study, we examined the effect of hypercholesterolemia on lung integrity using a mouse model (ApoE(-/-)) of high-fat (HF) diet-induced atherosclerosis. A 12-week HF diet regimen induced systemic production of TNF-alpha, IFN-gamma, GMC-SF, RANTES, IL-1alpha, IL-2 and IL-12 with TNF-alpha as the predominant cytokine in ApoE(-/-) mice. Concomitantly, TNF-alpha, IFN-gamma and MIP-1alpha were detected in brochoalveolar lavage (BAL) fluids of these mice, coinciding with lung inflammation consisting primarily of monocytes/macrophages. Such lung inflammation correlated with marked collagen deposition and an increase in matrix metalloproteinase-9 activity in ApoE(-/-)mice without mucus production. Although TGF-beta1 was undetectable in the BAL fluid of ApoE(-/-) mice on HF diet, it showed a much wider tissue distribution compared with that of control animals. Direct exposure of smooth muscle cells to oxidized-LDL, in vitro, induced a time-dependent expression of TNF-alpha. Direct intratracheal TNF-alpha-administration induced a lung inflammation pattern in wild-type mice that was strikingly similar to that induced by HF diet in ApoE(-/-) mice. TNF-alpha administration induced expression of several factors known to be critically involved in lung remodeling, such as MCP-1, IL-1beta, TGF-beta1, adhesion molecules, collagen type-I and TNF-alpha itself in the lungs of treated mice. These results suggest that hypercholesterolemia may promote chronic inflammatory conditions in lungs that are conducive to lung remodeling potentially through TNF-alpha-mediated processes.

  16. Resuscitation with lactated ringer's does not increase inflammatory response in a Swine model of uncontrolled hemorrhagic shock.

    PubMed

    Watters, Jennifer M; Brundage, Susan I; Todd, S Rob; Zautke, Nathan A; Stefater, J A; Lam, J C; Muller, Patrick J; Malinoski, Darren; Schreiber, Martin A

    2004-09-01

    Lactated Ringer's (LR) and normal saline (NS) are widely and interchangeably used for resuscitation of trauma victims. Studies show LR to be superior to NS in the physiologic response to resuscitation. Recent in vitro studies demonstrate equivalent effects of LR and NS on leukocytes. We aimed to determine whether LR resuscitation would produce an equivalent inflammatory response compared with normal saline (NS) resuscitation in a clinically relevant swine model of uncontrolled hemorrhagic shock. Thirty-two swine were randomized. Control animals (n = 6) were sacrificed following induction of anesthesia for baseline data. Sham animals (n = 6) underwent laparotomy and 2 h of anesthesia. Uncontrolled hemorrhagic shock animals (n = 10/group) underwent laparotomy, grade V liver injury, and blinded resuscitation with LR or NS to maintain baseline blood pressure for 1.5 h before sacrifice. Lung was harvested, and tissue mRNA levels of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and tumor necrosis factor-alpha (TNF-alpha) were determined using quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR). Sections of lung were processed and examined for neutrophils sequestered within the alveolar walls. Cytokine analysis showed no difference in IL-6 gene transcription in any group (P = 0.99). Resuscitated swine had elevated G-CSF and TNF-alpha gene transcription, but LR and NS groups were not different from each other (P= 0.96 and 0.10, respectively). Both resuscitation groups had significantly more alveolar neutrophils present than controls (P < 0.01) and shams (P < 0.05) but were not different from one another (P= 0.83). LR and NS resuscitation have equivalent effects on indices of inflammation in the lungs in our model of uncontrolled hemorrhagic shock.

  17. BURN-INDUCED ACUTE LUNG INJURY REQUIRES A FUNCTIONAL TOLL-LIKE RECEPTOR 4

    PubMed Central

    Krzyzaniak, Michael; Cheadle, Gerald; Peterson, Carrie; Loomis, William; Putnam, James; Wolf, Paul; Baird, Andrew; Eliceiri, Brian; Bansal, Vishal; Coimbra, Raul

    2014-01-01

    The role of the Toll-like receptor 4 (TLR4), a component of the innate immune system, in the development of burn-induced acute lung injury (ALI) has not been completely defined. Recent data suggested that an intact TLR4 plays a major role in the development of organ injury in sterile inflammation. We hypothesized that burn-induced ALI is a TLR4-dependent process. Male C57BL/6J (TLR4 wild-type [WT]) and C57BL/10ScN (TLR4 knockout [KO]) mice were subjected to a 30% total body surface area steam burn. Animals were killed at 6 and 24 h after the insult. Lung specimens were harvested for histological examination after hematoxylin-eosin staining. In addition, lung myeloperoxidase (MPO) and intercellular adhesion molecule 1 immunostaining was performed. Lung MPO was measured by an enzymatic assay. Total lung keratinocyte-derived chemoattractant (IL-8) content was measured by enzyme-linked immunosorbent assay. Western blot was performed to quantify phosphorylated IκBα, phosphorylated nuclear factor κB p65 (NF-κBp65), and high mobility group box 1 expression. Acute lung injury, characterized by thickening of the alveolar-capillary membrane, hyaline membrane formation, intraalveolar hemorrhage, and neutrophil infiltration, was seen in WT but not KO animals at 24 h. Myeloperoxidase and intercellular adhesion molecule 1 immunostaining of KO animals was also similar to sham but elevated in WT animals. In addition, a reduction in MPO enzymatic activity was observed in KO mice as well as a reduction in IL-8 levels compared with their WT counterparts. Burn-induced ALI develops within 24 h after the initial thermal insult in our model. Toll-like receptor 4 KO animals were clearly protected and had a much less severe lung injury. Our data suggest that burn-induced ALI is a TLR4-dependent process. PMID:21330948

  18. PKCδ/midkine pathway drives hypoxia-induced proliferation and differentiation of human lung epithelial cells.

    PubMed

    Zhang, Hanying; Okamoto, Miyako; Panzhinskiy, Evgeniy; Zawada, W Michael; Das, Mita

    2014-04-01

    Epithelial cells are key players in the pathobiology of numerous hypoxia-induced lung diseases. The mechanisms mediating such hypoxic responses of epithelial cells are not well characterized. Earlier studies reported that hypoxia stimulates protein kinase C (PKC)δ activation in renal cancer cells and an increase in expression of a heparin-binding growth factor, midkine (MK), in lung alveolar epithelial cells. We reasoned that hypoxia might regulate MK levels via a PKCδ-dependent pathway and hypothesized that PKCδ-driven MK expression is required for hypoxia-induced lung epithelial cell proliferation and differentiation. Replication of human lung epithelial cells (A549) was significantly increased by chronic hypoxia (1% O2) and was dependent on expression of PKCδ. Hypoxia-induced proliferation of epithelial cells was accompanied by translocation of PKCδ from Golgi into the nuclei. Marked attenuation in MK protein levels by rottlerin, a pharmacological antagonist of PKC, and by small interfering RNA-targeting PKCδ, revealed that PKCδ is required for MK expression in both normoxic and hypoxic lung epithelial cells. Sequestering MK secreted into the culture media with a neutralizing antibody reduced hypoxia-induced proliferation demonstrating that an increase in MK release from cells is linked with epithelial cell division under hypoxia. In addition, recombinant MK accelerated transition of hypoxic epithelial cells to cells of mesenchymal phenotype characterized by elongated morphology and increased expression of mesenchymal markers, α-smooth muscle actin, and vimentin. We conclude that PKCδ/MK axis mediates hypoxic proliferation and differentiation of lung epithelial cells. Manipulation of PKCδ and MK activity in epithelial cells might be beneficial for the treatment of hypoxia-mediated lung diseases.

  19. PKCδ/midkine pathway drives hypoxia-induced proliferation and differentiation of human lung epithelial cells

    PubMed Central

    Zhang, Hanying; Okamoto, Miyako; Panzhinskiy, Evgeniy; Zawada, W. Michael

    2014-01-01

    Epithelial cells are key players in the pathobiology of numerous hypoxia-induced lung diseases. The mechanisms mediating such hypoxic responses of epithelial cells are not well characterized. Earlier studies reported that hypoxia stimulates protein kinase C (PKC)δ activation in renal cancer cells and an increase in expression of a heparin-binding growth factor, midkine (MK), in lung alveolar epithelial cells. We reasoned that hypoxia might regulate MK levels via a PKCδ-dependent pathway and hypothesized that PKCδ-driven MK expression is required for hypoxia-induced lung epithelial cell proliferation and differentiation. Replication of human lung epithelial cells (A549) was significantly increased by chronic hypoxia (1% O2) and was dependent on expression of PKCδ. Hypoxia-induced proliferation of epithelial cells was accompanied by translocation of PKCδ from Golgi into the nuclei. Marked attenuation in MK protein levels by rottlerin, a pharmacological antagonist of PKC, and by small interfering RNA-targeting PKCδ, revealed that PKCδ is required for MK expression in both normoxic and hypoxic lung epithelial cells. Sequestering MK secreted into the culture media with a neutralizing antibody reduced hypoxia-induced proliferation demonstrating that an increase in MK release from cells is linked with epithelial cell division under hypoxia. In addition, recombinant MK accelerated transition of hypoxic epithelial cells to cells of mesenchymal phenotype characterized by elongated morphology and increased expression of mesenchymal markers, α-smooth muscle actin, and vimentin. We conclude that PKCδ/MK axis mediates hypoxic proliferation and differentiation of lung epithelial cells. Manipulation of PKCδ and MK activity in epithelial cells might be beneficial for the treatment of hypoxia-mediated lung diseases. PMID:24500281

  20. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation.

    PubMed

    Sunil, Vasanthi R; Vayas, Kinal N; Cervelli, Jessica A; Malaviya, Rama; Hall, LeRoy; Massa, Christopher B; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2014-08-01

    Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.

  1. Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma (EPR-CAT)

    DTIC Science & Technology

    2013-10-01

    hypothermia 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT...Emergency Preservation and Resuscitation (EPR) was developed to rapidly preserve the organism during ischemia, using hypothermia , drugs, and fluids, to “buy...time” for transport and resuscitative surgery. The purpose of this study is to test the feasibility of rapidly inducing profound hypothermia

  2. Enhancement of ozone-induced lung injury by exercise

    SciTech Connect

    Mautz, W.J.; McClure, T.R.; Reischl, P.; Phalen, R.F.; Crocker, T.T.

    1985-01-01

    Rats were exposed for up to 3.75 h to 0.20-0.80 ppm O/sub 3/ under conditions of rest and treadmill exercise up to 30 m/min, 20% grade, to assess the importance of exposure duration, O/sub 3/ concentration, and exercise on lung tissue injury. Focal lung parenchymal lesions increased in abundance and severity in response to the three variables; however, exercise was the most important. Lesion response to exercise was greater than that predicted by a simple proportion to estimated effective dose of O/sub 3/. The results emphasize the importance of including exercise in assessment of possible adverse health effects of exposure to airborne pollutants.

  3. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.

    PubMed

    Takyar, Seyedtaghi; Zhang, Yi; Haslip, Maria; Jin, Lei; Shan, Peiying; Zhang, Xuchen; Lee, Patty J

    2016-03-01

    TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.

  4. Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells.

    PubMed

    Babar, Imran A; Czochor, Jennifer; Steinmetz, Allison; Weidhaas, Joanne B; Glazer, Peter M; Slack, Frank J

    2011-11-15

    miR-155 is a prominent microRNA (miRNA) that regulates genes involved in immunity and cancer-related pathways. miR-155 is overexpressed in lung cancer, which correlates with poor patient prognosis. It is unclear how miR-155 becomes increased in lung cancers and how this increase contributes to reduced patient survival. Here, we show that hypoxic conditions induce miR-155 expression in lung cancer cells and trigger a corresponding decrease in a validated target, FOXO3A. Furthermore, we find that increased levels of miR-155 radioprotects lung cancer cells, while inhibition of miR-155 radiosensitizes these cells. Moreover, we reveal a therapeutically important link between miR-155 expression, hypoxia, and irradiation by demonstrating that anti-miR-155 molecules also sensitize hypoxic lung cancer cells to irradiation. Our study helps explain how miR-155 becomes elevated in lung cancers, which contain extensive hypoxic microenvironments, and demonstrates that inhibition of miR-155 may have important therapeutic potential as a means to radiosensitize hypoxic lung cancer cells.

  5. Resolution of experimental lung injury by Monocyte-derived inducible nitric oxide synthase (iNOS)

    PubMed Central

    D’Alessio, Franco R.; Tsushima, Kenji; Aggarwal, Neil R.; Mock, Jason R.; Eto, Yoshiki; Garibaldi, Brian T.; Files, Daniel C.; Avalos, Claudia R.; Rodriguez, Jackie V.; Waickman, Adam T.; Reddy, Sekhar P.; Pearse, David B.; Sidhaye, Venkataramana K.; Hassoun, Paul M.; Crow, Michael T.; King, Landon S.

    2012-01-01

    While early events in the pathogenesis of acute lung injury (ALI) have been defined, little is known about mechanisms mediating resolution. To search for determinants of resolution, we exposed wild type (WT) mice to intratracheal lipopolysacaccharide (i.t. LPS) and assessed the response at intervals to day 10, when injury had resolved. Inducible nitric oxide synthase (iNOS) was significantly upregulated in the lung at day 4 after LPS. When iNOS−/− mice were exposed to i.t. LPS, early lung injury was attenuated, however recovery was markedly impaired compared to wild type (WT) mice. iNOS−/− mice had increased mortality and sustained increases in markers of lung injury. Adoptive transfer of WT (iNOS+/+) bone marrow-derived monocytes or direct adenoviral gene delivery of iNOS into injured iNOS−/− mice restored resolution of ALI. Irradiated bone marrow chimeras confirmed the protective effects of myeloid-derived iNOS, but not of epithelial iNOS. Alveolar macrophages exhibited sustained expression of co-signalling molecule CD86 in iNOS−/− mice compared to WT mice. Antibody-mediated blockade of CD86 in iNOS−/− mice improved survival and enhanced resolution of lung inflammation. Our findings show that monocyte-derived iNOS plays a pivotal role in mediating resolution of ALI by modulating lung immune responses, thus facilitating clearance of alveolar inflammation and promoting lung repair. PMID:22844117

  6. Lipopolysaccharide-Induced Lung Injury Is Independent of Serum Vitamin D Concentration

    PubMed Central

    Klaff, Lindy S.; Gill, Sean E.; Wisse, Brent E.; Mittelsteadt, Kristen; Matute-Bello, Gustavo; Chen, Peter; Altemeier, William A.

    2012-01-01

    Vitamin D deficiency is increasing in incidence around the world. Vitamin D, a fat-soluble vitamin, has documented effects on the innate and adaptive immune system, including macrophage and T regulatory (Treg) cell function. Since Treg cells are important in acute lung injury resolution, we hypothesized that vitamin D deficiency increases the severity of injury and delays injury resolution in lipopolysaccharide (LPS) induced acute lung injury. Vitamin D deficient mice were generated, using C57BL/6 mice, through diet modification and limited exposure to ultraviolet light. At 8 weeks of age, vitamin D deficient and sufficient mice received 2.5 g/kg of LPS or saline intratracheal. At 1 day, 3 days and 10 days, mice were anesthetized and lung elastance measured. Mice were euthanized and bronchoalveolar lavage fluid, lungs and serum were collected. Ex vivo neutrophil chemotaxis was evaluated, using neutrophils from vitamin D sufficient and deficient mice exposed to the chemoattractants, KC/CXCL1 and C5a, and to bronchoalveolar lavage fluid from LPS-exposed mice. We found no difference in the degree of lung injury. Leukocytes were mildly decreased in the bronchoalveolar fluid of vitamin D deficient mice at 1 day. Ex-vivo, neutrophils from vitamin D deficient mice showed impaired chemotaxis to KC but not to C5a. Vitamin D deficiency modestly impairs neutrophil chemotaxis; however, it does not affect lung injury or its resolution in an LPS model of acute lung injury. PMID:23185294

  7. Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

    PubMed Central

    Unemori, E N; Pickford, L B; Salles, A L; Piercy, C E; Grove, B H; Erikson, M E; Amento, E P

    1996-01-01

    Pulmonary fibrosis is the common end stage of a number of pneumopathies. In this study, we examined the ability of the human cytokine, relaxin, to block extracellular matrix deposition by human lung fibroblasts in vitro, and to inhibit lung fibrosis in a bleomycin-induced murine model. In vitro, relaxin (1-100 ng/ml) inhibited the transforming growth factor-beta-mediated over-expression of interstitial collagen types I and III by human lung fibroblasts by up to 45% in a dose-dependent manner. Relaxin did not affect basal levels of collagen expression in the absence of TGF-beta-induced stimulation. Relaxin also blocked transforming growth factor-beta-induced upregulation of fibronectin by 80% at the highest relaxin dose tested (100 ng/ml). The expression of matrix metalloproteinase-1, or procollagenase, was stimulated in a biphasic, dose-dependent manner by relaxin. In vivo, relaxin, at a steady state circulating concentration of approximately 50 ng/ml, inhibited bleomycin-mediated alveolar thickening compared with the vehicle only control group (P < 0.05). Relaxin also restored bleomycin-induced collagen accumulation, as measured by lung hydroxyproline content, to normal levels (P < 0.05). In summary, relaxin induced a matrix degradative phenotype in human lung fibroblasts in vitro and inhibited bleomycin-induced fibrosis in a murine model in vivo. These data indicate that relaxin may be efficacious in the treatment of pathologies characterized by lung fibrosis. PMID:8981919

  8. Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner

    PubMed Central

    Tao, Shasha; Rojo de la Vega, Montserrat; Quijada, Hector; Wondrak, Georg T.; Wang, Ting; Garcia, Joe G. N.; Zhang, Donna D.

    2016-01-01

    Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2+/+ but not in Nrf2−/− mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment. PMID:26729554

  9. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis

    PubMed Central

    Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis. PMID:27992456

  10. The role of alveolar epithelium in radiation-induced lung injury.

    PubMed

    Almeida, Celine; Nagarajan, Devipriya; Tian, Jian; Leal, Sofia Walder; Wheeler, Kenneth; Munley, Michael; Blackstock, William; Zhao, Weiling

    2013-01-01

    Pneumonitis and fibrosis are major lung complications of irradiating thoracic malignancies. In the current study, we determined the effect of thoracic irradiation on the lungs of FVB/N mice. Survival data showed a dose-dependent increase in morbidity following thoracic irradiation with single (11-13 Gy) and fractionated doses (24-36 Gy) of (137)Cs γ-rays. Histological examination showed a thickening of vessel walls, accumulation of inflammatory cells, collagen deposition, and regional fibrosis in the lungs 14 weeks after a single 12 Gy dose and a fractionated 30 Gy dose; this damage was also seen 5 months after a fractionated 24 Gy dose. After both single and fractionated doses, i] aquaporin-5 was markedly decreased, ii] E-cadherin was reduced and iii] prosurfactant Protein C (pro-SP-c), the number of pro-SP-c(+) cells and vimentin expression were increased in the lungs. Immunofluorescence analysis revealed co-localization of pro-SP-c and α-smooth muscle actin in the alveoli after a single dose of 12 Gy. These data suggest that, i] the FVB/N mouse strain is sensitive to thoracic radiation ii] aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury; and iii] the epithelial-to-mesenchymal transition may play an important role in the development of radiation-induced lung fibrosis.

  11. Leptin attenuates lipopolysaccharide or oleic acid-induced acute lung injury in mice.

    PubMed

    Dong, Hai-Ying; Xu, Min; Ji, Zhen-Yu; Wang, Yan-Xia; Dong, Ming-Qing; Liu, Man-Ling; Xu, Dun-Quan; Zhao, Peng-Tao; Liu, Yi; Luo, Ying; Niu, Wen; Zhang, Bo; Ye, Jing; Li, Zhi-Chao

    2013-12-01

    Leptin is reported to be involved in acute lung injury (ALI). However, the role and underlying mechanisms of leptin in ALI remain unclear. The aim of this study was to determine whether leptin deficiency promoted the development of ALI. LPS or oleic acid (OA) were administered to wild-type and leptin deficient (ob/ob) mice to induce ALI. Leptin level, survival rate, and lung injury were examined. Results showed that leptin levels were predominantly increased in the lung, but also in the heart, liver, kidney, and adipose tissue after LPS adminiatration. Compared with wild-type mice, LPS- or OA-induced lung injury was worse and the survival rate was lower in ob/ob mice. Moreover, leptin deficiency promoted the release of proinflammatory cytokines. Exogenous administration of leptin reduced lethality in ob/ob mice and ameliorated lung injury partly through inhibiting the activation of NF-κB, p38, and ERK pathways. These results indicated that leptin deficiency contributed to the development of lung injury by enhancing inflammatory response, and a high level of leptin improved survival and protected against ALI.

  12. Nicotine prevents the apoptosis induced by menadione in human lung cancer cells

    SciTech Connect

    Zhang Tao; Lu Heng; Shang Xuan; Tian Yihao; Zheng Congyi; Wang Shiwen; Cheng Hanhua . E-mail: hhcheng@whu.edu.cn; Zhou Rongjia . E-mail: rjzhou@whu.edu.cn

    2006-04-14

    Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on lung cancer and other illnesses. Nicotine is a main component in tobacco and has been implicated as a potential factor in the pathogenesis of human lung cancer. However, the mechanism of nicotine action in the development of lung cancer remains largely unknown. In the present study, we designed a nicotine-apoptosis system, by pre-treatment of nicotine making lung cancer cell A549 to be in a physiological nicotine environment, and observed that nicotine promoted cell proliferation and prevented the menadione-induced apoptosis, and exerts its role of anti-apoptosis by shift of apoptotic stage induced by menadione from late apoptotic stage to early apoptotic stage, in which NF-{kappa}B was up-regulated. Interference analysis of NF-{kappa}B in A549 cells showed that knock down of NF-{kappa}B resulted in apoptosis promotion and counteracted the protective effect of nicotine. The findings suggest that nicotine has potential effect in lung cancer genesis, especially in patients with undetectable early tumor development and development of specific NF-{kappa}B inhibitors would represent a potentially exciting new pharmacotherapy for tobacco-related lung cancer.

  13. Hypoxia induced CCL28 promotes angiogenesis in lung adenocarcinoma by targeting CCR3 on endothelial cells.

    PubMed

    Huang, Guichun; Tao, Leilei; Shen, Sunan; Chen, Longbang

    2016-06-02

    Tumor hypoxia is one of the important features of lung adenocarcinoma. Chemokines might mediate the effects caused by tumor hypoxia. As confirmed in tumor tissue and serum of patients, CC chemokine 28 (CCL28) was the only hypoxia induced chemokine in lung adenocarcinoma cells. CCL28 could promote tube formation, migration and proliferation of endothelial cells. In addition, angiogenesis was promoted by CCL28 in the chick chorioallantoic membrane and matrigel implanted in dorsal back of athymic nude mice (CByJ.Cg-Foxn1(nu)/J). Tumors formed by lung adenocarcinoma cells with high expression of CCL28 grew faster and had a higher vascular density, whereas tumor formation rate of lung adenocarcinoma cells with CCL28 expression knockdown was quite low and had a lower vascular density. CCR3, receptor of CCL28, was highly expressed in vascular endothelial cells in lung adenocarcinoma when examining by immunohistochemistry. Further signaling pathways in endothelial cells, modulated by CCL28, were analyzed by Phosphorylation Antibody Array. CCL28/CCR3 signaling pathway could bypass that of VEGF/VEGFR on the levels of PI3K-Akt, p38 MAPK and PLC gamma. The effects could be neutralized by antibody against CCR3. In conclusion, CCL28, as a chemokine induced by tumor hypoxia, could promote angiogenesis in lung adenocarcinoma through targeting CCR3 on microvascular endothelial cells.

  14. Mechanical Ventilation Induces an Inflammatory Response in Preinjured Lungs in Late Phase of Sepsis.

    PubMed

    Xuan, Wei; Zhou, Quanjun; Yao, Shanglong; Deng, Qingzhu; Wang, Tingting; Wu, Qingping

    2015-01-01

    Mechanical ventilation (MV) may amplify the lung-specific inflammatory response in preinjured lungs by elevating cytokine release and augmenting damage to the alveolar integrity. In this study, we test the hypothesis that MV exerts different negative impacts on inflammatory response at different time points of postlung injury. Basic lung injury was induced by cecal ligation and puncture (CLP) surgery in rats. Physiological indexes including blood gases were monitored during MV and samples were assessed following each experiment. Low V T (tidal volume) MV caused a slight increase in cytokine release and tissue damage at day 1 and day 4 after sepsis induced lung injury, while cytokine release from the lungs in the two moderately ventilated V T groups was amplified. Interestingly, in the two groups where rats received low V T MV, we found that infiltration of inflammatory cells was only profound at day 4 after CLP. Marked elevation of protein leakage indicated a compromise in alveolar integrity in rats that received moderate V T MV at day 4 following CLP, correlating with architectural damage to the alveoli. Our study indicates that preinjured lungs are more sensitive to mechanical MV at later phases of sepsis, and this situation may be a result of differing immune status.

  15. Erdosteine ameliorates lung injury induced by transient aortic occlusion in rats.

    PubMed

    Kurtoglu, Tunay; Sacar, Mustafa; Inan, Bilal Kaan; Duver, M Harun; Guler, Adem; Ucak, Alper; Us, Melih Hulusi; Yilmaz, Ahmet Turan

    2007-01-01

    The aim of this experimental study was to evaluate the protective effect of erdosteine on lung injury induced by ischaemia-reperfusion (IR) of the lower extremities of rats. Wistar albino rats (n = 21) were divided into three groups. In the IR group (n = 7), the aorta was cross-clamped for two hours, followed by one hour of reperfusion. In the erdosteine group (n = 7), animals were pretreated with erdosteine 100 mg/kg daily via gastric lavage, starting three days before aortic occlusion. In the control group (n 5 7), the lungs were removed and blood samples were taken immediately after sternotomy. No treatment was given in the control and IR groups. After both lungs were removed, biochemical parameters were measured and broncho-alveolar lavage (BAL ) assessment was made. MDA levels and MPO activities in the lung tissue were significantly reduced in the erdosteine group compared to the IR group. BAL assessment revealed decreased neutrophil counts in the erdosteine-treated group. Pretreatment of animals with erdosteine significantly attenuated transient aortic occlusion-induced remote lung injury, characterised by leukocyte accumulation and lipid peroxidation. The results suggest that erdosteine may be beneficial in amelioration of lung injury caused by IR.

  16. Methylene Blue for Vasoplegia When on Cardiopulmonary Bypass During Double-Lung Transplantation.

    PubMed

    Carley, Michelle; Schaff, Jacob; Lai, Terrance; Poppers, Jeremy

    2015-10-15

    Vasoplegia syndrome, characterized by hypotension refractory to fluid resuscitation or high-dose vasopressors, low systemic vascular resistance, and normal-to-increased cardiac index, is associated with increased morbidity and mortality after cardiothoracic surgery. Methylene blue inhibits inducible nitric oxide synthase and guanylyl cyclase, and has been used to treat vasoplegia during cardiopulmonary bypass. However, because methylene blue is associated with increased pulmonary vascular resistance, its use in patients undergoing lung transplantion has been limited. Herein, we report the use of methylene blue to treat refractory vasoplegia during cardiopulmonary bypass in a patient undergoing double-lung transplantation.

  17. Therapeutic Potential of Lung Epithelial Progenitor Cells Derived from Embryonic and Induced Pluripotent Stem Cells

    PubMed Central

    Wetsel, Rick A.; Wang, Dachun; Calame, Daniel G.

    2015-01-01

    Embryonic stem (ES) cells derived from preimplantation blastocysts and induced pluripotent stem (iPS) cells generated from somatic cell sources are pluripotent and capable of indefinite expansion in vitro. They provide a possible unlimited source of cells that could be differentiated into lung progenitor cells for potential clinical use in pulmonary regenerative medicine. Because of inherent difficulties in deriving endodermal cells from undifferentiated cell cultures, applications using lung epithelial cells derived from ES and iPS cells have lagged behind similar efforts devoted to other tissues, such as the heart and spinal cord. However, during the past several years, significant advances in culture, differentiation, and purification protocols, as well as in bioengineering methodologies, have fueled enthusiasm for the development of stem cell–based lung therapeutics. This article provides an overview of recent research achievements and discusses future technical challenges that must be met before the promise of stem cell applications for lung disease can be realized. PMID:21226612

  18. Protective effect of erdosteine against hypochlorous acid-induced acute lung injury and lipopolysaccharide-induced neutrophilic lung inflammation in mice.

    PubMed

    Hayashi, K; Hosoe, H; Kaise, T; Ohmori, K

    2000-11-01

    The effect of erdosteine, a mucoactive drug, on hypochlorous acid (HOCl)-induced lung injury, and the lipopolysaccharide (LPS)-induced increase in tumour necrosis factor-alpha (TNF-alpha) production and neutrophil recruitment into the airway, was investigated. Male BALB/c mice were orally administered erdosteine (3-100 mgkg(-1)), ambroxol hydrochloride (ambroxol) (3-30 mgkg(-1)), S-carboxymethyl-L-cysteine (S-CMC) (100-600 mgkg(-1)) or prednisolone (10 mgkg(-1)), 1 h before intratracheal injection of HOCl or LPS. In the HOCl-injected mice, erdosteine markedly suppressed increases in the ratios of lung wet weight to bodyweight and lung dry weight to bodyweight, whereas the other mucoactive drugs ambroxol and S-CMC had little effect. Erdosteine also inhibited the LPS-induced neutrophil influx, although it did not affect the increased level of TNF-alpha in the bronchoalveolar lavage fluid. The results suggest that attenuation of reactive oxygen species and neutrophil recruitment is involved in the clinical efficacy of erdosteine in the treatment of chronic bronchitis.

  19. Tristetraprolin mediates radiation-induced TNF-α production in lung macrophages.

    PubMed

    Ray, Dipankar; Shukla, Shirish; Allam, Uday Sankar; Helman, Abigail; Ramanand, Susmita Gurjar; Tran, Linda; Bassetti, Michael; Krishnamurthy, Pranathi Meda; Rumschlag, Matthew; Paulsen, Michelle; Sun, Lei; Shanley, Thomas P; Ljungman, Mats; Nyati, Mukesh K; Zhang, Ming; Lawrence, Theodore S

    2013-01-01

    The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT). Although tumor necrosis factor-alpha (TNF-α) signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP), in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy) either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy) and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (-/-) mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTP(Ser178) phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT.

  20. Bone Marrow-Derived c-kit+ Cells Attenuate Neonatal Hyperoxia-Induced Lung Injury

    PubMed Central

    Ramachandran, Shalini; Suguihara, Cleide; Drummond, Shelley; Chatzistergos, Konstantinos; Klim, Jammie; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Rodrigues, Claudia O.; McNiece, Ian K.; Hare, Joshua M.; Young, Karen C.

    2016-01-01

    Recent studies suggest that bone marrow (BM)-derived stem cells have therapeutic efficacy in neonatal hyperoxia-induced lung injury (HILI). c-kit, a tyrosine kinase receptor that regulates angiogenesis, is expressed on several populations of BM-derived cells. Preterm infants exposed to hyperoxia have decreased lung angiogenesis. Here we tested the hypothesis that administration of BM-derived c-kit+ cells would improve angiogenesis in neonatal rats with HILI. To determine whether intratracheal (IT) administration of BM-derived c-kit+ cells attenuates neonatal HILI, rat pups exposed to either normobaric normoxia (21% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to P15 were randomly assigned to receive either IT BM-derived green fluorescent protein (GFP)+ c-kit− cells (PL) or BM-derived GFP+ c-kit+ cells on P8. The effect of cell therapy on lung angiogenesis, alveolarization, pulmonary hypertension, vascular remodeling, cell proliferation, and apoptosis was determined at P15. Cell engraftment was determined by GFP immunostaining. Compared to PL, the IT administration of BM-derived c-kit+ cells to neonatal rodents with HILI improved alveolarization as evidenced by increased lung septation and decreased mean linear intercept. This was accompanied by an increase in lung vascular density, a decrease in lung apoptosis, and an increase in the secretion of proangiogenic factors. There was no difference in pulmonary vascular remodeling or the degree of pulmonary hypertension. Confocal microscopy demonstrated that 1% of total lung cells were GFP+ cells. IT administration of BM-derived c-kit+ cells improves lung alveolarization and angiogenesis in neonatal HILI, and this may be secondary to an improvement in the lung angiogenic milieu. PMID:23759597

  1. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

    PubMed Central

    Chou, Wei-Chi; Kao, Ming-Chang; Yue, Chung-Tai; Tsai, Pei-Shan; Huang, Chun-Jen

    2015-01-01

    Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR) of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group), sham-operation (Sham), or sham plus caffeine (n = 12 in each group). To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection) was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P < 0.001 and P = 0.008, resp.). Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2) and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P < 0.05). These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs. PMID:26648663

  2. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats.

    PubMed

    Chou, Wei-Chi; Kao, Ming-Chang; Yue, Chung-Tai; Tsai, Pei-Shan; Huang, Chun-Jen

    2015-01-01

    Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR) of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group), sham-operation (Sham), or sham plus caffeine (n = 12 in each group). To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection) was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P < 0.001 and P = 0.008, resp.). Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2) and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P < 0.05). These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  3. Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach.

    PubMed Central

    Schwartz, D A; Galvin, J R; Yagla, S J; Speakman, S B; Merchant, J A; Hunninghake, G W

    1993-01-01

    To assess further the clinical significance of asbestos-induced pleural fibrosis, we used a computer algorithm to reconstruct images three dimensionally from the high-resolution computerized tomography (HRCT) scan of the chest in 60 asbestos-exposed subjects. Pulmonary function tests, chest radiographs, and HRCT scans were performed on all study subjects. The volume of asbestos-induced pleural fibrosis was computed from the three-dimensional reconstruction of the HRCT scan. Among those with pleural fibrosis identified on the HRCT scan (n = 29), the volume of the pleural lesion varied from 0.01% (0.5 ml) and 7.11% (260.4 ml) of the total chest cavity. To investigate the relationship between asbestos-induced pleural fibrosis and restrictive lung function, we compared the computer-derived estimate of pleural fibrosis to the total lung capacity and found that these measures were inversely related (r = -0.40; P = 0.002). After controlling for age, height, pack-years of cigarette smoking, and the presence of interstitial fibrosis on the chest radiograph, the volume of pleural fibrosis identified on the three-dimensional reconstructed image from the HRCT scan was inversely associated with the total lung capacity (P = 0.03) and independently accounted for 9.5% of the variance of this measure of lung volume. These findings further extend the scientific data supporting an independent association between pleural fibrosis and restrictive lung function. Images PMID:8514875

  4. Xuebijing Ameliorates Sepsis-Induced Lung Injury by Downregulating HMGB1 and RAGE Expressions in Mice.

    PubMed

    Wang, Qiao; Wu, Xin; Tong, Xiaowen; Zhang, Zhiling; Xu, Bing; Zhou, Wugang

    2015-01-01

    Xuebijing (XBJ) injection, a traditional Chinese medicine, has been reported as a promising approach in the treatment of sepsis in China. However, its actual molecular mechanisms in sepsis-induced lung injury are yet unknown. Therefore, this study aimed to investigate the beneficial effects of XBJ on inflammation and the underlying mechanisms in a model of caecal ligation and puncture-(CLP-) induced lung injury. The mice were divided into CLP group, CLP+XBJ group (XBJ, 4 mL/kg per 12 hours), and sham group. The molecular and histological examinations were performed on the lung, serum, and bronchoalveolar lavage (BAL) fluid samples of mice at the points of 6, 24, and 48 hours after CLP. The results show that XBJ reduces morphological destruction and neutrophil infiltration in the alveolar space and lung wet/dry weight ratio, which improves mortality of CLP-induced lung injury. Meanwhile, XBJ treatment downregulates high mobility group box protein 1 (HMGB1) and the receptor for advanced glycation end products (RAGE) expression, as well as neutrophil counts, production of IL-1β, IL-6, and TNF-α in the BAL fluids. In conclusion, these results indicate that XBJ may reduce the mortality through inhibiting proinflammatory cytokines secretion mediated by HMGB1/RAGE axis.

  5. Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation

    PubMed Central

    SONODA, AKINAGA; NITTA, NORIHISA; TSUCHIYA, KEIKO; OTANI, HIDEJI; WATANABE, SHOBU; MUKAISHO, KENICHI; TOMOZAWA, YUKI; NAGATANI, YUKIHIRO; OHTA, SHINICHI; TAKAHASHI, MASASHI; MURATA, KIYOSHI

    2014-01-01

    Acute lung injury, a critical illness characterized by acute respiratory failure with bilateral pulmonary infiltrates, remains unresponsive to current treatments. The condition involves injury to the alveolar capillary barrier, neutrophil accumulation and the induction of proinflammatory cytokines followed by lung fibrosis. In the present study, a rabbit model of bleomycin-induced acute lung injury was established to examine the effects of asialoerythropoietin (AEP), an agent with tissue-protective activities, on pulmonary inflammation. Six Japanese white rabbits were randomly divided into two equal groups. Acute lung injury was induced in all rabbits by intratracheally injecting bleomycin. The control group was injected with bleomycin only; the experimental (AEP) group was injected intravenously with AEP (80 μg/kg) prior to the bleomycin injection. Computed tomography (CT) studies were performed seven days later. The CT inflammatory scores of areas exhibiting abnormal density and the pathological inflammatory scores were recorded as a ratio on a 7×7 mm grid. The CT and pathological inflammatory scores were significantly different between the control and AEP groups [122±10 and 16.3±1.5 (controls) vs. 71±8.5 and 9.7±1.4 (AEP), respectively; P<0.01]. Thus, the present study revealed that AEP prevents bleomycin-induced acute lung injury in rabbits. PMID:25289037

  6. The therapeutic effects of tuberostemonine against cigarette smoke-induced acute lung inflammation in mice.

    PubMed

    Jung, Kyung-Hwa; Beak, Hyunjung; Park, Soojin; Shin, Dasom; Jung, Jaehoon; Park, Sangwon; Kim, Jinju; Bae, Hyunsu

    2016-03-05

    Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking and is characterized by the destruction of lung parenchyma, structural alterations of the small airways, and systemic inflammation. Tuberostemonine (TS) is an alkaloid-type phytochemical from Stemona tuberosa. In the present study, we evaluated the anti-inflammatory effect of TS in a cigarette smoke (CS)-induced mouse model of acute lung inflammation. The mice were whole-body exposed to CS or fresh air for 7 days. TS was administered by an intraperitoneal (i.p.) injection 1h before exposure to CS. To test the effects of TS, the numbers of total cells, neutrophils, macrophages and lymphocytes in the bronchoalveolar lavage (BAL) fluid were counted. Furthermore, we measured the levels of several chemokines, such as GCP-2, MIP-3α, MCP-1 and KC, in the lung tissue. The cellular profiles and histopathological analysis demonstrated that the infiltration of peribronchial and perivascular inflammatory cells significantly decreased in the TS-treated groups compared with the CS-exposure group. The TS treatment significantly ameliorated the airway epithelial thickness induced by CS exposure and caused a significant decrement in the production of chemokines in the lung. These results suggest that TS has anti-inflammatory effects against CS-induced acute lung inflammation.

  7. [Role of polymorphonuclear neutrophil in exogenous hydrogen sulfide attenuating endotoxin-induced acute lung injury].

    PubMed

    Huang, Xin-Li; Zhou, Xiao-Hong; Zhou, Jun-Lin; Ding, Chun-Hua; Xian, Xiao-Hui

    2009-08-25

    The animal model of acute lung injury (ALI) caused by intravenous injection of lipopolysaccharides (LPS) and cultured human peripheral blood polymorphonuclear neutrophil (PMN) were used to study the effects of sodium hydrosulfide (NaHS), hydrogen sulfide (H2S) donor, on LPS-induced PMN accumulation, microvascular permeability and PMN apoptosis. Control group, NaHS group, LPS group and LPS + NaHS group were established both in in vivo and in vitro studies. Microvascular permeability, PMN accumulation in lung and apoptosis of PMN were detected. The results showed that: (1) In in vivo study, PMN accumulation in lung, the protein content in bronchoalveolar lavage fluid (BALF) and the Evans blue dye in lung tissue of LPS group were markedly higher than those of both sham operation group and LPS + NaHS group (P<0.05, P<0.01); (2) In in vitro study, the apoptotic rates of PMN in LPS group and NaHS group were significantly higher than that in control group (P<0.01), while compared with LPS group, LPS + NaHS group showed significantly higher apoptotic rate (P<0.01). These results suggest that NaHS attenuates LPS-induced microvascular permeability and alleviates ALI. PMN apoptosis induced by NaHS is possibly one of the potential mechanisms underlying the decrease of PMN accumulation in lung tissue.

  8. Spred-2 Deficiency Exacerbates Lipopolysaccharide-Induced Acute Lung Inflammation in Mice

    PubMed Central

    Xu, Yang; Ito, Toshihiro; Fushimi, Soichiro; Takahashi, Sakuma; Itakura, Junya; Kimura, Ryojiro; Sato, Miwa; Mino, Megumi; Yoshimura, Akihiko; Matsukawa, Akihiro

    2014-01-01

    Background Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation. Methods Wild-type (WT) mice and Spred-2−/− mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2−/− mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. Results LPS-induced acute lung inflammation was significantly exacerbated in Spred-2−/− mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2−/− mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. Conclusions The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the

  9. Uncoupling Protein 2 Increases Susceptibility to Lipopolysaccharide-Induced Acute Lung Injury in Mice

    PubMed Central

    Wang, Qin; Wang, Jianchun; Hu, Mingdong; Yang, Yu; Guo, Liang; Xu, Jing; Lei, Chuanjiang; Jiao, Yan; Xu, JianCheng

    2016-01-01

    Uncoupling protein 2 (UCP2) is upregulated in patients with systemic inflammation and infection, but its functional role is unclear. We up- or downregulated UCP2 expression using UCP2 recombinant adenovirus or the UCP2 inhibitor, genipin, in lungs of mice, and investigated the mechanisms of UCP2 in ALI. UCP2 overexpression in mouse lungs increased LPS-induced pathological changes, lung permeability, lung inflammation, and lowered survival rates. Furthermore, ATP levels and mitochondrial membrane potential were decreased, while reactive oxygen species production was increased. Additionally, mitogen-activated protein kinases (MAPKs) activity was elevated, which increased the sensitivity to LPS-induced apoptosis and inflammation. LPS-induced apoptosis and release of inflammatory factors were alleviated by pretreatment of the Jun N-terminal kinase (JNK) inhibitor SP600125 or the p38 MAPK inhibitor SB203580, but not by the extracellular signal-regulated kinase (ERK) inhibitor PD98059 in UCP2-overexpressing mice. On the other hand, LPS-induced alveolar epithelial cell death and inflammation were attenuated by genipin. In conclusion, UCP2 increased susceptibility to LPS-induced cell death and pulmonary inflammation, most likely via ATP depletion and activation of MAPK signaling following ALI in mice. PMID:27057102

  10. Salvianolic acid B attenuates lung inflammation induced by cigarette smoke in mice.

    PubMed

    Zhang, Dong-Fang; Zhang, Jin; Li, Ran

    2015-08-15

    Salvianolic acid B (Sal B), a bioactive compound isolated from the Chinese herb Radix Salviae Miltiorrhizae, has been reported to exhibit anti-inflammatory and anti-oxidantive effects. The aim of this study was to investigate the protective effects of Sal B on cigarette smoke (CS)-induced acute lung inflammation. Sal B was given intraperitoneally (i.p.) to mice 1h before CS exposure daily for four consecutive days. Bronchoalveolar lavage fluid (BALF) was collected to assess the levels of inflammatory cytokines and cell counts. Lung tissues were used to analysis pathological changes, total glutathione (GSH), nuclear factor erythroid-2 related factor 2 (Nrf-2), and nuclear factor-kappa B (NF-κB) expression. The results showed that Sal B inhibited CS-induced lung pathological changes, the infiltration of inflammatory cells, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein 1 (MCP-1) productions. Sal B also up-regulated CS-induced total glutathione (GSH) production. Furthermore, Sal B was found to up-regulate Nrf-2, hemeoxygenase1 (HO1) expression and suppress CS-induced NF-κB activation. In conclusion, the current study demonstrated that Sal B exhibited a protective effect on CS-induced lung injury and the possible mechanism was involved in activating Nrf-2 and inhibiting NF-κB activation.

  11. Protective Effect of Isorhamnetin on Lipopolysaccharide-Induced Acute Lung Injury in Mice.

    PubMed

    Yang, Bo; Li, Xiao-Ping; Ni, Yun-Feng; Du, Hong-Yin; Wang, Rong; Li, Ming-Jiang; Wang, Wen-Chen; Li, Ming-Ming; Wang, Xu-Hui; Li, Lei; Zhang, Wei-Dong; Jiang, Tao

    2016-02-01

    Isorhamnetin has been reported to have anti-inflammatory, anti-oxidative, and anti-proliferative effects. The aim of this study was to investigate the protective effect of isorhamnetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice by inhibiting the expression of cyclooxygenase-2 (COX-2). The effects of isorhamnetin on LPS-induced lung pathological damage, wet/dry ratios and the total protein level in bronchoalveolar lavage fluid (BALF), inflammatory cytokine release, myeloperoxidase (MPO) and superoxide dismutase (SOD) activities, and malondialdehyde (MDA) level were examined. In addition, the COX-2 activation in lung tissues was detected by Western blot. Isorhamnetin pretreatment improved the mice survival rates. Moreover, isorhamnetin pretreatment significantly attenuated edema and the pathological changes in the lung and inhibited protein extravasation in BALF. Isorhamnetin also significantly decreased the levels of inflammatory cytokines in BALF. In addition, isorhamnetin markedly prevented LPS-induced oxidative stress. Furthermore, isorhamnetin pretreatment significantly suppressed LPS-induced activation of COX-2. Isorhamnetin has been demonstrated to protect mice from LPS-induced ALI by inhibiting the expression of COX-2.

  12. Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation

    PubMed Central

    Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

    2017-01-01

    Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway. PMID:27922691

  13. Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation.

    PubMed

    Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

    2017-01-01

    Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway.

  14. The Protective Effect of Sodium Ferulate and Oxymatrine Combination on Paraquat-induced Lung Injury

    PubMed Central

    Wang, Wei; Pei, Xiaokun; Xu, Mengxin; Sun, Songmei; Zhang, Chunlei; Mu, Keying; Liu, Zhifeng

    2015-01-01

    Experimental evidence suggested that sodium ferulate (SF) and oxymatrine (OMT) combination had synergistic anti-inflammatory and antioxidant effects. We hypothesized that SF and OMT combination treatment might have protective effects on paraquat-induced acute lung injury. In our study, the Swiss mice were randomly divided into seven groups, including control, paraquat (PQ), SF (6.2 mg/Kg/day); OMT (13.8 mg/Kg/day) and three SF+OMT groups (3.1 + 6.9; 6.2 + 13.8 and 12.3 + 27.7 mg/Kg/day). The mortality and death time were monitored. Sprague-Dawley rats were randomly divided into seven groups including control, PQ, SF (3.1 mg/Kg/day); OMT (6.9 mg/Kg/day) and three SF+OMT groups (1.6 + 3.4; 3.1 + 6.9 and 6.2 + 13.8 mg/Kg/day). The lung wet/dry weight (W/D) ratio, lung histopathologic changes, C-reactive protein (CRP), interleukin-6 (IL-6), nuclear factor κB (NF-κB), malondialdehyde (MDA) and superoxidase dismutase (SOD) were analysed. Compared with PQ group, the mortality significantly decreased and the death time prolonged in SF and OMT combination treatment groups of mice. Also in SF and OMT combination treatment groups of rats, the increased lung W/D ratio and histopathological score induced by PQ injection were significantly decreased; the levels of CRP, IL-6, NF-κB and MDA in serum and lung homogenate were significantly decreased; the SOD activities in serum and lung homogenate were improved. These results suggested that SF and OMT combination had an obvious protective effect on PQ-induced lung injury. The anti-inflammatory and antioxidant effect might be involved in the mechanism. PMID:25901166

  15. CD147 deficiency blocks IL-8 secretion and inhibits lung cancer-induced osteoclastogenesis

    SciTech Connect

    Wang, Hongkai; Zhuo, Yunyun; Hu, Xu; Shen, Weiwei; Zhang, Ying; Chu, Tongwei

    2015-03-06

    Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and poor prognosis; however, the molecular basis of this process is still unknown. This study investigated the role of extracellular matrix metalloproteinase inducer (also known as cluster of differentiation (CD)147) in osteoclastogenesis resulting from bone metastasis, based on the enrichment of this glycoprotein on the surface of many malignant bone tumors. RNA interference was used to silence CD147 expression in A549 human lung cancer cells. Compared with conditioned medium (CM) from control cells (A549-CM), CM from CD147-deficient cells (A549-si-CM) suppressed receptor activator of nuclear factor κB ligand-stimulated osteoclastogenesis in RAW 264.7 cells and bone marrow-derived macrophages. The mRNA levels of osteoclast-specific genes such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K were also reduced in the presence of A549-si-CM. CD147 knockdown in A549 cells decreased interleukin (IL)-8mRNA and protein expression. IL-8 is present in large amounts in A549-CM and mimicked its inductive effect on osteoclastogenesis; this was reversed by depletion of IL-8 from the medium. Taken together, these results indicate that CD147 promotes lung cancer-induced osteoclastogenesis by modulating IL-8 secretion, and suggest that CD147 is a potential therapeutic target for cancer-associated bone resorption in lung cancer patients. - Highlights: • Bone loss frequently results from lung cancer metastasis. • Cluster of differentiation (CD)147 was depleted in A549 lung adenocarcinoma cells. • RAW 264.7 cell osteoclastogenesis was blocked by medium from CD147-deficient cells. • Interleukin (IL)-8 level was reduced in the conditioned medium. • Osteoclastogenesis induced by lung tumor cells requires CD147-mediated IL-8 release.

  16. Role of hypoxia-inducible factor 1{alpha} in modulating cobalt-induced lung inflammation.

    PubMed

    Saini, Yogesh; Kim, Kyung Y; Lewandowski, Ryan; Bramble, Lori A; Harkema, Jack R; Lapres, John J

    2010-02-01

    Hypoxia plays an important role in development, cellular homeostasis, and pathological conditions, such as cancer and stroke. There is also growing evidence that hypoxia is an important modulator of the inflammatory process. Hypoxia-inducible factors (HIFs) are a family of proteins that regulate the cellular response to oxygen deficit, and loss of HIFs impairs inflammatory cell function. There is little known, however, about the role of epithelial-derived HIF signaling in modulating inflammation. Cobalt is capable of eliciting an allergic response and promoting HIF signaling. To characterize the inflammatory function of epithelial-derived HIF in response to inhaled cobalt, a conditional lung-specific HIF1alpha, the most ubiquitously expressed HIF, deletion mouse, was created. Control mice showed classic signs of metal-induced injury following cobalt exposure, including fibrosis and neutrophil infiltration. In contrast, HIF1alpha-deficient mice displayed a Th2 response that resembled asthma, including increased eosinophilic infiltration, mucus cell metaplasia, and chitinase-like protein expression. The results suggest that epithelial-derived HIF signaling has a critical role in establishing a tissue's inflammatory response, and compromised HIF1alpha signaling biases the tissue towards a Th2-mediated reaction.

  17. Threshold for Radon-Induced Lung Cancer From Inhaled Plutonium Data.

    PubMed

    Cuttler, Jerry M; Sanders, Charles L

    2015-01-01

    Cohen's lung cancer mortality data, from his test of the LNT theory, do not extend to the no observed adverse effects level (NOAEL) above which inhaled radon decay products begin to induce excess lung cancer mortality. Since there is concern about the level of radon in homes, it is important to set the radon limit near the NOAEL to avoid the risk of losing a health benefit. Assuming that dogs model humans, data from a study on inhaled plutonium dioxide particulates in dogs were assessed, and the NOAEL for radon-induced lung tumors was estimated to be about 2100 Bq/m(3). The US Environmental Protection Agency should consider raising its radon action level from 150 to at least 1000 Bq/m(3).

  18. The intracerebroventricular injection of rimonabant inhibits systemic lipopolysaccharide-induced lung inflammation.

    PubMed

    Johnson, Arnold; Neumann, Paul H; Peng, Jianya; James, Janey; Russo, Vincenzo; MacDonald, Hunter; Gertzberg, Nancy; Feleder, Carlos

    2015-09-15

    We investigated the role of intracerebroventricular (ICV) injection of rimonabant (500ng), a CB1 antagonist, on lipopolysaccharide ((LPS) 5mg/kg)-induced pulmonary inflammation in rats in an isolated perfused lung model. There were decreases in pulmonary capillary pressure (Ppc) and increases in the ((Wet-Dry)/Dry lung weight)/(Ppc) ratio in the ICV-vehicle/LPS group at 4h. There were decreases in TLR4 pathway markers, such as interleukin receptor-associated kinase-1, IκBα, Raf1 and phospho-SFK (Tyr416) at 30min and at 4h increases in IL-6, vascular cell adhesion molecule-1 and myeloperoxidase in lung homogenate. Intracerebroventricular rimonabant attenuated these LPS-induced responses, indicating that ICV rimonabant modulates LPS-initiated pulmonary inflammation.

  19. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    SciTech Connect

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Ngalame, Ntube N. Olive; Waalkes, Michael P.

    2013-12-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. - Highlights: • Chronic cadmium exposure induces cancer cell characteristics in human lung cells. • This provides an in vitro model of cadmium-induced human lung cell transformation. • This occurred with general and lung specific changes typical for cancer cells. • These findings add insight to the relationship

  20. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    SciTech Connect

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai; Bai, Xianyong

    2013-11-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO{sub 2}), carbon dioxide tension, pH, and the PaO{sub 2}/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22{sup phox} levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may

  1. CYLD Promotes TNF-α-Induced Cell Necrosis Mediated by RIP-1 in Human Lung Cancer Cells

    PubMed Central

    Lin, Xing; Chen, Qianshun; Huang, Chen

    2016-01-01

    Lung cancer is one of the most common cancers in the world. Cylindromatosis (CYLD) is a deubiquitination enzyme and contributes to the degradation of ubiquitin chains on RIP1. The aim of the present study is to investigate the levels of CYLD in lung cancer patients and explore the molecular mechanism of CYLD in the lung cancer pathogenesis. The levels of CYLD were detected in human lung cancer tissues and the paired paracarcinoma tissues by real-time PCR and western blotting analysis. The proliferation of human lung cancer cells was determined by MTT assay. Cell apoptosis and necrosis were determined by FACS assay. The results demonstrated that low levels of CYLD were detected in clinical lung carcinoma specimens. Three pairs of siRNA were used to knock down the endogenous CYLD in lung cancer cells. Knockdown of CYLD promoted cell proliferation of lung cancer cells. Otherwise overexpression of CYLD induced TNF-α-induced cell death in A549 cells and H460 cells. Moreover, CYLD-overexpressed lung cancer cells were treated with 10 μM of z-VAD-fmk for 12 hours and the result revealed that TNF-α-induced cell necrosis was significantly enhanced. Additionally, TNF-α-induced cell necrosis in CYLD-overexpressed H460 cells was mediated by receptor-interacting protein 1 (RIP-1) kinase. Our findings suggested that CYLD was a potential target for the therapy of human lung cancers. PMID:27738385

  2. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    SciTech Connect

    Gan, Lu; Xue, Jian-Xin; Li, Xin; Liu, De-Song; Ge, Yan; Ni, Pei-Yan; Deng, Lin; Lu, You; Jiang, Wei

    2011-05-27

    Highlights: {yields} Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. {yields} Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. {yields} VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. {yields} LPA-LPAR1/3 signaling regulated TGF{beta}1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. {yields} LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGF{beta}1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor {beta}1 (TGF{beta}1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1

  3. Effects of surfactant/budesonide therapy on oxidative modifications in the lung in experimental meconium-induced lung injury.

    PubMed

    Mikolka, P; Kopincova, J; Tomcikova Mikusiakova, L; Kosutova, P; Antosova, M; Calkovska, A; Mokra, D

    2016-02-01

    Meconium aspiration syndrome (MAS) is a serious condition, which can be treated with exogenous surfactant and mechanical ventilation. However, meconium-induced inflammation, lung edema and oxidative damage may inactivate delivered surfactant and thereby reduce effectiveness of the therapy. As we presumed that addition of anti-inflammatory agent into the surfactant may alleviate inflammation and enhance efficiency of the therapy, this study was performed to evaluate effects of surfactant therapy enriched with budesonide versus surfactant-only therapy on markers of oxidative stress in experimental model of MAS. Meconium suspension (25 mg/ml, 4 ml/kg) was instilled into the trachea of young rabbits, whereas one group of animals received saline instead of meconium (C group, n = 6). In meconium-instilled animals, respiratory failure developed within 30 min. Then, meconium-instilled animals were divided into 3 groups according to therapy (n = 6 each): with surfactant therapy (M + S group), with surfactant + budesonide therapy (M + S + B), and without therapy (M group). Surfactant therapy consisted of two bronchoalveolar lavages (BAL) with diluted surfactant (Curosurf, 5 mg phospholipids/ml, 10 ml/kg) followed by undiluted surfactant (100 mg phospholipids/kg), which was in M + S + B group enriched with budesonide (Pulmicort, 0.5 mg/ml). Animals were oxygen-ventilated for additional 5 hours. At the end of experiment, blood sample was taken for differential white blood cell (WBC) count. After euthanizing animals, left lung was saline-lavaged and cell differential in BAL was determined. Oxidative damage, i.e. oxidation of lipids (thiobarbituric acid reactive substance (TBARS) and conjugated dienes) and proteins (dityrosine and lysine-lipoperoxidation products) was estimated in lung homogenate and isolated mitochondria. Total antioxidant capacity was evaluated in lung homogenate and plasma. Meconium instillation increased transmigration of neutrophils and production of free

  4. Analysis of Clinical and Dosimetric Factors Influencing Radiation-Induced Lung Injury in Patients with Lung Cancer

    PubMed Central

    Han, Shuiyun; Gu, Feiying; Lin, Gang; Sun, Xiaojiang; Wang, Yuezhen; Wang, Zhun; Lin, Qingren; Weng, Denghu; Xu, Yaping; Mao, Weimin

    2015-01-01

    Purpose: Dose escalation of thoracic radiation can improve the local tumor control and surivival, and is in the meantime limited by the occurrence of radiation-induced lung injury (RILI). This study investigated the clinical and dosimetric factors influencing RILI in lung-cancer patients receiving chemoradiotherapy for better radiation planning. Methods and Materials: A retrospective analysis was carried out on 161 patients with non-small-cell or small-cell lung cancer (NSCLC and SCLC, respectively), who underwent chemoradiotherapy between April 2010 and May 2011 with a median follow-up time of 545 days (range: 39-1453). Chemotherapy regimens were based on the histological type (squamous cell carcinoma, adenocarcinoma, or SCLC), and radiotherapy was delivered in 1.8-3.0 Gy (median, 2.0 Gy) fractions, once daily, to a total of 39-66 Gy (median, 60 Gy). Univariate analysis was performed to analyze clinical and dosimetric factors associated with RILI. Multivariate analysis using logistic regression identified independent risk factors correlated to RILI. Results: The incidence of symptomatic RILI (≥grade 2) was 31.7%. Univariate analysis showed that V5, V20, and mean lung dose (MLD) were significantly associated with RILI incidence (P=0.029, 0.048, and 0.041, respectively). The association was not statistically significant for histological type (NSCLC vs. SCLC, P = 0.092) or radiation technology (IMRT vs. 3D-CRT, P = 0.095). Multivariate analysis identified MLD as an independent risk factor for symptomatic RILI (OR=1.249, 95%CI=1.055-1.48, P= 0.01). The incidence of bilateral RILI in cases where the tumor was located unilaterally was 22.7% (32/141) and all dosimetric-parameter values were not significantly different (P>0.05) for bilateral versus ipsilateral injury, except grade-1 (low) RILI (P < 0.05). The RILI grade was higher in cases of ipsilateral lung injury than in bilateral cases (Mann-Whitney U test, z=8.216, P< 0.001). Conclusion: The dosimetric parameter

  5. Hesperidin as Radioprotector against Radiation-induced Lung Damage in Rat: A Histopathological Study

    PubMed Central

    Haddadi, Gholam Hassan; Rezaeyan, Abolhasan; Mosleh-Shirazi, Mohammad Amin; Hosseinzadeh, Massood; Fardid, Reza; Najafi, Masoud; Salajegheh, Ashkan

    2017-01-01

    Reactive oxygen species (ROS) are generated by ionizing radiation, and one of the organs commonly affected by ROS is the lung. Radiation-induced lung injury including pneumonia and lung fibrosis is a dose-limiting factor in radiotherapy (RT) of patients with thorax irradiation. Administration of antioxidants has been proved to protect against ROS. The present study was aimed to assess the protective effect of hesperidin (HES) against radiation-induced lung injury of male rats. Fifty rats were divided into three groups. G1: Received no HES and radiation (sham). G2: Underwent γ-irradiation to the thorax. G3: Received HES and underwent γ-irradiation. The rats were exposed to a single dose of 18 Gy using cobalt-60 unit and were administered HES (100 mg/kg) for 7 days before irradiation. Histopathological analysis was performed 24 h and 8 weeks after RT. Histopathological results in 24 h showed radiation-induced inflammation and presence of more inflammatory cells as compared to G1 (P < 0.05). Administration of HES significantly decreased such an effect when compared to G2 (P < 0.05). Histopathological evaluation in 8 weeks showed a significant increase in mast cells, inflammation, inflammatory cells, alveolar thickness, vascular thickness, pulmonary edema, and fibrosis in G2 when compared to G1 (P < 0.05). HES significantly decreased inflammatory response, fibrosis, and mast cells when compared to G2 (P < 0.05). Administration of HES resulted in decreased radiation pneumonitis and radiation fibrosis in the lung tissue. Thus, the present study showed HES to be an efficient radioprotector against radiation-induced damage in the lung of tissue rats.

  6. NLRP3 inflammasome activation is essential for paraquat-induced acute lung injury.

    PubMed

    Liu, Zhenning; Zhao, Hongyu; Liu, Wei; Li, Tiegang; Wang, Yu; Zhao, Min

    2015-02-01

    The innate immune response is important in paraquat-induced acute lung injury, but the exact pathways involved are not elucidated. The objectives of this study were to determine the specific role of the NLRP3 inflammasome in the process. Acute lung injury was induced by administering paraquat (PQ) intraperitoneally. NLRP3 inflammasome including NLRP3, ASC, and caspase-1 mRNA and protein expression in lung tissue and IL-1β and IL-18 levels in BALF were detected at 4, 8, 24, and 72 h after PQ administration in rats. Moreover, rats were pretreated with 10, 30, and 50 mg/kg NLRP3 inflammasome blocker glybenclamide, respectively, 1 h before PQ exposure. At 72 h after PQ administration, lung histopathology changes, NLRP3, ASC, and caspase-1 protein expression, as well as secretion of cytokines including IL-1β and IL-18 in BALF were investigated. The NLRP3 inflammasome including NLRP3, ASC, caspase-1 expression, and cytokines IL-1β and IL-18 levels in PQ poisoning rats were significantly higher than that in the control group. NLRP3 inflammasome blocker glybenclamide pretreatment attenuated lung edema, inhibited the NLRP3, ASC, and caspase-1 activation, and reduced IL-1β and IL-18 levels in BALF. In the in vitro experiments, IL-1β and IL-18 secreted from RAW264.7 mouse macrophages treated with paraquat were attenuated by glybenclamide. In conclusion, paraquat can induce IL-1β/IL-18 secretion via NLRP3-ASC-caspase-1 pathway, and the NLRP3 inflammasome is essential for paraquat-induced acute lung injury.

  7. Melatonin alleviates lung damage induced by the chemical warfare agent nitrogen mustard.

    PubMed

    Ucar, Muharrem; Korkmaz, Ahmet; Reiter, Russel J; Yaren, Hakan; Oter, Sükrü; Kurt, Bülent; Topal, Turgut

    2007-09-10

    The cytotoxic mechanism of mustards has not been fully elucidated; recently, we reported that reactive oxygen species, nitric oxide [produced by inducible nitric oxide synthase (iNOS)] and peroxynitrite are involved in the pathogenesis and responsible for mustard-induced toxicity. Melatonin, a potent antioxidant molecule, acts as an iNOS inhibitor and a peroxynitrite scavenger. Using the prototypic nitrogen mustard (mechlorethamine/HN2) as a model and based on its known cytotoxic mechanisms, the present study was performed to test melatonin for its capability in protecting the lungs of injured male Wistar rats. Lung mustard toxicity was induced via an intratracheally injection of HN2 (0.5mg/kg) dissolved in saline (100microl). Control animals were injected the same amount of saline only. Melatonin was administered intraperitoneally with two different doses (20mg/kg or 40mg/kg) beginning 1h before HN2 application and continued every 12h for six replications. Forty-eight hours after the last melatonin injection, the animals were sacrificed and their lungs were taken for further assay, i.e., malondialdehyde (MDA) levels, and superoxide dismutase (SOD), glutathione peroxidase (GPx) and iNOS activity. Additionally their urine was collected for nitrite-nitrate (NO(x)) analysis. HN2 injection caused increased iNOS activity and MDA levels in lung tissue and NO(x) values in urine; lung GPx activity was significantly depressed. Melatonin restored all of these oxidative and nitrosative stress markers in a dose-dependent manner. In conclusion, the results of study provide evidence that melatonin may have the ability to reduce mustard-induced toxicity in the lungs.

  8. Ukrain (NSC 631570) ameliorates intestinal ischemia-reperfusion-induced acute lung injury by reducing oxidative stress

    PubMed Central

    Kocak, Cengiz; Kocak, Fatma Emel; Akcilar, Raziye; Akcilar, Aydin; Savran, Bircan; Zeren, Sezgin; Bayhan, Zulfu; Bayat, Zeynep

    2016-01-01

    Intestinal ischemia-reperfusion (I/R) causes severe destruction in remote organs. Lung damage is a frequently seen complication after intestinal I/R. Ukrain (NSC 631570) is a synthetic thiophosphate derivative of alkaloids from the extract of the celandine (Chelidonium majus L.) plant. We investigated the effect of Ukrain in animals with lung injury induced by intestinal I/R. Adult male Spraque-Dawley rats were randomly divided into four groups: control, Ukrain, I/R, I/R with Ukrain. Before intestinal I/R was induced, Ukrain was administered intraperitoneally at a dose of 7.0 mg/body weight. After 1 h ischemia and 2 h reperfusion period, lung tissues were excised. Tissue levels of total oxidative status (TOS), total antioxidant status (TAS) were measured and oxidative stress indices (OSI) were calculated. Lung tissues were also examined histopathologically. TOS and OSI levels markedly increased and TAS levels decreased in the I/R group compared to the control group (P < 0.05). TOS and OSI levels markedly decreased and TAS levels increased in the I/R with Ukrain group compared with the group subjected to IR only (P < 0.05). Severe hemorrhage, alveolar septal thickening, and leukocyte infiltration were observed in the I/R group. In the I/R with Ukrain group, morphologic changes occurring as a result of lung damage attenuated and histopathological scores reduced compared to the I/R group (P < 0.05). Our results suggest that Ukrain pretreatment could reduce lung injury induced by intestinal I/R induced via anti-inflammatory and antioxidant effects. PMID:26773189

  9. Differential involvement of gp130 signalling pathways in modulating tobacco carcinogen-induced lung tumourigenesis.

    PubMed

    Miller, A; Brooks, G D; McLeod, L; Ruwanpura, S; Jenkins, B J

    2015-03-19

    Interleukin (IL)-6 family cytokines signal exclusively via the gp130 coreceptor, and are implicated in smoking-associated lung cancer, the most lethal cancer worldwide. However, the role of gp130 signalling pathways in transducing the carcinogenic effects of tobacco-related compounds is ill-defined. Here, we report that lung tumourigenesis induced by the potent tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (Nicotine-derived Nitrosamine Ketone; NNK) is suppressed in gp130(F/F) knock-in mice characterized by the contrasting gp130-dependant hypoactivation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) and phosphatidylinositol 3-kinase/Akt, and hyperactivation of signal transducer and activator of transcription (STAT)3 signalling cascades. Specifically, in response to NNK, the absolute number and size of lung lesions in gp130(F/F) mice were significantly reduced compared with gp130(+/+) littermate controls, and associated with lower cellular proliferation without any alteration to the level of apoptosis in gp130(F/F) lung tumours. At the molecular level, reduced activation of ERK MAPK, but not Akt, was observed in lung tumours of gp130(F/F) mice, and corresponded with impaired expression of several tumour suppressor genes (for example, Trp53, Tsc2). Notably, STAT3 was not activated in the lungs of gp130(+/+) mice by NNK, and genetic normalization of STAT3 activation in gp130(F/F):Stat3(-/+) mice had no effect on NNK-induced tumourigenesis. The expression of tumour suppressor genes was reduced in tumours from current versus never-smoking lung cancer patients, and in vitro pharmacological inhibition of ERK MAPK signalling in human lung cancer cells abrogated NNK-induced downmodulation of tumour suppressor gene expression. Among IL-6 cytokine family members, IL-6 gene expression was specifically upregulated by NNK in vitro and in vivo, and inversely correlated with tumour suppressor gene expression. Collectively

  10. Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

    PubMed

    Zhao, Hongyu; Zhao, Min; Wang, Yu; Li, Fengchun; Zhang, Zhigang

    2016-02-01

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. However, the effects of GA on sepsis-induced acute lung injury (ALI) have not been determined. Tthe aim of this study was to investigate the molecular mechanism involved in the effects of GA against sepsis-induced ALI in rats. We found that GA alleviated sepsis-induced ALI through improvements in various pathological changes, as well as decreases in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid, and a significant increase in the survival rate of treated rats. Additionally, GA markedly inhibited sepsis-induced pulmonary inflammatory responses. Moreover, we found that treatment with GA inhibited oxidative stress damage and apoptosis in lung tissue induced by ALI. Finally, GA treatment significantly inhibited NF-κ B, JNK and P38 MAPK activation. Our data indicate that GA has a protective effect against sepsis-induced ALI by inhibiting the inflammatory response, damage from oxidative stress, and apoptosis via inactivation of NF-κB and MAPK signaling pathways, providing a molecular basis for a new medical treatment for sepsis-induced ALI.

  11. Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram

    SciTech Connect

    Chang, Weiyuan; Chen, Jing; Schlueter, Connie F.; Rando, Roy J.; Pathak, Yashwant V.; Hoyle, Gary W.

    2012-09-01

    Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228–270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery. -- Highlights: ► Chlorine causes lung injury when inhaled and is considered a chemical threat agent. ► Rolipram inhibited chlorine-induced pulmonary edema and airway hyperreactivity. ► Post-exposure rolipram treatments by both systemic and local delivery were effective. ► Rolipram shows promise as a rescue treatment for chlorine-induced lung injury.

  12. Mast cells protect against Pseudomonas aeruginosa-induced lung injury.

    PubMed

    Junkins, Robert D; Carrigan, Svetlana O; Wu, Zhengli; Stadnyk, Andrew W; Cowley, Elizabeth; Issekutz, Thomas; Berman, Jason; Lin, Tong-Jun

    2014-08-01

    Pseudomonas aeruginosa, an opportunistic pathogen, is the leading cause of morbidity and mortality in immune-compromised individuals. Maintaining the integrity of the respiratory epithelium is critical for an effective host response to P. aeruginosa. Given the close spatial relationship between mast cells and the respiratory epithelium, and the importance of tightly regulated epithelial permeability during lung infections, we examined whether mast cells influence airway epithelial integrity during P. aeruginosa lung infection in a mouse model. We found that mast cell-deficient Kit(W-sh)/Kit(W-sh) mice displayed greatly increased epithelial permeability, bacterial dissemination, and neutrophil accumulation compared with wild-type animals after P. aeruginosa infection; these defects were corrected on reconstitution with mast cells. An in vitro Transwell co-culture model further demonstrated that a secreted mast cell factor decreased epithelial cell apoptosis and tumor necrosis factor production after P. aeruginosa infection. Together, our data demonstrate a previously unrecognized role for mast cells in the maintenance of epithelial integrity during P. aeruginosa infection, through a mechanism that likely involves prevention of epithelial apoptosis and tumor necrosis factor production. Our understanding of mechanisms of the host response to P. aeruginosa will open new avenues for the development of successful preventative and treatment strategies.

  13. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    EPA Science Inventory

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  14. MATRILYSIN PARTICIPATES IN THE ACUTE LUNG INJURY INDUCED BY OIL COMBUSTION PRODUCTS

    EPA Science Inventory

    ROLE OF MATRILYSIN IN THE ACUTE LUNG INJURY INDUCED BY OIL COMBUSTION PARTICLES.

    K L Dreher1, WY Su2 and C L Wilson3. 1US Environmental Protection Agency, Research Triangle Park, NC; 2Duke University, Durham, NC;3Washington University, St. Louis, MO.

    Mechanisms by ...

  15. Treatment with the hyaluronic acid synthesis inhibitor 4-methylumbelliferone suppresses SEB-induced lung inflammation.

    PubMed

    McKallip, Robert J; Hagele, Harriet F; Uchakina, Olga N

    2013-10-17

    Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.

  16. Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation

    PubMed Central

    McKallip, Robert J.; Hagele, Harriet F.; Uchakina, Olga N.

    2013-01-01

    Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB. PMID:24141285

  17. Lung epithelial cells are essential effectors of inducible resistance to pneumonia

    PubMed Central

    Cleaver, Jeffrey O.; You, Dahui; Michaud, Danielle R.; Guzmán Pruneda, Francisco A.; Leiva Juarez, Miguel M.; Zhang, Jiexin; Weill, Patrick M.; Adachi, Roberto; Gong, Lei; Moghaddam, Seyed; Poynter, Matthew E.; Tuvim, Michael J.; Evans, Scott E.

    2013-01-01

    Infectious pneumonias are a leading cause of death worldwide, particularly among immunocompromised patients. Therapeutic stimulation of the lungs’ intrinsic defenses with a unique combination of inhaled Toll-like receptor agonists broadly protects mice against otherwise lethal pneumonias. As the survival benefit persists despite cytotoxic chemotherapy-related neutropenia, the cells required for protection were investigated. The inducibility of resistance was tested in mice with deficiencies of leukocyte lineages due to genetic deletions and in wild type mice with leukocyte populations significantly reduced by antibodies or toxins. Surprisingly, these serial reductions in leukocyte lineages did not appreciably impair inducible resistance, but targeted disruption of Toll-like receptor signaling in the lung epithelium resulted in complete abrogation of the protective effect. Isolated lung epithelial cells were also induced to kill pathogens in the absence of leukocytes. Proteomic and gene expression analyses of isolated epithelial cells and whole lungs revealed highly congruent antimicrobial responses. Taken together, these data indicate that lung epithelial cells are necessary and sufficient effectors of inducible resistance. These findings challenge conventional paradigms about the role of epithelia in antimicrobial defense and offer a novel potential intervention to protect patients with impaired leukocyte-mediated immunity from fatal pneumonias. PMID:23632328

  18. EFFECT OF ANTIOXIDANT SUPPLEMENTATION ON OZONE-INDUCED LUNG INJURY IN HUMAN SUBJECTS

    EPA Science Inventory

    Epidemiological, in vitro and animal studies suggest that dietary antioxidants can modulate the cellular and physiologic effects of ozone (O3) inhalation in humans. To determine whether antioxidants can influence human susceptibility to O3-induced changes in lung function and a...

  19. Treatment with the hyaluronic Acid synthesis inhibitor 4-methylumbelliferone suppresses LPS-induced lung inflammation.

    PubMed

    McKallip, Robert J; Ban, Hao; Uchakina, Olga N

    2015-01-01

    Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS-induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS.

  20. STRAIN-DEPENDENT SUSCEPTIBILITY TO TRANSPLACENTALLY-INDUCED MURINE LUNG TUMORS

    EPA Science Inventory

    STRAIN-DEPENDENT SUSCEPTIBILITY TO TRANSPLACENTALLY-INDUCED MURINE LUNG TUMORS
    M S Miller, J E Moore, M Xu, G B Nelson, S T Dance, N D Kock, J A Ross Wake Forest University, Winston-Salem, NC and USEPA, Research Triangle Park, NC

    Previously, our laboratory demonstrated...

  1. Successful EGFR-TKI rechallenge of leptomeningeal carcinomatosis after gefitinib-induced interstitial lung disease.

    PubMed

    Nakamichi, Shinji; Kubota, Kaoru; Horinouchi, Hidehito; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Tamura, Tomohide

    2013-04-01

    We report the case of a 49-year-old non-smoking Japanese woman with backache and difficulty in walking. She was diagnosed as having advanced lung adenocarcinoma, and an epithelial growth factor receptor mutation (in-frame deletions in exon 19) was found. After radiation therapy of bone metastases with spinal cord compression and brain metastases, gefitinib was administered. On day 2, she developed acute interstitial lung disease. Gefitinib therapy was discontinued and treatment with high-dose steroid therapy improved the interstitial lung disease. Cisplatin plus pemetrexed was initiated as second-line chemotherapy, but she was hospitalized again for leptomeningeal carcinomatosis. Considering the poor prognosis of leptomeningeal carcinomatosis, we decided that erlotinib was our only choice of treatment. As a third-line treatment, erlotinib was administered after informing the patient about the high risk of interstitial lung disease. Neurological symptoms were improved within a week and interstitial lung disease did not recur. The patient has received erlotinib successfully for 18 months without the recurrence of leptomeningeal carcinomatosis. Erlotinib rechallenge after gefitinib-induced interstitial lung disease must be carefully chosen based on the balance of a patient's risk and benefit.

  2. Therapeutic Effect of the Tuber of Alisma orientale on Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Kwun, Min Jung; Choi, Jun-Yong; Ahn, Kyung-Seop; Oh, Sei-Ryang; Lee, Yong Gyu; Christman, John W.; Sadikot, Ruxana T.

    2013-01-01

    Although Alisma orientale, an ethnic herb, has been prescribed for treating various diseases in Asian traditional medicine, experimental evidence to support its therapeutic effects is lacking. Here, we sought to determine whether A. orientale has a therapeutic effect on acute lung injury (ALI). Ethanol extract of the tuber of A. orientale (EEAO) was prepared and fingerprinted by HPLC for its constituents. Mice received an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) for the induction of ALI. At 2 h after LPS treatment, mice received an intratracheal (i.t.) spraying of various amounts of EEAO to the lung. Bioluminescence imaging of transgenic NF-κB/luciferase reporter mice shows that i.t. EEAO posttreatment suppressed lung inflammation. In similar experiments with C57BL/6 mice, EEAO posttreatment significantly improved lung inflammation, as assessed by H&E staining of lung sections, counting of neutrophils in bronchoalveolar lavage fluid, and semiquantitative RT-PCR analyses of proinflammatory cytokines and Nrf2-dependent genes in the inflamed lungs. Furthermore, EEAO posttreatment enhanced the survival of mice that received a lethal dose of LPS. Together, our results provide evidence that A. orientale has a therapeutic effect on ALI induced by sepsis. PMID:23983806

  3. Contribution of Lung Macrophages to the Inflammatory Responses Induced by Exposure to Air Pollutants

    PubMed Central

    van Eeden, Stephan F.

    2013-01-01

    Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants. PMID:24058272

  4. Immunohistochemical detection of CCR2 and CX3CR1 in sepsis-induced lung injury.

    PubMed

    An, Jun-Ling; Ishida, Yuko; Kimura, Akihiko; Tsokos, Michael; Kondo, Toshikazu

    2009-11-20

    Sepsis is a systemic inflammatory disease with high mortality. In the present study, we immunohistochemically examined CCR2 and CX3CR1 expression in sepsis-induced lung injury, and discussed its availability for the postmortem diagnosis of sepsis. Lung samples were obtained from different lung lobes of nine sepsis and eight control cases with postmortem intervals between 12 and 48h. Immunohistochemically, mononuclear cells recruited into the lungs expressed CCR2 and CX3CR1 in both sepsis and non-septic groups. In double-color immunofluorescence analysis, CCR2- or CX3CR1-positive cells could be identified as CD68-positive macrophages. Moreover, most of CD68-positive macrophages expressed both CCR2 and CX3CR1. Morphometrically, the average of CCR2- and CX3CR1-positive macrophages was significantly increased in sepsis group, compared with control group (sepsis vs. control: 41.6+/-1.3% vs. 8.0+/-0.4% in CCR2; 36.2+/-1.3% vs. 9.2+/-0.4% in CX3CR1). These observations implied that CCR2- or CX3CR1-positive macrophages were recruited into the lungs under several pathological conditions. In particular, their recruitment might be more evident in sepsis. Moreover, from the forensic aspects, immunohistochemical detection of CCR2 and CX3CR1 expression in the lungs can be considered as valuable diagnostic tools for the postmortem diagnosis of sepsis.

  5. Activated protein C protection from lung inflammation in endotoxin-induced injury.

    PubMed

    Pirrone, Federica; Mazzola, Silvia M; Pastore, Camilla; Paltrinieri, Saverio; Sironi, Giuseppe; Riccaboni, Pietro; Viola, Manuela; Passi, Alberto; Clement, Maria G; Albertini, Mariangela

    2008-11-01

    We studied the protection of recombinant human activated protein C (rhAPC) in endotoxin-induced lung inflammation and injury and whether this effect is correlated with modulation of lung matrix metalloproteinase (MMP) activity. We randomly assigned 12 Large White pigs to receive intravenous Escher-ichia coli lipopolysaccharide (LPS; 40 mu g/kg/hr), rhAPC (24 mu g/ kg/hr), or both. We monitored respiratory mechanics and function, cell counts, and cytokine concentrations in bron-choalveolar lavage fluid (BALF). Lung samples were collected for the zymography of MMP-2 and MMP-9 activities and for histology. In septic pigs, rhAPC decreased proMMP-9 release as well as MMP-9 activation, and increased proMMP-2 presence without any evident activation compared with specimens that were given LPS alone. In addition, lung injury in rhAPC-treated animals was significantly attenuated, as shown by higher respiratory compliance, delayed increase in tumor necrosis alfa and interleukin-1beta as well as neutrophil recruitment in the BALF, reduced lung edema, and histologic changes. In conclusion, rhAPC is beneficial in acute lung injury, and the protection may depend, at least in part, on modulation of MMP-2/9 activity.

  6. Protective effect of carvacrol on acute lung injury induced by lipopolysaccharide in mice.

    PubMed

    Feng, Xiaosheng; Jia, Aiqing

    2014-08-01

    Carvacrol, the major component of Plectranthus amboinicus, has been known to exhibit anti-inflammatory activities. The aim of this study was to investigate the effects of carvacrol on lipopolysaccharide (LPS)-induced endotoxemia and acute lung injury (ALI) in mice. Mice were injected intraperitoneally (i.p.) with LPS and the mortality of mice for 7 days were observed twice a day. Meanwhile, the protective effect of carvacrol (20, 40 or 80 mg/kg) on LPS-induced endotoxemia were detected. Using an experimental model of LPS-induced ALI, we examined the effect of carvacrol in resolving lung injury. The results showed that carvacrol could improve survival during lethal endotoxemia and attenuate LPS-induced ALI in mice. The anti-inflammatory mechanisms of carvacrol may be due to its ability to inhibit NF-κB and MAPKs signaling pathways, thereby inhibiting inflammatory cytokines TNF-α, IL-6 and IL-1β production.

  7. Diethylcarbamazine attenuates the development of carrageenan-induced lung injury in mice.

    PubMed

    Ribeiro, Edlene Lima; Barbosa, Karla Patricia de Souza; Fragoso, Ingrid Tavares; Donato, Mariana Aragão Matos; Gomes, Fabiana Oliveira dos Santos; da Silva, Bruna Santos; Soares e Silva, Amanda Karolina; Rocha, Sura Wanessa Santos; da Silva Junior, Valdemiro Amaro; Peixoto, Christina Alves

    2014-01-01

    Diethylcarbamazine (DEC) is an antifilarial drug with potent anti-inflammatory properties as a result of its interference with the metabolism of arachidonic acid. The aim of the present study was to evaluate the anti-inflammatory activity of DEC in a mouse model of acute inflammation (carrageenan-induced pleurisy). The injection of carrageenan into the pleural cavity induced the accumulation of fluid containing a large number of polymorphonuclear cells (PMNs) as well as infiltration of PMNs in lung tissues and increased production of nitrite and tumor necrosis factor-α and increased expression of interleukin-1β, cyclooxygenase (COX-2), and inducible nitric oxide synthase. Carrageenan also induced the expression of nuclear factor-κB. The oral administration of DEC (50 mg/Kg) three days prior to the carrageenan challenge led to a significant reduction in all inflammation markers. The present findings demonstrate that DEC is a potential drug for the treatment of acute lung inflammation.

  8. Dietary Curcumin Increases Antioxidant Defenses in Lung, Ameliorates Radiation-Induced Pulmonary Fibrosis, and Improves Survival in Mice

    PubMed Central

    Lee, James C.; Kinniry, Paul A.; Arguiri, Evguenia; Serota, Matthew; Kanterakis, Stathis; Chatterjee, Shampa; Solomides, Charalambos C.; Javvadi, Prashanthi; Koumenis, Constantinos; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2010-01-01

    The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1%or 5%(w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-α production in lungs, only 5%dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation. PMID:20426658

  9. Aminophylline treatment in meconium-induced acute lung injury in a rabbit model.

    PubMed

    Mokra, D; Mokry, J; Tatarkova, Z; Redfors, B; Petraskova, M; Calkovska, A

    2007-11-01

    Administration of methylxanthines may diminish meconium-induced acute lung injury. Meconium-instilled rabbits intravenously received aminophylline (2.0 mg/kg) at two doses 0.5 h and 2.5 h after meconium instillation or were left without treatment, and were oxygen-ventilated for additional 5 h. At the end of experiment, lungs and trachea were excised. Within 5 h after the first dose of treatment, aminophylline significantly improved gas exchange and decreased right-to-left pulmonary shunts, central venous pressure, and ventilatory pressures. Moreover, aminophylline reduced meconium-induced lung edema formation, airway hyperreactivity to histamine, count of neutrophils in bronchoalveolar lavage fluid associated with higher total white blood cells and neutrophils in the blood, and diminished oxidative modifications of proteins and lipids in lung tissue compared with the non-treated meconium-instilled group. In a rabbit model of the meconium aspiration syndrome, aminophylline treatment enhanced pulmonary functions and alleviated oxidative injury and changes in airway reactivity related to lung inflammation.

  10. Genetic Targets of Hydrogen Sulfide in Ventilator-Induced Lung Injury – A Microarray Study

    PubMed Central

    Spassov, Sashko; Pfeifer, Dietmar; Strosing, Karl; Ryter, Stefan; Hummel, Matthias; Faller, Simone; Hoetzel, Alexander

    2014-01-01

    Recently, we have shown that inhalation of hydrogen sulfide (H2S) protects against ventilator-induced lung injury (VILI). In the present study, we aimed to determine the underlying molecular mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million). Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection. PMID:25025333

  11. The protective effect of C-phycocyanin on paraquat-induced acute lung injury in rats.

    PubMed

    Sun, Yingxin; Zhang, Juan; Yan, Yongjian; Chi, Mingfeng; Chen, Wenwen; Sun, Peng; Qin, Song

    2011-09-01

    To investigate the potential protective effect of C-phycocyanin (PC) on paraquat (PQ)-induced acute lung injury, rats were divided into control, PQ-treated and PQ+PC-treated groups. Rats in PQ-treated group were orally administered with 50mg/kg PQ, and rats in PQ+PC-treated group were intraperitoneally injected with 50mg/kg PC after administration of PQ. At 8, 24, 48 and 72h after treatments, GSH-Px and SOD activities, MDA levels in plasma and BALF, HYP, NF-κB, IκB-α and TNF-α contents in lung tissues were measured. The pathological changes in lung were observed. After treatment with PC, the levels of MDA and the relative contents of NF-κB and TNF-α were significantly decreased, the activities of GSH-Px and SOD and the relative contents of IκB-α were significantly increased. The degree of rat lung damage was obviously reduced in PQ+PC-treated group. The results suggested that PC treatment significantly attenuated PQ-induced acute lung injury.

  12. Activation of Akt protects alveoli from neonatal oxygen-induced lung injury.

    PubMed

    Alphonse, Rajesh S; Vadivel, Arul; Coltan, Lavinia; Eaton, Farah; Barr, Amy J; Dyck, Jason R B; Thébaud, Bernard

    2011-02-01

    Bronchopulmonary dysplasia (BPD) is the main complication of extreme prematurity, resulting in part from mechanical ventilation and oxygen therapy. Currently, no specific treatment exists for BPD. BPD is characterized by an arrest in alveolar development and increased apoptosis of alveolar epithelial cells (AECs). Type 2 AECs are putative distal lung progenitor cells, capable of regenerating alveolar homeostasis after injury. We hypothesized that the protection of AEC2 death via the activation of the prosurvival Akt pathway prevents arrested alveolar development in experimental BPD. We show that the pharmacologic inhibition of the prosurvival factor Akt pathway with wortmannin during the critical period of alveolar development impairs alveolar development in newborn rats, resulting in larger and fewer alveoli, reminiscent of BPD. Conversely, in an experimental model of BPD induced by oxygen exposure of newborn rats, alveolar simplification is associated with a decreased activation of lung Akt. In vitro studies with rat lung epithelial (RLE) cells cultured in hyperoxia (95% O(2)) showed decreased apoptosis and improved cell survival after the forced expression of active Akt by adenovirus-mediated gene transfer. In vivo, adenovirus-mediated Akt gene transfer preserves alveolar architecture in the newborn rat model of hyperoxia-induced BPD. We conclude that inhibition of the prosurvival factor Akt disrupts normal lung development, whereas the expression of active Akt in experimental BPD preserves alveolar development. We speculate that the modulation of apoptosis may have therapeutic potential in lung diseases characterized by alveolar damage.

  13. Molecular Mechanisms of Cigarette Smoke-Induced Proliferation of Lung Cells and Prevention by Vitamin C

    PubMed Central

    Dey, Neekkan; Chattopadhyay, Dhruba J.; Chatterjee, Indu B.

    2011-01-01

    Lung cancer is the leading cause of cancer dearth. Cigarette smoking is the strongest risk factor for developing lung cancer, which is conceivably initiated by proliferation. Here, we show that low concentration of aqueous extract of cigarette smoke (AECS) causes excessive proliferation of human lung epithelial cells (A549) without any apoptotic cell death. The causative factor responsible for AECS-induced proliferation has been identified as p-benzoquinone (p-BQ). Coimmunoprecipitation and immunoblot experiments indicate that p-BQ binds with epidermal growth factor receptor (EGFR). However, in contrast to EGF, it causes aberrant phosphorylation of EGFR that lacks c-Cbl-mediated ubiquitination and degradation resulting in persistent activation of EGFR. This is followed by activation of Hras + Kras and the downstream survival and proliferative signaling molecules Akt and ERK1/2, as well as the nuclear transcription factors c-Myc and c-Fos. Vitamin C and/or antibody to p-BQ prevents AECS/p-BQ-induced proliferation of lung cells apparently by inactivating p-BQ and thereby preventing activation of EGFR and the downstream signaling molecules. The results suggest that vitamin C and/or antibody to p-BQ may provide a novel intervention for preventing initiation of lung cancer in smokers. PMID:21772844

  14. Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures.

    PubMed

    Uhl, Franziska E; Vierkotten, Sarah; Wagner, Darcy E; Burgstaller, Gerald; Costa, Rita; Koch, Ina; Lindner, Michael; Meiners, Silke; Eickelberg, Oliver; Königshoff, Melanie

    2015-10-01

    Chronic obstructive pulmonary disease (COPD) is characterised by a progressive loss of lung tissue. Inducing repair processes within the adult diseased lung is of major interest and Wnt/β-catenin signalling represents a promising target for lung repair. However, the translation of novel therapeutic targets from model systems into clinical use remains a major challenge.We generated murine and patient-derived three-dimensional (3D) ex vivo lung tissue cultures (LTCs), which closely mimic the 3D lung microenvironment in vivo. Using two well-known glycogen synthase kinase-3β inhibitors, lithium chloride (LiCl) and CHIR 99021 (CT), we determined Wnt/β-catenin-driven lung repair processes in high spatiotemporal resolution using quantitative PCR, Western blotting, ELISA, (immuno)histological assessment, and four-dimensional confocal live tissue imaging.Viable 3D-LTCs exhibited preserved lung structure and function for up to 5 days. We demonstrate successful Wnt/β-catenin signal activation in murine and patient-derived 3D-LTCs from COPD patients. Wnt/β-catenin signalling led to increased alveolar epithelial cell marker expression, decreased matrix metalloproteinase-12 expression, as well as altered macrophage activity and elastin remodelling. Importantly, induction of surfactant protein C significantly correlated with disease stage (per cent predicted forced expiratory volume in 1 s) in patient-derived 3D-LTCs.Patient-derived 3D-LTCs represent a valuable tool to analyse potential targets and drugs for lung repair. Enhanced Wnt/β-catenin signalling attenuated pathological features of patient-derived COPD 3D-LTCs.

  15. Brain Resuscitation in the Drowning Victim

    PubMed Central

    Topjian, Alexis A.; Berg, Robert A.; Bierens, Joost J. L. M.; Branche, Christine M.; Clark, Robert S.; Friberg, Hans; Hoedemaekers, Cornelia W. E.; Holzer, Michael; Katz, Laurence M.; Knape, Johannes T. A.; Kochanek, Patrick M.; Nadkarni, Vinay; van der Hoeven, Johannes G.

    2013-01-01

    Drowning is a leading cause of accidental death. Survivors may sustain severe neurologic morbidity. There is negligible research specific to brain injury in drowning making current clinical management non-specific to this disorder. This review represents an evidence-based consensus effort to provide recommendations for management and investigation of the drowning victim. Epidemiology, brain-oriented prehospital and intensive care, therapeutic hypothermia, neuroimaging/monitoring, biomarkers, and neuroresuscitative pharmacology are addressed. When cardiac arrest is present, chest compressions with rescue breathing are recommended due to the asphyxial insult. In the comatose patient with restoration of spontaneous circulation, hypoxemia and hyperoxemia should be avoided, hyperthermia treated, and induced hypothermia (32–34 °C) considered. Arterial hypotension/hypertension should be recognized and treated. Prevent hypoglycemia and treat hyperglycemia. Treat clinical seizures and consider treating non-convulsive status epilepticus. Serial neurologic examinations should be provided. Brain imaging and serial biomarker measurement may aid prognostication. Continuous electroencephalography and N20 somatosensory evoked potential monitoring may be considered. Serial biomarker measurement (e.g., neuron specific enolase) may aid prognostication. There is insufficient evidence to recommend use of any specific brain-oriented neuroresuscitative pharmacologic therapy other than that required to restore and maintain normal physiology. Following initial stabilization, victims should be transferred to centers with expertise in age-specific post-resuscitation neurocritical care. Care should be documented, reviewed, and quality improvement assessment performed. Preclinical research should focus on models of asphyxial cardiac arrest. Clinical research should focus on improved cardiopulmonary resuscitation, re-oxygenation/reperfusion strategies, therapeutic hypothermia

  16. Rural Hospital Preparedness for Neonatal Resuscitation

    ERIC Educational Resources Information Center

    Jukkala, Angela; Henly, Susan J.; Lindeke, Linda

    2008-01-01

    Context: Neonatal resuscitation is a critical component of perinatal services in all settings. Purpose: To systematically describe preparedness of rural hospitals for neonatal resuscitation, and to determine whether delivery volume and level of perinatal care were associated with overall preparedness or its indicators. Methods: We developed the…

  17. Cardiac arrest: resuscitation and reperfusion.

    PubMed

    Patil, Kaustubha D; Halperin, Henry R; Becker, Lance B

    2015-06-05

    The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and

  18. Hyperoxia, but not thoracic X-irradiation, potentiates bleomycin- and cyclophosphamide-induced lung damage in mice

    SciTech Connect

    Hakkinen, P.J.; Whiteley, J.W.; Witschi, H.R.

    1982-08-01

    The intraperitoneal administration of cyclophosphamide or bleomycin to BALB/c mice resulted in lung cell damage followed by cellular proliferation, which was quantitated by measuring the increase in thymidine incorporation into pulmonary DNA. We have previously shown that administration of the antioxidant butylated hydroxytoluene produces lung damage that can be potentiated by both hyperoxia and thoracic X-irradiation. In the present study we show that hyperoxic exposure also potentiates bleomycin- and cyclophosphamide-induced acute lung damage. However, thoracic X-irradiation does not potentiate bleomycin- and cyclophosphamide-induced lung toxicity.

  19. Diet‐induced obese mice exhibit altered immune responses to acute lung injury induced by Escherichia coli

    PubMed Central

    Wan, Taomei; Yuan, Guiqiang; Ren, Yi; Wang, Zhengyi; Jia, Yiping; Cui, Hengmin; Peng, Xi; Fang, Jing; Deng, Junliang; Yu, Shumin; Hu, Yanchun; Shen, Liuhong; Ma, Xiaoping; Wang, Ya; Ren, Zhihua

    2016-01-01

    Objective Obesity has been associated with impaired immunity and increased susceptibility to bacterial infection. It also exerts protective effects against mortality secondary to acute lung injury. The effects of obesity on immune responses to acute lung injury induced by Escherichia coli were investigated to determine if the above‐mentioned differences in its effects were related to infection severity. Methods Diet‐induced obesity (DIO) and lean control mice received intranasal instillations of 109 or 1010 CFUs of E. coli. The immune responses were examined at 0 h (uninfected), 24 h, and 96 h postinfection. Results Following infection, the DIO mice exhibited higher leukocyte, interleukin (IL)−10, IL‐6, and tumor necrosis factor‐α levels and more severe lung injury than the lean mice. Following inoculation with 1010 CFUs of E. coli, the DIO mice exhibited higher mortality and more severe inflammation‐induced injury than the lean mice, but no differences in E. coli counts were noted between the two groups. However, inoculated with 109 CFUs of E. coli, the DIO mice exhibited smaller E. coli burdens at 24 h and 96 h after infection, as well as lower concentrations of IL‐10 and tumor necrosis factor‐α and less severe lung injury at 96 h after infection. Conclusions The results support the emerging view that obesity may be beneficial in the setting of milder infection but detrimental in the setting of more severe infection. PMID:27558300

  20. Aryl Hydrocarbon Receptor Protects Lungs from Cockroach Allergen Induced Inflammation by Modulating Mesenchymal Stem Cells

    PubMed Central

    Xu, Ting; Zhou, Yufeng; Qiu, Lipeng; Do, Danh C; Zhao, Yilin; Cui, Zhuang; Wang, Heng; Liu, Xiaopeng; Saradna, Arjun; Cao, Xu; Wan, Mei; Gao, Peisong

    2015-01-01

    Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen treated AhR-deficient (AhR−/−) mice showed exacerbation of lung inflammation when compared to wild-type (WT) mice. In contrast, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen challenged AhR−/− mice as compared to WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes, cyp1a1 and cyp1b1. Furthermore, we tracked the migration of intravenously injected GFP+ MSCs and found that cockroach allergen-challenged AhR−/− mice displayed less migration of MSCs to the lungs compared to WT. The AhR mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium (ECM) prepared from CRE-challenged epithelial cells significantly induced MSC migrations, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGFβ1 neutralizing antibody. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity. PMID:26561548

  1. Aryl Hydrocarbon Receptor Protects Lungs from Cockroach Allergen-Induced Inflammation by Modulating Mesenchymal Stem Cells.

    PubMed

    Xu, Ting; Zhou, Yufeng; Qiu, Lipeng; Do, Danh C; Zhao, Yilin; Cui, Zhuang; Wang, Heng; Liu, Xiaopeng; Saradna, Arjun; Cao, Xu; Wan, Mei; Gao, Peisong

    2015-12-15

    Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen-treated AhR-deficient (AhR(-/-)) mice showed exacerbation of lung inflammation when compared with wild-type (WT) mice. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen-challenged AhR(-/-) mice as compared with WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR, and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes cyp1a1 and cyp1b1. Furthermore, we tracked the migration of i.v.-injected GFP(+) MSCs and found that cockroach allergen-challenged AhR(-/-) mice displayed less migration of MSCs to the lungs compared with WT. The AhR-mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium prepared from cockroach extract-challenged epithelial cells significantly induced MSC migration, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGF-β1-neutralizing Ab. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity.

  2. Cruciform position for trauma resuscitation.

    PubMed

    Mitra, Biswadev; Fitzgerald, Mark C; Olaussen, Alexander; Thaveenthiran, Prasanthan; Bade-Boon, Jordan; Martin, Katherine; Smit, De Villiers; Cameron, Peter A

    2017-04-01

    Multiply injured patients represent a particularly demanding subgroup of trauma patients as they require urgent simultaneous clinical assessments using physical examination, ultrasound and invasive monitoring together with critical management, including tracheal intubation, thoracostomies and central venous access. Concurrent access to multiple body regions is essential to facilitate the concept of 'horizontal' resuscitation. The current positioning of trauma patient, with arms adducted, restricts this approach. Instead, the therapeutic cruciform positioning, with arms abducted at 90°, allows planning and performing of multiple life-saving interventions simultaneously. This positioning also provides a practical surgical field with improved sterility and procedural access.

  3. Calmodulin inhibition contributes to sensitize TRAIL-induced apoptosis in human lung cancer H1299 cells.

    PubMed

    Hwang, Mi-kyung; Min, Yong Ki; Kim, Seong Hwan

    2009-12-01

    Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells. However, TRAIL alone is not effective in treating TRAIL-resistant tumors. We evaluated the effect of 180 enzyme inhibitors on TRAIL-induced apoptosis in human lung cancer H1299 cells, and found fluphenazine-N-2-chloroethane (a calmodulin (CaM) antagonist) sensitized TRAIL-induced apoptosis. Interestingly, in the presence of TRAIL, it increased caspase-8 binding to the Fas-associated death domain (FADD), but decreased binding of FADD-like interleukin-1beta-converting enzyme inhibitory proteins (FLIPs). Additionally, its combination with TRAIL inhibited Akt phosphorylation. These results were consistently observed in cells treated with CaM siRNA. We suggested the blockade of CaM could sensitize lung cancer cells to TRAIL-induced apoptosis in at least 2 ways: (i) it can activate death-inducing signaling complex mediated apoptosis by inhibiting TRAIL-induced binding of FLIP and TRAIL-enhanced binding of caspase-8 to FADD; (ii) it can inhibit Akt phosphorylation, consequently leading to decreased expression of anti-apoptotic molecules such as FLIP and members of the inhibitor of apoptosis protein family. This study suggests the combination of CaM antagonists with TRAIL may have the therapeutic potential to overcome the resistance of lung cancers to apoptosis.

  4. Enhancement of CD147 on M1 macrophages induces differentiation of Th17 cells in the lung interstitial fibrosis.

    PubMed

    Geng, Jie-jie; Zhang, Kui; Chen, Li-na; Miao, Jin-lin; Yao, Meng; Ren, Ying; Fu, Zhi-guang; Chen, Zhi-nan; Zhu, Ping

    2014-09-01

    Lung interstitial fibrosis is a chronic lung disease, and few effective therapies are available to halt or reverse the progression of the disease. In murine and human lung fibrosis, the expression of CD147 is increased. However, the role of CD147 in lung fibrosis has not been identified, and it remains to be determined whether lung fibrosis would be improved by decreasing the expression of CD147. A murine bleomycin-induced lung interstitial fibrosis model was used in the experiments, and HAb18 mAbs and CsA were administered during the induction of lung fibrosis. In our study, we found that the HAb18 mAbs markedly reduced the collagen score and down-regulated M1 macrophages and Th17 cells. In vitro, flow cytometry analysis showed that M1 macrophages induced higher Th17 differentiation than M2 macrophages. After treatment with HAb18 mAbs or after reducing the expression of CD147 by lentivirus interference in M1 macrophages, the level of Th17 cells were significantly inhibited. In conclusion, HAb18 mAbs or CsA treatment ameliorates lung interstitial fibrosis. CD147 promoted M1 macrophage and induced the differentiation of Th17 cells in lung interstitial fibrosis, perhaps by regulating some cytokines such as IL-6, IL-1β, IL-12 and IL-23. These results indicated that CD147 may play an important role in the development of lung interstitial fibrosis.

  5. A preclinical rodent model of acute radiation-induced lung injury after ablative focal irradiation reflecting clinical stereotactic body radiotherapy.

    PubMed

    Hong, Zhen-Yu; Lee, Hae-June; Choi, Won Hoon; Lee, Yoon-Jin; Eun, Sung Ho; Lee, Jung Il; Park, Kwangwoo; Lee, Ji Min; Cho, Jaeho

    2014-07-01

    In a previous study, we established an image-guided small-animal micro-irradiation system mimicking clinical stereotactic body radiotherapy (SBRT). The goal of this study was to develop a rodent model of acute phase lung injury after ablative irradiation. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice using a small animal stereotactic irradiator. At days 1, 3, 5, 7, 9, 11 and 14 after irradiation, the lungs were perfused with formalin for fixation and paraffin sections were stained with hematoxylin and eosin (H&E) and Masson's trichrome. At days 7 and 14 after irradiation, micro-computed tomography (CT) images of the lung were taken and lung functional measurements were performed with a flexiVent™ system. Gross morphological injury was evident 9 days after irradiation of normal lung tissues and dynamic sequential events occurring during the acute phase were validated by histopathological analysis. CT images of the mouse lungs indicated partial obstruction located in the peripheral area of the left lung. Significant alteration in inspiratory capacity and tissue damping were detected on day 14 after irradiation. An animal model of radiation-induced lung injury (RILI) in the acute phase reflecting clinical stereotactic body radiotherapy was established and validated with histopathological and functional analysis. This model enhances our understanding of the dynamic sequential events occurring in the acute phase of radiation-induced lung injury induced by ablative dose focal volume irradiation.

  6. Sulforaphane‐induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC‐05

    PubMed Central

    Zhou, Lan; Yao, Qian; Huang, Yun‐chao; Jiang, Hua; Wang, Chuan‐qiong; Fan, Lei

    2016-01-01

    Background Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non‐smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane‐induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL‐05) to explore the value of sulforaphane in lung cancer prevention and treatment. Methods Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B‐cell lymphoma 2 (Bcl‐2) and Bcl‐2‐like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl‐2, and caspase‐9 protein expression were detected by Western blotting. Results Sulforaphane inhibited XWLC‐05 cell growth with inhibitory concentration (IC)50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC‐05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl‐2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase‐9 protein expression (P < 0.05). Conclusion Sulforaphane induces Xuanwei lung adenocarcinoma cell apoptosis. Its possible mechanism may involve the upregulation of p73 expression and its effector target genes PUMA and Bax in lung cancer cells, downregulation of the anti‐apoptotic gene B cl ‐2, and activation of caspase‐9. It may also involve downregulation of the mutant p53 protein. PMID:27878984

  7. Effect of Human and Sheep Lung Orientation on Primary Blast Injury Induced by Single Blast

    DTIC Science & Technology

    2010-09-01

    kPa 200 500 700 Positive phase duration, ms 2 2 2 From the wo rk do ne by O ’ Brien et al. an d Coop er et al. [ Refs. 5, 6], pressure w...Effect of human and sheep lung orientation on primary blast injury induced by single blast A. Bouamoul, K. Williams DRDC Valcartier, 2459 Pie...main goal o f this stud y is to verify if the injuries observed in the animal are trul y representative of human lung injuries for simple blast

  8. History of Mechanical Ventilation. From Vesalius to Ventilator-induced Lung Injury.

    PubMed

    Slutsky, Arthur S

    2015-05-15

    Mechanical ventilation is a life-saving therapy that catalyzed the development of modern intensive care units. The origins of modern mechanical ventilation can be traced back about five centuries to the seminal work of Andreas Vesalius. This article is a short history of mechanical ventilation, tracing its origins over the centuries to the present day. One of the great advances in ventilatory support over the past few decades has been the development of lung-protective ventilatory strategies, based on our understanding of the iatrogenic consequences of mechanical ventilation such as ventilator-induced lung injury. These strategies have markedly improved clinical outcomes in patients with respiratory failure.

  9. Role of E-selectin in bleomycin induced lung fibrosis in mice

    PubMed Central

    Azuma, A.; Takahashi, S.; Nose, M.; Araki, K.; Araki, M.; Takahashi, T.; Hirose, M.; Kawashima, H.; Miyasaka, M.; Kudoh, S.

    2000-01-01

    BACKGROUND—Bleomycin (BLM), a well known anti-cancer drug, often causes acute lung injury and fibrosis by mechanisms that are not well understood. It is suspected that some proteases and active oxygen species generated from inflammatory cells cause the lung injury and subsequent lung fibrosis. It was therefore hypothesised that inhibition of adhesion of inflammatory cells to the endothelium might prevent these developments.
METHODS—BLM (100 mg/kg) was injected into the tail veins of ICR mice to evaluate the induction of E-selectin, an adhesion molecule known to induce neutrophil attachment on endothelial cells. E-selectin mRNA induction was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The myeloperoxidase (MPO) activities in the lung tissues of BLM treated and control mice were compared to evaluate neutrophil infiltration. Pathological changes in the lungs of soluble E-selectin transgenic mice (TG) and their TG negative (non-TG) littermates after BLM treatment were also compared. Serum samples of TG mice and non-TG mice were tested for their ability to block the binding of sialyl Lewisx to recombinant E-selectin in vitro.
RESULTS—E-selectin mRNA was maximally induced at six hours after BLM treatment in the ICR mice. The soluble form of E-selectin which can competitively inhibit the binding of sialylated antigens on inflammatory cells to E- and P-selectins on the endothelium was detected in the serum of TG mice. BLM induced lung fibrosis occurred in non-TG mice but not in TG mice. This result confirms the finding that the serum of TG mice inhibits the binding of sialyl Lewisx to E-selectin in vitro.
CONCLUSION—E-selectin plays an essential role in BLM induced lung fibrosis through the induction of neutrophil and other inflammatory cell accumulation, and soluble E-selectin may be of use in the prophylactic treatment of lung fibrosis.

 PMID:10639534

  10. Multi-step lung carcinogenesis model induced by oral administration of N-nitrosobis(2-hydroxypropyl)amine in rats.

    PubMed

    Tsujiuchi, Toshifumi; Nakae, Dai; Konishi, Yoichi

    2014-03-01

    N-Nitrosobis(2-hydroxypropyl)amine (BHP) was first synthesized by Krüger et al. (1974), and has been shown to primarily induce pancreatic duct adenocarcinomas by a subcutaneous injection in Syrian hamsters. By contrast, the carcinogenic effect of BHP has been indicated at the different target organs in rats, namely the lung. When rats are received by an oral administration of BHP in drinking water for 25 weeks, a high incidence of lung carcinomas are induced, which include adenocarcinomas, squamous cell carcinomas and combined squamous cell and adenocarcinomas. So many similarities are observed in terms of not only histological appearances but also gene alterations between human and BHP-induced rat lung cancers. Moreover, the step by step development of lung lesions, from preneoplastic lesions to cancers in rat lung carcinogenesis by BHP offers a good model to investigate the mechanisms underlying the pathogenesis of lung cancers. Because data for genetic and epigenetic alterations have indeed been accumulated during the BHP-induced rat lung carcinogenesis, we will introduce them in this review and hence demonstrate that this lung carcinogenesis model provides a useful opportunity for the research on the pathogenesis of lung cancers of both humans and rats.

  11. Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response

    PubMed Central

    Chen, Xueyu; Walther, Frans J.; Sengers, Rozemarijn M. A.; Laghmani, El Houari; Salam, Asma; Folkerts, Gert; Pera, Tonio

    2015-01-01

    Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD. PMID:26047641

  12. Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

    SciTech Connect

    Yoo, Seong Ho; Abdelmegeed, Mohamed A.; Song, Byoung-Joon

    2013-07-05

    Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.

  13. Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response.

    PubMed

    Chen, Xueyu; Walther, Frans J; Sengers, Rozemarijn M A; Laghmani, El Houari; Salam, Asma; Folkerts, Gert; Pera, Tonio; Wagenaar, Gerry T M

    2015-08-01

    Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.

  14. Oxidative Lung Injury in Virus-Induced Wheezing

    DTIC Science & Technology

    2014-05-01

    activating Nrf2. Among them, hepatitis B and C viruses, human cytomegalovirus and the Kaposi’s sarcoma-associated herpes virus, which can all induce ROS...1055-1060, 1996. 48. Schaedler S, Krause J, Himmelsbach K, Carvajal-Yepes M, Lieder F, Klingel K et al. Hepatitis B virus induces expression of...designed to simultaneously probe for 12 viral targets in a single patient specimen (RSV/A, RSV/ B , Influenza A, Influenza A subtype H1, Influenza A subtype

  15. Lung injury after hemorrhage is age-dependent: role of peroxisome proliferator activated receptor γ

    PubMed Central

    Zingarelli, Basilia; Hake, Paul W.; O’Connor, Michael; Burroughs, Timothy J.; Wong, Hector R.; Solomkin, Joseph S.; Lentsch, Alex B.

    2009-01-01

    Objective The incidence of multiple organ failure in pediatric trauma victims is lower than in the adult population. However, the molecular mechanisms are not yet defined. We investigated whether the pathophysiologic characteristics of hemorrhage-induced lung injury may be age-dependent and may be regulated by the peroxisome proliferator activator receptor γ (PPARγ). Design Prospective, laboratory investigation that used an established rodent model of hemorrhagic shock. Setting University hospital laboratory. Subjects Young (n=67; 3–5 months old) and mature (n=66; 11–13 months old) male rats. Interventions Hemorrhagic shock was induced in young and mature rats by withdrawing blood to a mean arterial blood pressure of 50 mmHg. After 3 hrs, rats were rapidly resuscitated by infusing the shed blood and sacrificed 3 hrs thereafter. Measurements and Main Results In young rats, lung injury was characterized by accumulation of red cells and neutrophils at the end of the resuscitation period; at Western blot analysis, lung expression of intercellular adhesion molecule-1 (ICAM-1) was increased. In contrast, the severity of lung injury was more pronounced in mature rats. Lung myeloperoxidase activity and expression of constitutive and inducible ICAM-1 was significantly higher in mature rats when compared to young rats. Mature rats also had higher plasma levels of cytokines and chemokines when compared to young rats. This heightened inflammation was associated with higher degree of activation of nuclear factor-κB and down-regulation of PPARγ and heat shock factor-1 in the lung of mature rats when compared to young rats. Treatment with the PPARγ ligand, the cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2, ameliorated lung injury in young, but not in mature animals. Conclusions Lung injury after severe hemorrhage is age-dependent and may be secondary to a diverse regulation of PPARγ. PMID:19384226

  16. Enhanced cough reflex in a model of bleomycin-induced lung fibrosis in guinea pigs.

    PubMed

    Fernández-Blanco, Joan Antoni; Aguilera, Mònica; Domènech, Anna; Tarrasón, Gema; Prats, Neus; Miralpeix, Montse; De Alba, Jorge

    2015-12-01

    Fibrotic lung diseases, such as idiopathic pulmonary fibrosis, are associated with spontaneous dry cough and hypersensitivity to tussive agents. Understanding the pathophysiology driving enhanced cough may help us to define better therapies for patients. We hypothesized that lung fibrosis induced by intratracheal bleomycin would exacerbate the cough reflex induced by tussive agents in guinea pigs. Disease progression in the lungs was characterized at days 1, 7, 14, 21 and 28 after bleomycin administration. Inflammatory and fibrotic markers, as well as neurotrophin levels, were assessed in bronchoalveolar lavage fluid and/or lung tissue. Cough sensitivity to citric acid, capsaicin and allylisothiocyanate was evaluated in conscious animals at days 14 and 21 after bleomycin administration. Pulmonary lesions evolved from an early inflammatory phase (from day 1 to day 7) to a fibrotic stage (between days 14 and 28). Fibrosis was related to increased levels of matrix metalloproteinase-2 in bronchoalveolar lavage fluid (day 21: saline, 0.26 ng/ml; bleomycin, 0.49 ng/ml). At day 14, we also observed increased cough reflexes to citric acid (163%), capsaicin (125%) and allylisothiocyanate (178%). Cough exacerbation persisted, but at a lower extent, by day 21 for capsaicin (100%) and allylisothiocyanate (54%). Moreover, bronchoalveolar lavage fluid concentrations of brain-derived neurotrophic factor, suggested to induce nerve remodelling in chronic cough, were also enhanced (day 1: saline, 14.21 pg/ml; bleomycin, 30.09 pg/ml). In summary, our model of bleomycin-induced cough exacerbation may be a valuable tool to investigate cough hypersensitivity and develop antitussive therapies for fibrotic lung diseases.

  17. Critical role of CFTR-dependent lipid rafts in cigarette smoke-induced lung epithelial injury

    PubMed Central

    Bodas, Manish; Min, Taehong

    2011-01-01

    Apoptosis of lung epithelial and endothelial cells by exposure to cigarette smoke (CS) severely damages the lung tissue, leading to the pathogenesis of emphysema, but the underlying mechanisms are poorly understood. We have recently established a direct correlation between decreased lipid raft CFTR expression and emphysema progression through increased ceramide accumulation. In the present work, we investigated the role of membrane CFTR in regulating apoptosis and autophagy responses to CS exposure. We report a constitutive and CS-induced increase in the number of TUNEL-positive apoptotic cells in Cftr−/− murine lungs compared with Cftr+/+ murine lungs that also correlated with a concurrent increase in the expression of ceramide, NF-κB, CD95/Fas, lipid raft proteins, and zonula occludens (ZO)-1/2 (P < 0.001). We also verified that stable wild-type CFTR expression in CFBE41o− cells controls constitutively elevated caspase-3/7 activity (−1.6-fold, P < 0.001). Our data suggest that membrane CFTR regulates ceramide-enriched lipid raft signaling platforms required for the induction of Fas-mediated apoptotic signaling. In addition, lack of membrane CFTR also modulates autophagy, as demonstrated by the significant increase in constitutive (P < 0.001) and CSE-induced (P < 0.005) perinuclear accumulation of green fluorescent protein-microtubule-associated protein 1 light chain-3 (LC3) in the absence of membrane CFTR (CFBE41o− cells). The significant constitutive and CS-induced increase (P < 0.05) in p62 and LC3β expression in CFTR-deficient cells and mice corroborates these findings and suggest a defective autophagy response in the absence of membrane CFTR. Our data demonstrate the critical role of membrane-localized CFTR in regulating apoptotic and autophagic responses in CS-induced lung injury that may be involved in the pathogenesis of severe emphysema. PMID:21378025

  18. Critical role of CFTR-dependent lipid rafts in cigarette smoke-induced lung epithelial injury.

    PubMed

    Bodas, Manish; Min, Taehong; Vij, Neeraj

    2011-06-01

    Apoptosis of lung epithelial and endothelial cells by exposure to cigarette smoke (CS) severely damages the lung tissue, leading to the pathogenesis of emphysema, but the underlying mechanisms are poorly understood. We have recently established a direct correlation between decreased lipid raft CFTR expression and emphysema progression through increased ceramide accumulation. In the present work, we investigated the role of membrane CFTR in regulating apoptosis and autophagy responses to CS exposure. We report a constitutive and CS-induced increase in the number of TUNEL-positive apoptotic cells in Cftr(-/-) murine lungs compared with Cftr(+/+) murine lungs that also correlated with a concurrent increase in the expression of ceramide, NF-κB, CD95/Fas, lipid raft proteins, and zonula occludens (ZO)-1/2 (P < 0.001). We also verified that stable wild-type CFTR expression in CFBE41o(-) cells controls constitutively elevated caspase-3/7 activity (-1.6-fold, P < 0.001). Our data suggest that membrane CFTR regulates ceramide-enriched lipid raft signaling platforms required for the induction of Fas-mediated apoptotic signaling. In addition, lack of membrane CFTR also modulates autophagy, as demonstrated by the significant increase in constitutive (P < 0.001) and CSE-induced (P < 0.005) perinuclear accumulation of green fluorescent protein-microtubule-associated protein 1 light chain-3 (LC3) in the absence of membrane CFTR (CFBE41o(-) cells). The significant constitutive and CS-induced increase (P < 0.05) in p62 and LC3β expression in CFTR-deficient cells and mice corroborates these findings and suggest a defective autophagy response in the absence of membrane CFTR. Our data demonstrate the critical role of membrane-localized CFTR in regulating apoptotic and autophagic responses in CS-induced lung injury that may be involved in the pathogenesis of severe emphysema.

  19. R-roscovitine reduces lung inflammation induced by lipoteichoic acid and Streptococcus pneumoniae.

    PubMed

    Hoogendijk, Arie J; Roelofs, Joris J T H; Duitman, Janwillem; van Lieshout, Miriam H P; Blok, Dana C; van der Poll, Tom; Wieland, Catharina W

    2012-09-25

    Bacterial pneumonia remains associated with high morbidity and mortality. The gram-positive pathogen Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. Lipoteichoic acid (LTA) is an important proinflammatory component of the gram-positive bacterial cell wall. R-roscovitine, a purine analog, is a potent cyclin-dependent kinase (CDK)-1, -2, -5 and -7 inhibitor that has the ability to inhibit the cell cycle and to induce polymorphonuclear cell (PMN) apoptosis. We sought to investigate the effect of R-roscovitine on LTA-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LTA or viable S. pneumoniae in vivo. In vitro R-roscovitine enhanced apoptosis in PMNs and reduced tumor necrosis factor (TNF)-α and keratinocyte chemoattractant (KC) production in MH-S (alveolar macrophage) and MLE-12/MLE-15 (respiratory epithelial) cell lines. In vivo R-roscovitine treatment reduced PMN numbers in bronchoalveolar lavage fluid during LTA-induced lung inflammation; this effect was reversed by inhibiting apoptosis. Postponed treatment with R-roscovitine (24 and 72 h) diminished PMN numbers in lung tissue during gram-positive pneumonia; this step was associated with a transient increase in pulmonary bacterial loads. R-roscovitine inhibits proinflammatory responses induced by the gram-positive stimuli LTA and S. pneumoniae. R-roscovitine reduces PMN numbers in lungs upon LTA administration by enhancing apoptosis. The reduction in PMN numbers caused by R-roscovitine during S. pneumoniae pneumonia may hamper antibacterial defense.

  20. Atrial natriuretic peptide protects against Staphylococcus aureus-induced lung injury and endothelial barrier dysfunction

    PubMed Central

    Xing, Junjie; Moldobaeva, Nurgul

    2011-01-01

    Lung inflammation and alterations in endothelial cell (EC) permeability are key events to development of acute lung injury (ALI). Protective effects of atrial natriuretic peptide (ANP) have been shown against inflammatory signaling and endothelial barrier dysfunction induced by gram-negative bacterial wall liposaccharide. We hypothesized that ANP may possess more general protective effects and attenuate lung inflammation and EC barrier dysfunction by suppressing inflammatory cascades and barrier-disruptive mechanisms shared by gram-negative and gram-positive pathogens. C57BL/6J wild-type or ANP knockout mice (Nppa−/−) were treated with gram-positive bacterial cell wall compounds, Staphylococcus aureus-derived peptidoglycan (PepG) and/or lipoteichoic acid (LTA) (intratracheal, 2.5 mg/kg each), with or without ANP (intravenous, 2 μg/kg). In vitro, human pulmonary EC barrier properties were assessed by morphological analysis of gap formation and measurements of transendothelial electrical resistance. LTA and PepG markedly increased pulmonary EC permeability and activated p38 and ERK1/2 MAP kinases, NF-κB, and Rho/Rho kinase signaling. EC barrier dysfunction was further elevated upon combined LTA and PepG treatment, but abolished by ANP pretreatment. In vivo, LTA and PepG-induced accumulation of protein and cells in the bronchoalveolar lavage fluid, tissue neutrophil infiltration, and increased Evans blue extravasation in the lungs was significantly attenuated by intravenous injection of ANP. Accumulation of bronchoalveolar lavage markers of LTA/PepG-induced lung inflammation and barrier dysfunction was further augmented in ANP−/− mice and attenuated by exogenous ANP injection. These results strongly suggest a protective role of ANP in the in vitro and in vivo models of ALI associated with gram-positive infection. Thus ANP may have important implications in therapeutic strategies aimed at the treatment of sepsis and ALI-induced gram-positive bacterial

  1. In vivo effect of surfactant on inflammatory cytokines during endotoxin-induced lung injury in rodents.

    PubMed

    Mittal, Neha; Sanyal, Sankar Nath

    2011-01-01

    Lipopolysaccharide (LPS) is a known inducer of acute respiratory distress syndrome (ARDS) in humans and animals. In this study, ARDS was developed in rats by intratracheal instillation of LPS and the effect of two types of surfactant (natural vs. synthetic) was examined to determine their potential corrective roles in general, as well as to compare the two surfactants against one another in particular, in endotoxin-induced lung injury. Sprague-Dawley male rats were divided into four groups, i.e., rats given: buffer controls; 055:B5 E. coli LPS only; LPS and then porcine surfactant (P-SF); or, LPS and then synthetic surfactant (S-SF). In vivo administration of LPS led to an increase in expression of the cytokines tumor necrosis factor-α, interleukin (IL)-1β, IL-2, IL-4, interferon-γ, monocyte chemotactic protein-1, and macrophage inflammatory protein-1β in the lungs of rats. These effects were confirmed by immunofluorescence in lung tissue sections and/or by protein (Western immunoblot) and mRNA expression (reverse transcription polymerase chain reaction) analyses of tissue samples. Apart from IL-4, concentrations of each of these cytokines in bronchoalveolar lavage fluid recovered from the animals were significantly increased in the LPS-treated hosts. Instillation of either surfactant (70 h after the LPS) into the airways diminished the expression of each of the inducible-cytokines, with the porcine (natural) form seeming having the greater inhibitory effect. These data suggest that surfactant can play an important role in the treatment of endotoxin-induced lung injury and might possess robust anti-inflammatory effects. Further, it seems that both the natural and synthetic surfactants prevent inflammatory outcomes in the lungs by controlling cytokine(s) production by various inflammatory cells. Last, the studies here clearly indicated that in this aspect, natural surfactant appears to be more beneficial compared to synthetic surfactant.

  2. Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

    SciTech Connect

    Tilton, Susan C.; Waters, Katrina M.; Karin, Norman J.; Webb-Robertson, Bobbie-Jo M.; Zangar, Richard C.; Lee, K. Monica; Bigelow, Diana J.; Pounds, Joel G.; Corley, Richard A.

    2013-03-01

    The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts, but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared with RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures. - Highlights: ► Obesity modulates inflammatory markers in BAL fluid after LPS exposure. ► Obese animals have a unique transcriptional signature in lung after LPS exposure. ► Obesity elevates inflammatory stress and reduces antioxidant capacity in the lung

  3. Cocaine enhances HIV-1 gp120-induced lymphatic endothelial dysfunction in the lung

    PubMed Central

    Zhang, Xuefeng; Jiang, Susan; Yu, Jinlong; Kuzontkoski, Paula M; Groopman, Jerome E

    2015-01-01

    Pulmonary complications are common in both AIDS patients and cocaine users. We addressed the cellular and molecular mechanisms by which HIV and cocaine may partner to induce their deleterious effects. Using primary lung lymphatic endothelial cells (L-LECs), we examined how cocaine and HIV-1 gp120, alone and together, modulate signaling and functional properties of L-LECs. We found that brief cocaine exposure activated paxillin and induced cytoskeletal rearrangement, while sustained exposure increased fibronectin (FN) expression, decreased Robo4 expression, and enhanced the permeability of L-LEC monolayers. Moreover, incubating L-LECs with both cocaine and HIV-1 gp120 exacerbated hyperpermeability, significantly enhanced apoptosis, and further impaired in vitro wound healing as compared with cocaine alone. Our studies also suggested that the sigma-1 receptor (Sigma-1R) and the dopamine-4 receptor (D4R) are involved in cocaine-induced pathology in L-LECs. Seeking clinical correlation, we found that FN levels in sera and lung tissue of HIV+ donors were significantly elevated as compared to HIV− donors. Our in vitro data demonstrate that cocaine and HIV-1 gp120 induce dysfunction and damage of lung lymphatics, and suggest that cocaine use may exacerbate pulmonary edema and fibrosis associated with HIV infection. Continued exploration of the interplay between cocaine and HIV should assist the design of therapeutics to ameliorate HIV-induced pulmonary disorders within the drug using population. PMID:26311830

  4. Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.

    PubMed

    Allen, Thaddeus D; Rodriguez, Elena M; Jones, Kirk D; Bishop, J Michael

    2011-09-15

    Notch1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect Notch1 in T-cell acute lymphoblastic leukemia (T-ALL) and, recently, have been found in non-small-cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated Notch1 in the lung by developing a transgenic mouse model in which activated Notch1 was overexpressed in the alveolar epithelium. The initial response to activated Notch1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas appeared in the transgenic mice but failed to progress to become carcinomas. Interestingly, Myc and MycL1 were expressed in the adenomas, suggesting that selection for enhanced Myc activity may facilitate tumorigenesis. Using mice engineered to coexpress activated Notch1 and Myc, we found that supplementing Myc expression resulted in increased frequency of Notch1 intracellular domain (N1ICD)-induced adenoma formation and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by Myc and/or activated Notch1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated Notch1 substitutes for RAS activation synergistically with Myc in the development of NSCLC. These tumor models should be valuable for exploring the role of activated Notch1 in the genesis of NSCLC and for testing therapies targeting either activated Notch1 or its downstream effectors.

  5. Influenza virus-induced lung injury: pathogenesis and implications for treatment.

    PubMed

    Herold, Susanne; Becker, Christin; Ridge, Karen M; Budinger, G R Scott

    2015-05-01

    The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy.

  6. Successful and not so successful chemoprevention of tobacco smoke-induced lung tumors.

    PubMed

    Witschi, H

    2000-12-01

    Strain A/J mice underwent whole body exposure for 6 hours a day, 5 days a week, for 5 months to a mixture of cigarette sidestream and mainstream smoke (89%-11%; total suspended particulates 80-150 mg/m3), then were kept for another 4 months in air before being killed for scoring of lung tumors. In 7 independent experiments, lung tumor multiplicity was significantly increased in all 7 trials and lung tumor incidence in 5. When animals were kept for 9 months in smoke, lung tumor multiplicity was not significantly higher than in controls, although lung tumor incidence was. The following chemopreventive agents were evaluated: green tea, phenethyl isothiocyanate (PEITC), acetylsalicylic acid (ASA), N-acetylcysteine (NAC), p-XSC (1,4-phenylenebis[methylene]selenocyanate), d-limonene (DL), and a mixture of PEITC and BITC (benzyl isothiocyanate). In animals exposed to tobacco smoke, none of these agents reduced lung tumor multiplicity or incidence. As a control, the effects of the same agents were examined in A/J mice initiated with 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK) or urethane. In mice injected with NNK, green tea and ASA did not reduce lung tumor multiplicities and NAC had no effect on urethane-induced lung tumors, whereas PEITC, p-XSC and DL reduced NNK-induced tumor multiplicities to 20% to 50% of control values. On the other hand, dietary mixture of myoinositol and dexamethasone was not only highly protective against NNK, but reduced lung tumor multiplicities and incidence in smoke-exposed animals to control values. This effect was also seen when the animals were fed the myo-inositol-dexamethasone mixture once they were removed from smoke. It is concluded that in animal studies it might be preferable to evaluate the effectiveness of putative chemopreventive agents against full tobacco smoke rather than against selected model compounds. The observations made with myo-inositol-dexamethasone suggest that people who have recently quit smoking might

  7. Platycodin D protects against cigarette smoke-induced lung inflammation in mice.

    PubMed

    Gao, Wei; Guo, Ying; Yang, Hongxia

    2017-03-28

    Cigarette smoke is the one of the major factors that leads to chronic obstructive pulmonary disease (COPD). Inflammation and oxidant stress have been known to play critical roles in the development of COPD. Platycodin D (PLD) has been reported to have anti-inflammatory and anti-oxidant effects. In this study, we aimed to investigate the protective effects of PLD on cigarette smoke (CS)-induced lung inflammation in mice. PLD was adminstrated i.p. to mice 2h before CS exposure daily for five consecutive days. The production of inflammatory cytokines TNF-α and IL-1β were measured by ELISA. The levels of malonaldehyde (MDA) and nitric oxide (NO) were also detected in this study. The expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NF-κB, and IκBα were detected by western blot analysis. The results showed that PLD significantly attenuated CS-induced lung pathological changes, inflammatory cells infiltration, as well as TNF-α and IL-1β production. CS-induced MDA and NO production were also inhibited by treatment of PLD. Western blot analysis showed that PLD significantly suppressed CS-induced NF-κB activation. In addition, PLD was found to increase the expression of Nrf2 and HO-1. Taken together, these results indicated that PLD protected against CS-induced lung inflammation by inhibiting inflammatory and oxidative response through activating Nrf2 signaling pathway. PLD might be an effective treatment for CS-induced lung inflammation.

  8. Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

    PubMed

    Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

    2015-04-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.

  9. Acute ozone-induced lung injury in rats: Structural-functional relationships of developing alveolar edema

    SciTech Connect

    Paterson, J.F.; Hammond, M.D.; Montgomery, M.R.; Sharp, J.T.; Farrier, S.E.; Balis, J.U. )

    1992-11-01

    As part of a study on the effects of acute ozone stress on the lung surfactant system, we correlated morphometric, biochemical, and functional indices of lung injury using male rats exposed to 3 ppm ozone for 1, 2, 4, and 8 hr. Evaluation of lung mechanics, using the Pulmonary Evaluation and Diagnostic Laboratory System, revealed a significant decrease in dynamic lung compliance (ml/cmH[sub 2]O/kg) from a control value of 0.84 [plus minus] 0.02 (SEM) to 0.72 [plus minus] 0.04 and 0.57 [plus minus] 0.06 at 4 and 8 hr, respectively. At 2 hr there was a transient increase in PaO[sub 2] to 116 torr (control = 92 torr) followed by a decrease at 4 hr (65 torr) and 8 hr (55 torr). Morphometry of lung tissue, fixed by perfusion of fixative via the pulmonary artery at 12 cm H[sub 2]O airway distending pressure, demonstrated an increase in the area of the intravascular compartment at 8 hr, in association with a 65 and 39% replacement of the alveolar area by fluid in ventral and dorsal lung regions, respectively. There was a positive correlation (r = 0.966) between alveolar edema and transudated proteins in lavage fluid. A stepwise multiple regression model, with edema as the dependent variable, suggested that pulmonary vasodilatation, hypoxemia, and depletion of surfactant tubular myelin in lavage fluid were indices for predicting alveolar edema. In a second model, with lavage protein concentration as the dependent variable, decreasing dynamic compliance and hypoxemia were predictors of progressive, intraalveolar transudation of plasma proteins. The above structural-functional relationships support the concept that ozone-induced high-protein alveolar edema is pathogenetically linked to pulmonary hyperemia, deficiency of surfactant tubular myelin, and associated lung dysfunctions.

  10. LOW DOSE NITRITE ENHANCES PERFUSION AFTER FLUID RESUSCITATION FROM HEMORRHAGIC SHOCK

    PubMed Central

    Cabrales, Pedro

    2010-01-01

    This study determines the systemic and microvascular hemodynamic consequences of administering a low dose sodium nitrite after fluid resuscitation from hemorrhagic shock. Hemodynamic responses to hemorrhagic shock and resuscitation were studied in the hamster window chamber model. Moderated hemorrhage was induced by arterial controlled bleeding of 50% of the blood volume (BV) and the hypovolemic state was maintained for one hour. Volume restitution was performed by infusion of 25% of BV using Hextend® (6% Hetastarch 670 kDa in lactated electrolyte solution) 10 min after fluid resuscitation 100μl of specific concentrations of sodium nitrite were infused. The experimental groups were named based on the nitrite concentration used, namely: 0 μM, 10 μM and 50 μM. Systemic parameters, microvascular hemodynamics and capillary perfusion (functional capillary density, FCD) were followed during entire protocol. Exogenous 10 μM nitrite maintained systemic and microhemodynamic conditions post fluid resuscitation from hemorrhagic shock, compared to 50 μM or no nitrite. A moderated increase in plasma nitrite during the early phase of resuscitation reversed arteriolar vasoconstriction and increased capillary perfusion and venous return, improving central cardiac function. Nitrite effects on resistance vessels, directly influenced intravascular pressure redistribution, sustained blood flow, and prevented tissue ischemia. In conclusion, increasing nitrite plasma bioavailability after fluid resuscitation from hemorrhagic shock can be a potential therapy to enhance microvascular perfusion and to improve overall outcome. PMID:19804938

  11. Protective Role of Liriodendrin in Sepsis-Induced Acute Lung Injury.

    PubMed

    Yang, Lei; Li, Dihua; Zhuo, Yuzhen; Zhang, Shukun; Wang, Ximo; Gao, Hongwei

    2016-10-01

    In current study, we investigated the role of liriodendrin, a constituent isolated from Sargentodoxa cuneata (Oliv.) Rehd. Et Wils (Sargentodoxaceae), in cecal ligation and puncture (CLP)-induced acute lung inflammatory response and injury (ALI). The inflammatory mediator levels in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay (ELISA). Pathologic changes in lung tissues were evaluated via pathological section with hematoxylin and eosin (H&E) staining. To investigate the mechanism whereby liriodendrin regulates lung inflammation, the phosphorylation of the NF-kB (p65) and expression of vascular endothelial growth factor (VEGF) were determined by western blot assay. We show that liriodendrin treatment significantly improved the survival rate of mice with CLP-induced sepsis. Pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration were markedly decreased by liriodendrin. In addition, liriodendrin decreased the production of the proinflammatory mediators including (TNF-α, IL-1β, MCP-1, and IL-6) in lung tissues. Vascular permeability and lung myeloperoxidase (MPO) accumulation in the liriodendrin-treated mice were substantially reduced. Moreover, liriodendrin treatment significantly suppressed the expression of VEGF and activation of NF-kB in the lung. We further show that liriodendrin significantly reduced the production of proinflammatory mediators and downregulated NF-kB signaling in LPS-stimulated RAW 264.7 macrophage cells. Moreover, liriodendrin prevented the generation of reactive oxygen species (ROS) by upregulating the expression of SIRT1 in RAW 264.7 cells. These findings provide a novel theoretical basis for the possible application of liriodendrin in clinic.

  12. Rtp801 Suppression of Epithelial mTORC1 Augments Endotoxin-Induced Lung Inflammation

    PubMed Central

    Nadon, Aaron M.; Perez, Mario J.; Hernandez-Saavedra, Daniel; Smith, Lynelle P.; Yang, Yimu; Sanders, Linda A.; Gandjeva, Aneta; Chabon, Jacob; Koyanagi, Daniel E.; Graham, Brian B.; Tuder, Rubin M.; Schmidt, Eric P.

    2015-01-01

    The mechanistic target of rapamycin (mTOR) is a central regulator of cellular responses to environmental stress. mTOR (and its primary complex mTORC1) is, therefore, ideally positioned to regulate lung inflammatory responses to an environmental insult, a function directly relevant to disease states such as the acute respiratory distress syndrome. Our previous work in cigarette smoke–induced emphysema identified a novel protective role of pulmonary mTORC1 signaling. However, studies of the impact of mTORC1 on the development of acute lung injury are conflicting. We hypothesized that Rtp801, an endogenous inhibitor of mTORC1, which is predominantly expressed in alveolar type II epithelial cells, is activated during endotoxin-induced lung injury and functions to suppress anti-inflammatory epithelial mTORC1 responses. We administered intratracheal lipopolysaccharide to wild-type mice and observed a significant increase in lung Rtp801 mRNA. In lipopolysaccharide-treated Rtp801−/− mice, epithelial mTORC1 activation significantly increased and was associated with an attenuation of lung inflammation. We reversed the anti-inflammatory phenotype of Rtp801−/− mice with the mTORC1 inhibitor, rapamycin, reassuring against mTORC1-independent effects of Rtp801. We confirmed the proinflammatory effects of Rtp801 by generating a transgenic Rtp801 overexpressing mouse, which displayed augmented inflammatory responses to intratracheal endotoxin. These data suggest that epithelial mTORC1 activity plays a protective role against lung injury, and its inhibition by Rtp801 exacerbates alveolar injury caused by endotoxin. PMID:25016184

  13. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer.

    PubMed

    Lim, Do Young; Shin, Seung Ho; Lee, Mee-Hyun; Malakhova, Margarita; Kurinov, Igor; Wu, Qiong; Xu, Jinglong; Jiang, Yanan; Dong, Ziming; Liu, Kangdong; Lee, Kun Yeong; Bae, Ki Beom; Choi, Bu Young; Deng, Yibin; Bode, Ann; Dong, Zigang

    2016-06-07

    Various carcinogens induce EGFR/RAS/MAPK signaling, which is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 in lung carcinogenesis could be beneficial. We examined the therapeutic effect of catechol in lung cancer treatment. Catechol suppressed anchorage-independent growth of murine KP2 and human H460 lung cancer cell lines in a dose-dependent manner. Catechol inhibited ERK2 kinase activity in vitro, and its direct binding to the ERK2 active site was confirmed by X-ray crystallography. Phosphorylation of c-Myc, a substrate of ERK2, was decreased in catechol-treated lung cancer cells and resulted in reduced protein stability and subsequent down-regulation of total c-Myc. Treatment with catechol induced G1 phase arrest in lung cancer cells and decreased protein expression related to G1-S progression. In addition, we showed that catechol inhibited the growth of both allograft and xenograft lung cancer tumors in vivo. In summary, catechol exerted inhibitory effects on the ERK2/c-Myc signaling axis to reduce lung cancer tumor growth in vitro and in vivo, including a preclinical patient-derived xenograft (PDX) model. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis in future clinical approaches.

  14. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer

    PubMed Central

    Lim, Do Young; Shin, Seung Ho; Lee, Mee-Hyun; Malakhova, Margarita; Kurinov, Igor; Wu, Qiong; Xu, Jinglong; Jiang, Yanan; Dong, Ziming; Liu, Kangdong; Lee, Kun Yeong; Bae, Ki Beom; Choi, Bu Young; Deng, Yibin; Bode, Ann; Dong, Zigang

    2016-01-01

    Various carcinogens induce EGFR/RAS/MAPK signaling, which is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 in lung carcinogenesis could be beneficial. We examined the therapeutic effect of catechol in lung cancer treatment. Catechol suppressed anchorage-independent growth of murine KP2 and human H460 lung cancer cell lines in a dose-dependent manner. Catechol inhibited ERK2 kinase activity in vitro, and its direct binding to the ERK2 active site was confirmed by X-ray crystallography. Phosphorylation of c-Myc, a substrate of ERK2, was decreased in catechol-treated lung cancer cells and resulted in reduced protein stability and subsequent down-regulation of total c-Myc. Treatment with catechol induced G1 phase arrest in lung cancer cells and decreased protein expression related to G1-S progression. In addition, we showed that catechol inhibited the growth of both allograft and xenograft lung cancer tumors in vivo. In summary, catechol exerted inhibitory effects on the ERK2/c-Myc signaling axis to reduce lung cancer tumor growth in vitro and in vivo, including a preclinical patient-derived xenograft (PDX) model. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis in future clinical approaches. PMID:27167001

  15. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

    PubMed Central

    Grabner, Beatrice; Schramek, Daniel; Mueller, Kristina M.; Moll, Herwig P.; Svinka, Jasmin; Hoffmann, Thomas; Bauer, Eva; Blaas, Leander; Hruschka, Natascha; Zboray, Katalin; Stiedl, Patricia; Nivarthi, Harini; Bogner, Edith; Gruber, Wolfgang; Mohr, Thomas; Zwick, Ralf Harun; Kenner, Lukas; Poli, Valeria; Aberger, Fritz; Stoiber, Dagmar; Egger, Gerda; Esterbauer, Harald; Zuber, Johannes; Moriggl, Richard; Eferl, Robert; Győrffy, Balázs; Penninger, Josef M.; Popper, Helmut; Casanova, Emilio

    2015-01-01

    STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3–NF-κB–IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance. PMID:25734337

  16. Subamolide a induces mitotic catastrophe accompanied by apoptosis in human lung cancer cells.

    PubMed

    Hung, Jen-Yu; Wen, Ching-Wen; Hsu, Ya-Ling; Lin, En-Shyh; Huang, Ming-Shyan; Chen, Chung-Yi; Kuo, Po-Lin

    2013-01-01

    This study investigated the anticancer effects of subamolide A (Sub-A), isolated from Cinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS) production and decreased glutathione level. The elevated ROS triggered the activation of ataxia-telangiectasia mutation (ATM), which further enhanced the ATF3 upregulation and subsequently enhanced p53 function by phosphorylation at Serine 15 and Serine 392. The antioxidant, EUK8, significantly decreased mitotic catastrophe by inhibiting ATM activation, ATF3 expression, and p53 phosphorylation. The reduction of ATM and ATF3 expression by shRNA decreased Sub-A-mediated p53 phosphorylation and mitotic catastrophe. Sub-A also caused a dramatic 70% reduction in tumor size in an animal model. Taken together, cell death of lung cancer cells in response to Sub-A is dependent on ROS generation, which triggers mitotic catastrophe followed by apoptosis. Therefore, Sub-A may be a novel anticancer agent for the treatment of nonsmall cell lung cancer.

  17. Tracking of Mesenchymal Stem Cells with Fluorescence Endomicroscopy Imaging in Radiotherapy-Induced Lung Injury

    PubMed Central

    Perez, Jessica R.; Ybarra, Norma; Chagnon, Frederic; Serban, Monica; Lee, Sangkyu; Seuntjens, Jan; Lesur, Olivier; El Naqa, Issam

    2017-01-01

    Mesenchymal stem cells (MSCs) have potential for reducing inflammation and promoting organ repair. However, limitations in available techniques to track them and assess this potential for lung repair have hindered their applicability. In this work, we proposed, implemented and evaluated the use of fluorescence endomicroscopy as a novel imaging tool to track MSCs in vivo. MSCs were fluorescently labeled and injected into a rat model of radiation-induced lung injury via endotracheal (ET) or intravascular (IV) administration. Our results show that MSCs were visible in the lungs with fluorescence endomicroscopy. Moreover, we developed an automatic cell counting algorithm to quantify the number of detected cells in each condition. We observed a significantly higher number of detected cells in ET injection compared to IV and a slight increase in the mean number of detected cells in irradiated lungs compared to control, although the latter did not reach statistical significance. Fluorescence endomicroscopy imaging is a powerful new minimally invasive and translatable tool that can be used to track and quantify MSCs in the lungs and help assess their potential in organ repair. PMID:28102237

  18. Mechanical stretch-induced serotonin release from pulmonary neuroendocrine cells: implications for lung development.

    PubMed

    Pan, Jie; Copland, Ian; Post, Martin; Yeger, Herman; Cutz, Ernest

    2006-01-01

    Pulmonary neuroendocrine cells (PNEC) produce amine (serotonin, 5-HT) and peptides (e.g., bombesin, calcitonin) with growth factor-like properties and are thought to play an important role in lung development. Because physical forces are essential for lung growth and development, we investigated the effects of mechanical strain on 5-HT release in PNEC freshly isolated from rabbit fetal lung and in the PNEC-related tumor H727 cell line. Cultures exposed to sinusoidal cyclic stretch showed a significant 5-HT release inhibitable with gadolinium chloride (10 nM), a blocker of mechanosensitive channels. In contrast to hypoxia (Po2 approximately 20 mmHg), stretch-induced 5-HT release was not affected by Ca2+-free medium or nifedipine (50 microM), excluding the exocytic pathway. In H727 cells, stretch failed to release calcitonin, a peptide stored within dense core vesicles (DCV), whereas hypoxia caused massive calcitonin release. 5-HT released by mechanical stretch is derived predominantly from the cytoplasmic pool, because it is rapid ( approximately 5 min) and is releasable from early (20 days of gestation) fetal PNEC containing few DCV. Both mechanical stretch and hypoxia upregulated expression of tryptophan hydroxylase, the rate-limiting enzyme of 5-HT synthesis. We conclude that mechanical strain is an important physiological stimulus for the release of 5-HT from PNEC via mechanosensitive channels with potential effects on lung development and resorption of lung fluid at the time of birth.

  19. Tracking of Mesenchymal Stem Cells with Fluorescence Endomicroscopy Imaging in Radiotherapy-Induced Lung Injury

    NASA Astrophysics Data System (ADS)

    Perez, Jessica R.; Ybarra, Norma; Chagnon, Frederic; Serban, Monica; Lee, Sangkyu; Seuntjens, Jan; Lesur, Olivier; El Naqa, Issam

    2017-01-01

    Mesenchymal stem cells (MSCs) have potential for reducing inflammation and promoting organ repair. However, limitations in available techniques to track them and assess this potential for lung repair have hindered their applicability. In this work, we proposed, implemented and evaluated the use of fluorescence endomicroscopy as a novel imaging tool to track MSCs in vivo. MSCs were fluorescently labeled and injected into a rat model of radiation-induced lung injury via endotracheal (ET) or intravascular (IV) administration. Our results show that MSCs were visible in the lungs with fluorescence endomicroscopy. Moreover, we developed an automatic cell counting algorithm to quantify the number of detected cells in each condition. We observed a significantly higher number of detected cells in ET injection compared to IV and a slight increase in the mean number of detected cells in irradiated lungs compared to control, although the latter did not reach statistical significance. Fluorescence endomicroscopy imaging is a powerful new minimally invasive and translatable tool that can be used to track and quantify MSCs in the lungs and help assess their potential in organ repair.

  20. Benzo(a)pyrene induced structural and functional modifications in lung cystatin.

    PubMed

    Khan, Mohd Shahnawaz; Priyadarshini, Medha; Shah, Aaliya; Tabrez, Shams; Jagirdar, Haseeb; Alsenaidy, Abdulrahman M; Bano, Bilqees

    2013-10-01

    Cystatins are thiol proteinase inhibitors ubiquitously present in the mammalian body. They serve a protective function to regulate the activities of endogenous proteinases, which may cause uncontrolled proteolysis and damage. In the present study, the effect of benzo(a)pyrene [BaP] on lung cystatin was studied to explore the hazardous effects of environmental pollutant on structural and functional integrity of the protein. The basic binding interaction was studied by UV-absorption, FT-IR, and fluorescence spectroscopy. The enhancement of total protein fluorescence with a red shift of 5 nm suggests structural scratch of lung cystatin by benzo(a)pyrene. Further, ANS binding studies reaffirm the unfolding of the thiol protease inhibitor (GLC-I) after treating with benzo(a)pyrene. The results of FT-IR spectroscopy reflect perturbation of the secondary conformation (alpha-helix to β-sheet) in goat lung cystatin on interaction with BaP. Finally, functional inactivation of cystatin on association with BaP was checked by its papain inhibitory activity. Benzo(a)pyrene (10 μM) caused complete inactivation of goat lung cystatin. Benzo(a)pyrene-induced loss of structure and function in the thiol protease inhibitor could provide a caution for lung injury caused by the pollutants and smokers.

  1. Protective role of ascorbic acid against asbestos induced toxicity in rat lung: in vitro study.

    PubMed

    Khan, S G; Ali, S; Rahman, Q

    1990-01-01

    Asbestos fibers adsorb cytochrome P-450 and P-448 proteins from rat lung micosomal fractions and liberate heme from cytochrome P-448 on prolonged incubation in vitro. further, fibers, decrease the activities of benzo(a)pyrene hydroxylase and glutathione-S-transferase in microsomal and cytosolic fractions respectively. Mineral fibers also stimulate both the enzymatic (NADPH-induced) and non-enzymatic (Fe2(+)-induced) lipid peroxidation in microsomal fractions. Preincubation of microsomal and cytosolic fractions with a physiological concentration of ascorbic acid ameliorates, to a large extent, the changes induced by asbestos fibers.

  2. Effects of erdosteine on bleomycin-induced lung fibrosis in rats.

    PubMed

    Boyaci, Haşim; Maral, Hale; Turan, Gupse; Başyiğit, Ilknur; Dillioğlugil, Meltem O; Yildiz, Füsun; Tugay, Melih; Pala, Ayşe; Erçin, Cengiz

    2006-01-01

    This study was designed to examine the effects of erdosteine on bleomycin (BLM)-induced lung fibrosis in rats. Thirty-three Sprague-Dawley rats were divided randomly into three groups, bleomycin alone (BLM), bleomycin + erdosteine (BLM + ERD), and saline alone (control). The BLM and BLM + ERD groups, were given 2.5 mg/kg BLM intratracheally. The first dose of oral erdosteine (10 mg/kg/day) in the BLM + ERD group was started 2 days before BLM administration and continued until animals were sacrificed. Animals were sacrificed 14 days after intratracheal instillation of BLM. The effect of erdosteine on pulmonary fibrosis was studied by analysis of bronchoalveolar lavage (BAL) fluid, histopathology, and biochemical measurements of lung tissue superoxide dismutase (SOD) and glutathione (GSH) as antioxidants, malondialdehyde (MDA) as an index for lipid peroxidation, and nitrite/nitrate levels. Bleomycin-induced lung fibrosis as determined by lung histology was prevented with erdosteine (grades of fibrosis were 4.9, 2.3, and 0.2 in BLM, BLM + ERD, and control groups, respectively). Erdosteine also prevented bleomycin-induced increase in MDA (MDA levels were 0.50 +/- 0.15, 0.11 +/- 0.02, and 0.087+/- 0.03 nmol/mg protein in BLM, BLM + ERD, and control groups, respectively) and nitrite/nitrate (nitrite/nitrate levels were 0.92 +/- 0.06, 0.60 +/- 0.09, and 0.56+/- 0.1 micromol/mg protein in BLM, BLM + ERD, and control groups respectively) levels. Bleomycin-induced decrease in GSH and SOD levels in the lung tissue also prevented by erdosteine [(GSH levels were 213.5 +/- 12.4, 253.2+/- 25.2, and 287.9+/- 34.4 nmol/mg protein) (SOD levels were 1.42+/- 0.12, 1.75+/- 0.17, and 1.89+/- 0.09 U/mg protein) in BLM, BLM + ERD, and control groups respectively]. Erdosteine prevented bleomycin-induced increases in total cell number and neutrophil content of the BAL fluid. In conclusion, oral erdosteine is effective in prevention of BLM-induced lung fibrosis in rats possibly via the

  3. Altered surfactant homeostasis and alveolar epithelial cell stress in amiodarone-induced lung fibrosis.

    PubMed

    Mahavadi, Poornima; Henneke, Ingrid; Ruppert, Clemens; Knudsen, Lars; Venkatesan, Shalini; Liebisch, Gerhard; Chambers, Rachel C; Ochs, Matthias; Schmitz, Gerd; Vancheri, Carlo; Seeger, Werner; Korfei, Martina; Guenther, Andreas

    2014-11-01

    Amiodarone (AD) is a highly efficient antiarrhythmic drug with potentially serious side effects. Severe pulmonary toxicity is reported in patients receiving AD even at low doses and may cause interstitial pneumonia as well as lung fibrosis. Apoptosis of alveolar epithelial type II cells (AECII) has been suggested to play an important role in this disease. In the current study, we aimed to establish a murine model of AD-induced lung fibrosis and analyze surfactant homeostasis, lysosomal, and endoplasmic reticulum (ER) stress in this model. AD/vehicle was instilled intratracheally into C57BL/6 mice, which were sacrificed on days 7, 14, 21, and 28. Extent of lung fibrosis development was assessed by trichrome staining and hydroxyproline measurement. Cytotoxicity was assessed by lactate dehydrogenase assay. Phospholipids (PLs) were analyzed by mass spectrometry. Surfactant proteins (SP) and markers for apoptosis, lysosomal, and ER stress were studied by Western blotting and immunohistochemistry. AECII morphology was evaluated by electron microscopy. Extensive lung fibrosis and AECII hyperplasia were observed in AD-treated mice already at day 7. Surfactant PL and SP accumulated in AECII over time. In parallel, induction of apoptosis, lysosomal, and ER stress was encountered in AECII of mice lungs and in MLE12 cells treated with AD. In vitro, siRNA-mediated knockdown of cathepsin D did not alter the AD-induced apoptotic response. Our data suggest that mice exposed to intratracheal AD develop severe pulmonary fibrosis, exhibit extensive surfactant alterations and cellular stress, but AD-induced AECII apoptosis is not mediated primarily via cathepsin D.

  4. Identification of gene markers in the development of smoking-induced lung cancer.

    PubMed

    Yang, Zhao; Zhuan, Bing; Yan, Ying; Jiang, Simin; Wang, Tao

    2016-01-15

    Lung cancer is a malignant tumor with high mortality in both women and men. To study the mechanisms of smoking-induced lung cancer, we analyzed microarray of GSE4115. GSE4115 was downloaded from Gene Expression Omnibus including 78 and 85 bronchial epithelium tissue samples separately from smokers with and without lung cancer. Limma package in R was used to screen differentially expressed genes (DEGs). Hierarchical cluster analysis for DEGs was conducted using orange software and visualized by distance map. Using DAVID software, functional and pathway enrichment analyses separately were conducted for the DEGs. And protein-protein interaction (PPI) network was constructed using Cytoscape software. Then, the pathscores of enriched pathways were calculated. Besides, functional features were screened and optimized using the recursive feature elimination (RFE) method. Additionally, the support vector machine (SVM) method was used to train model. Total 1923 DEGs were identified between the two groups. Hierarchical cluster analysis indicated that there were differences in gene level between the two groups. And SVM analysis indicated that the five features had potential diagnostic value. Importantly, MAPK1 (degree=30), SRC (degree=29), SMAD4 (degree=23), EEF1A1 (degree=21), TRAF2 (degree=21) and PLCG1 (degree=20) had higher degrees in the PPI network of the DEGs. They might be involved in smoking-induced lung cancer by interacting with each other (e.g. MAPK1-SMAD4, SMAD4-EEF1A1 and SRC-PLCG1). MAPK1, SRC, SMAD4, EEF1A1, TRAF2 and PLCG1 might be responsible for the development of smoking-induced lung cancer.

  5. Leptin treatment ameliorates acute lung injury in rats with cerulein-induced acute pancreatitis

    PubMed Central

    Gultekin, Fatma Ayca; Kerem, Mustafa; Tatlicioglu, Ertan; Aricioglu, Aysel; Unsal, Cigdem; Bukan, Neslihan

    2007-01-01

    AIM: To determine the effect of exogenous leptin on acute lung injury (ALI) in cerulein-induced acute pancreatitis (AP). METHODS: Forty-eight rats were randomly divided into 3 groups. AP was induced by intraperitoneal (i.p.) injection of cerulein (50 μg/kg) four times, at 1 h intervals. The rats received a single i.p. injection of 10 μg/kg leptin (leptin group) or 2 mL saline (AP group) after cerulein injections. In the sham group, animals were given a single i.p. injection of 2 mL saline. Experimental samples were collected for biochemical and histological evaluations at 24 h and 48 h after the induction of AP or saline administration. Blood samples were obtained for the determination of amylase, lipase, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, macrophage inflammatory peptide (MIP)-2 and soluble intercellular adhesion molecule (sICAM)-1 levels, while pancreatic and lung tissues were removed for myeloperoxidase (MPO) activity, nitric oxide (NOx) level, CD40 expression and histological evaluation. RESULTS: Cerulein injection caused severe AP, confirmed by an increase in serum amylase and lipase levels, histopathological findings of severe AP, and pancreatic MPO activity, compared to the values obtained in the sham group. In the leptin group, serum levels of MIP-2, sICMA-1, TNF-α, and IL-1β, pancreatic MPO activity, CD40 expression in pancreas and lung tissues, and NOx level in the lung tissue were lower compared to those in the AP group. Histologically, pancreatic and lung damage was less severe following leptin administration. CONCLUSION: Exogenous leptin attenuates inflamma-tory changes, and reduces pro-inflammatory cytokines, nitric oxide levels, and CD40 expression in cerulein-induced AP and may be protective in AP associated ALI. PMID:17589942

  6. Susceptibility to quantum dot induced lung inflammation differs widely among the Collaborative Cross founder mouse strains

    PubMed Central

    Scoville, David K.; White, Collin C.; Botta, Dianne; McConnachie, Lisa A.; Zadworny, Megan E.; Schmuck, Stefanie C.; Hu, Xiaoge; Gao, Xiaohu; Yu, Jianbo; Dills, Russell L.; Sheppard, Lianne; Delaney, Martha A.; Griffith, William C.; Beyer, Richard P.; Zangar, Richard C.; Pounds, Joel G.; Faustman, Elaine M.; Kavanagh, Terrance J.

    2015-01-01

    Quantum dots (QDs) are engineered semiconductor nanoparticles with unique physicochemical properties that make them potentially useful in clinical, research and industrial settings. However, a growing body of evidence indicates that like other engineered nanomaterials, QDs have the potential to be respiratory hazards, especially in the context of the manufacture of QDs and products containing them, as well as exposures to consumers using these products. The overall goal of this study was to investigate the role of mouse strain in determining susceptibility to QD-induced pulmonary inflammation and toxicity. Male mice from 8 genetically diverse inbred strains (the Collaborative Cross founder strains) were exposed to CdSe–ZnS core–shell QDs stabilized with an amphiphilic polymer. QD treatment resulted in significant increases in the percentage of neutrophils and levels of cytokines present in bronchoalveolar lavage fluid (BALF) obtained from NOD/ShiLtJ and NZO/HlLtJ mice relative to their saline (Sal) treated controls. Cadmium measurements in lung tissue indicated strain-dependent differences in disposition of QDs in the lung. Total glutathione levels in lung tissue were significantly correlated with percent neutrophils in BALF as well as with lung tissue Cd levels. Our findings indicate that QD-induced acute lung inflammation is mouse strain dependent, that it is heritable, and that the choice of mouse strain is an important consideration in planning QD toxicity studies. These data also suggest that formal genetic analyses using additional strains or recombinant inbred strains from these mice could be useful for discovering potential QD-induced inflammation susceptibility loci. PMID:26476918

  7. Protective Effects of Apigenin Against Paraquat-Induced Acute Lung Injury in Mice.

    PubMed

    Luan, Rui-Ling; Meng, Xiang-Xi; Jiang, Wei

    2016-04-01

    This study aimed to investigate the protective effects of apigenin against paraquat (PQ)-induced acute lung injury (ALI) in mice. Male Kunming mice were randomly divided into five groups: group 1 (control), group 2 (PQ), group 3 (PQ + apigenin 25 mg/kg), group 4 (PQ + apigenin 50 mg/kg), and group 5 (PQ + apigenin 100 mg/kg). The PQ + apigenin group received apigenin by gavage daily for consecutive 7 days, respectively, while the mice in control and PQ groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined using enzyme-linked immunosorbent assay (ELISA) kits. The activity of nuclear factor (NF)-κB was also determined. The results indicated that apigenin administration decreased biochemical parameters of inflammation and oxidative stress, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of apigenin were associated with inhibition of NF-κB. In conclusion, apigenin reduces PQ-induced ALI by inhibition of inflammation and oxidative stress.

  8. Cromolyn Sodium Attenuates Paraquat-Induced Lung Injury by Modulation of Proinflammatory Cytokines.

    PubMed

    Harchegani, Amir Larki; Hemmati, Ali Asghar; Nili-Ahmadabadi, Amir; Darabi, Borhan; Shabib, Somayeh

    2017-02-21

    The current study aimed to investigate the effects of Cromolyn Sodium (CS) on proinflammatory cytokines in Paraquat (PQ)-induced lung damage in rat. Animals were randomly divided into 5 groups. Group 1 and 2 received nebulized vehicle and CS (8 mg/kg) for 3 consecutive weeks, respectively. Group 3 was treated with single oral dose of PQ (40 mg/kg). Groups 4 and 5 were PQ groups which received nebulized CS (6 and 8 mg/kg/day, respectively) from 1 week before to 2 weeks after PQ administration. Finally, the animals were scarified and the changes of hydroxyproline (HP) and histology were evaluated in lung tissue. In addition, IL-1β, TNF-α and IL-8 levels were determined in serum samples. The results showed that lung HP level as well as IL-1β, TNF-α and IL-8 were significantly lower in the CS treated rats as compared to PQ group. The best response, however, was observed with the 8 mg/kg of CS as confirmed by histology findings. This study suggests that CS may prevent progression of PQ-induced lung damage by decreasing of inflammatory cytokines.

  9. Effect of inhaled gas density on the pendelluft-induced lung injury.

    PubMed

    Alzahrany, Mohammed; Banerjee, Arindam

    2016-12-08

    Helium, sulfur hexafluoride-oxygen, and air were modeled to examine the role of the gas density on the pendelluft-induced lung injury (PILI) under high frequency oscillatory ventilation (HFOV). Large eddy simulation coupled with physiological resistance-compliance boundary conditions was applied to capture pendelluft-induced gas entrapment and mechanical stresses in an image-based human lung model. The flow characteristics were strongly dependent on the inspired gas density. The flow partitioning, globally between the left and right lung and locally between adjacent units branches, was significantly affected by the density of inhaled gas and was more balanced when inspiring lighter gas. The incomplete loops of flow-volume and volume-pressure curves were significantly influenced by the variations of the flow redistribution, resistance, and turbulence associated with the pendelluft mechanism. Inhaling light gas reduced the entrapped gas volume and mechanical stress surrounding carina ridges signifying the important role of inhaled gas properties on PILI. In general, lung ventilation by HFOV with a gas mixture of large amounts of Helium is thought to mitigate ventilator complications.

  10. Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody.

    PubMed

    Mamesaya, Nobuaki; Kenmotsu, Hirotsugu; Katsumata, Mineo; Nakajima, Takashi; Endo, Masahiro; Takahashi, Toshiaki

    2017-02-01

    We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint infiltrations were observed in the bilateral lung field. Bronchoalveolar lavage fluid mainly contained lymphocytes (CD4+/CD8+ ratio of 0.3), and a transbronchial lung biopsy specimen showed lymphocytic alveolitis with partial organization in several alveolar spaces. Therefore we diagnosed the patient with osimertinib-induced interstitial lung disease (ILD) after treatment with anti-PD1 antibody. We considered anti-PD1 therapies may be the risk factor of EGFR-TKI-induced ILD.

  11. CD147 deficiency blocks IL-8 secretion and inhibits lung cancer-induced osteoclastogenesis.

    PubMed

    Wang, Hongkai; Zhuo, Yunyun; Hu, Xu; Shen, Weiwei; Zhang, Ying; Chu, Tongwei

    2015-03-06

    Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and poor prognosis; however, the molecular basis of this process is still unknown. This study investigated the role of extracellular matrix metalloproteinase inducer (also known as cluster of differentiation (CD)147) in osteoclastogenesis resulting from bone metastasis, based on the enrichment of this glycoprotein on the surface of many malignant bone tumors. RNA interference was used to silence CD147 expression in A549 human lung cancer cells. Compared with conditioned medium (CM) from control cells (A549-CM), CM from CD147-deficient cells (A549-si-CM) suppressed receptor activator of nuclear factor κB ligand-stimulated osteoclastogenesis in RAW 264.7 cells and bone marrow-derived macrophages. The mRNA levels of osteoclast-specific genes such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K were also reduced in the presence of A549-si-CM. CD147 knockdown in A549 cells decreased interleukin (IL)-8mRNA and protein expression. IL-8 is present in large amounts in A549-CM and mimicked its inductive effect on osteoclastogenesis; this was reversed by depletion of IL-8 from the medium. Taken together, these results indicate that CD147 promotes lung cancer-induced osteoclastogenesis by modulating IL-8 secretion, and suggest that CD147 is a potential therapeutic target for cancer-associated bone resorption in lung cancer patients.

  12. Mechanical stretch induces MMP-2 release and activation in lung endothelium: role of EMMPRIN.

    PubMed

    Haseneen, Nadia A; Vaday, Gayle G; Zucker, Stanley; Foda, Hussein D

    2003-03-01

    High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.

  13. Modulation of Pseudomonas aeruginosa lipopolysaccharide-induced lung inflammation by chronic iron overload in rat.

    PubMed

    Lê, Bá Vuong; Khorsi-Cauet, Hafida; Bach, Véronique; Gay-Quéheillard, Jérôme

    2012-03-01

    Iron constitutes a critical nutrient source for bacterial growth, so iron overload is a risk factor for bacterial infections. This study aimed at investigating the role of iron overload in modulating bacterial endotoxin-induced lung inflammation. Weaning male Wistar rats were intraperitoneally injected with saline or iron sucrose [15 mg kg(-1) body weight (bw), 3 times per week, 4 weeks]. They were then intratracheally injected with Pseudomonas aeruginosa lipopolysaccharide (LPS) (5 μg kg(-1) bw) or saline. Inflammatory indices were evaluated 4 or 18 h post-LPS/saline injection. At 4 h, LPS-treated groups revealed significant increases in the majority of inflammatory parameters (LPS-binding protein (LBP), immune cell recruitment, inflammatory cytokine synthesis, myeloperoxidase activity, and alteration of alveolar-capillary permeability), as compared with control groups. At 18 h, these parameters reduced strongly with the exception for LBP content and interleukin (IL)-10. In parallel, iron acted as a modulator of immune cell recruitment; LBP, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant 3, and IL-10 synthesis; and alveolar-capillary permeability. Therefore, P. aeruginosa LPS may only act as an acute lung inflammatory molecule, and iron overload may modulate lung inflammation by enhancing different inflammatory parameters. Thus, therapy for iron overload may be a novel and efficacious approach for the prevention and treatment of bacterial lung inflammations.

  14. Effects of oleic acid-induced lung injury on oxygen transport and aerobic capacity.

    PubMed

    Crocker, George H; Jones, James H

    2014-06-01

    We tested the hypothesis that oleic-acid (OA) infusion impairs gas exchange, decreases total cardiopulmonary O2 delivery and lowers maximal aerobic capacity ( [Formula: see text] ). We infused 0.05ml OAkg(-1) (∼3ml) and ∼563ml saline into the right atria of four goats [59.1±14.0 (SD) kg] prior to running them on a treadmill at [Formula: see text] 2-h and 1-d following OA-induced acute lung injury, and with no lung injury. Acute lung injury decreased [Formula: see text] , O2 delivery, arterial O2 concentration and arterial O2 partial pressure compared to no lung injury. The [Formula: see text] positively correlated with O2 delivery and inversely correlated with alveolar-arterial O2 partial pressure difference, suggesting that impaired pulmonary gas exchange decreased O2 delivery and uptake. Results indicate OA infusion may be a useful model for acutely impairing pulmonary gas exchange for exercise studies. Seven OA infusions induced smaller chronic gas exchange and arterial O2 partial pressure changes than acute infusion.

  15. TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury

    PubMed Central

    Ding, Xibing; Jin, Shuqing; Tong, Yao; Jiang, Xi; Chen, Zhixia; Mei, Shuya; Zhang, Liming; Billiar, Timothy R.; Li, Quan

    2017-01-01

    Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host’s innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4−/− and Myd88−/− mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system. PMID:28198368

  16. Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice

    PubMed Central

    Weissmann, Norbert; Sydykov, Akylbek; Kalwa, Hermann; Storch, Ursula; Fuchs, Beate; Schnitzler, Michael Mederos y; Brandes, Ralf P.; Grimminger, Friedrich; Meissner, Marcel; Freichel, Marc; Offermanns, Stefan; Veit, Florian; Pak, Oleg; Krause, Karl-Heinz; Schermuly, Ralph T.; Brewer, Alison C; Schmidt, Harald H.H.W.; Seeger, Werner; Shah, Ajay M.; Gudermann, Thomas; Ghofrani, Hossein A.; Dietrich, Alexander

    2012-01-01

    Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE. PMID:22337127

  17. Chidamide alleviates TGF-β-induced epithelial-mesenchymal transition in lung cancer cell lines.

    PubMed

    Lin, Sheng-Hao; Wang, Bing-Yen; Lin, Ching-Hsiung; Chien, Peng-Ju; Wu, Yueh-Feng; Ko, Jiunn-Liang; Chen, Jeremy J W

    2016-07-01

    Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition is a critical process in the initiation of metastasis of various types of cancer. Chidamide is a class I histone deacetylase inhibitor with anti-tumor activity. This study investigated the effects of chidamide on TGF-β-mediated suppression of E-cadherin expression in adenocarcinomic lung epithelial cells and the molecular mechanisms involved in these effects. Western blot analysis, confocal microscopy, Quantitative methyl-specific PCR and bisulfite sequencing were used to evaluate the effects of different treatments on chidamide ameliorating TGF-β induced-E-cadherin loss. H3 acetylation binding to the promoter of E-cadherin was detected by chromatin immunoprecipitations (CHIP). We found that chidamide reduced the level of lung cancer cell migration observed using a Boyden chamber assay (as an indicator of metastatic potential). Chidamide inhibited TGF-β-induced SMAD2 phosphorylation and attenuated TGF-β-induced loss of E-cadherin expression in lung cancer cells by Western blotting and confocal microscopy, respectively. Quantitative methyl-specific PCR and bisulfite sequencing revealed that TGF-β-enhanced E-cadherin promoter methylation was ameliorated in cells treated with chidamide. We demonstrated that histone H3 deacetylation within the E-cadherin promoter was required for TGF-β-induced E-cadherin loss; cell treatment with chidamide increased the H3 acetylation detected by CHIP. Taken together, our results demonstrate that TGF-β suppressed E-cadherin expression by regulating promoter methylation and histone H3 acetylation. Chidamide significantly enhanced E-cadherin expression in TGF-β-treated cells and inhibited lung cancer cell migration. These findings indicate that chidamide has a potential therapeutic use due to its capacity to prevent cancer cell metastasis.

  18. MUC1 in macrophage contributions to cigarette smoke-induced lung cancer

    PubMed Central

    Xu, Xiuling; Padilla, Mabel T.; Li, Bilan; Wells, Alexandria; Kato, Kosuke; Tellez, Carmen; Belinsky, Steven A.; Kim, Kwang Chul; Lin, Yong

    2013-01-01

    Expression of the pro-oncogenic mucin MUC1 is elevated by inflammation in airway epithelial cells, but the contributions of MUC1 to the development of lung cancer are uncertain. In this study, we developed our finding that cigarette smoke (CS) increases Muc1 expression in lung macrophages, where we hypothesized it might contribute to CS-induced transformation of bronchial epithelial cells. In human macrophages, CS extract (CSE) strongly induced MUC1 expression through a mechanism involving the nuclear receptor PPAR-γ. CSE-induced ERK activation was also required for MUC1 expression, but it had little effect on MUC1 transcription. RNAi-mediated attenuation of MUC1 suppressed CSE-induced secretion of TNF-α from macrophages, by suppressing the activity of the TNF-α processing enzyme TACE, arguing that MUC1 is required for CSE-induced and TACE-mediated TNF-α secretion. Similarly, MUC1 blockade after CSE induction through suppression of PPAR-γ or ERK inhibited TACE activity and TNF-α secretion. Conditioned media from CSE-treated macrophages induced MUC1 expression and potentiated CSE-induced transformation of human bronchial epithelial cells (HBEC) in a TNF-α-dependent manner. Together, our results identify a signaling pathway involving PPAR-γ, ERK and MUC1 that is used by CSE to trigger TNF-α secretion from macrophages. Further, our results show how that MUC1 contributes to smoking-induced lung cancers that are driven by inflammatory signals driven by macrophages PMID:24282280

  19. Photodynamic activity of aloe-emodin induces resensitization of lung cancer cells to anoikis.

    PubMed

    Lee, Hong-Zin; Yang, Wen-Hui; Hour, Mann-Jen; Wu, Chi-Yu; Peng, Wen-Huang; Bao, Bo-Ying; Han, Ping-Hsiu; Bau, Da-Tian

    2010-12-01

    Aloe-emodin was found to be a photosensitizer and possess anti-tumor activity. However, the detailed mechanism underlying the biological effects of aloe-emodin remains unknown. In this study, we explored the mechanisms of photocytotoxicity induced by aloe-emodin in lung cancer H460 cells. According to the results of the photoactivated aloe-emodin-induced disruption of cytoskeleton, we verify that aloe-emodin with irradiation induces anoikis of H460 cells. Photosensitized aloe-emodin-induced anoikis is associated with the protein expression of α-actinin and mitogen-activated protein (MAP) kinase members. In this study, a rapid opening of the mitochondrial permeability transition pore and the change in apoptosis-related protein expression were involved in photoactivated aloe-emodin-induced cell death. We also demonstrated that anoikis induced by aloe-emodin with irradiation is mediated through the intrinsic and extrinsic death pathways in a caspase-dependent manner in H460 cells.

  20. Combined alpha-tocopherol and ascorbic acid protects against smoke-induced lung squamous metaplasia in ferrets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many epidemiological studies show the benefit of fruits and vegetables on reducing risk of lung cancer, the leading cause of cancer death in the United States. Previously, we demonstrated that cigarette smoke exposure (SM)-induced lung lesions in ferrets were prevented by a combination of carotene,...

  1. Beta-Cryptoxanthin supplementation prevents cigarette smoke-induced lung inflammation, oxidative damage and squamous metaplasia in ferrets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In epidemiologic studies, high intake of beta-cryptoxanthin has been associated with a decreased risk of lung cancer, particularly among current smokers. However, data are not available from well-controlled animal studies to examine the effects of beta-cryptoxanthin on cigarette smoke-induced lung ...

  2. Erlotinib Induced Fatal Interstitial Lung Disease in a Patient with Metastatic Non-Small Cell Lung Cancer: Case Report and Review of Literature.

    PubMed

    Mangla, Ankit; Agarwal, Nikki; Carmel, Chou; Lad, Thomas

    2016-09-05

    Erlotinib is one of the most widely used tyrosine kinase inhibitor targeting human epidermal growth factor receptor. Since its introduction, it has revolutionized the treatment of advanced non-small cell lung cancer. Skin rashes and diarrhea are the most often reported side effects of erlotinib however it is also associated with interstitial pneumonitis or interstitial lung disease, which often turns out to be fatal complication of using this medicine. Though reported scarcely in the western world, the association of interstitial lung disease with epidermal growth factor receptor has attracted a lot of attention in the recent times. Various researches working with murine models of bleomycin-induced pulmonary fibrosis have found a pro and con role of the receptor in development of the interstitial lung disease. We present the case of a patient diagnosed with stage IV adenocarcinoma of the lung with metastasis to brain. He was found to be positive for the human epidermal growth factor mutation and was hence started on erlotinib. Within a few weeks of starting the medicine the patient was admitted with diarrhea. During the course of this admission he developed acute shortness of breath diagnosed as interstitial pneumonitis. The purpose of this case report is to review the literature associated with erlotinib induced interstitial pneumonitis and make the practicing oncologists aware of this rare yet fatal complication of erlotinib. Here we will also review literature, pertaining to the role of epidermal growth factor receptor in development of interstitial lung disease.

  3. The protective role of MLCP-mediated ERM dephosphorylation in endotoxin-induced lung injury in vitro and in vivo

    PubMed Central

    Kovacs-Kasa, Anita; Gorshkov, Boris A.; Kim, Kyung-Mi; Kumar, Sanjiv; Black, Stephen M.; Fulton, David J.; Dimitropoulou, Christiana; Catravas, John D.; Verin, Alexander D.

    2016-01-01

    The goal of this study was to investigate the role of MLC phosphatase (MLCP) in a LPS model of acute lung injury (ALI). We demonstrate that ectopic expression of a constitutively-active (C/A) MLCP regulatory subunit (MYPT1) attenuates the ability of LPS to increase endothelial (EC) permeability. Down-regulation of MYPT1 exacerbates LPS-induced expression of ICAM1 suggesting an anti-inflammatory role of MLCP. To determine whether MLCP contributes to LPS-induced ALI in vivo, we utilized a nanoparticle DNA delivery method to specifically target lung EC. Expression of a C/A MYPT1 reduced LPS-induced lung inflammation and vascular permeability. Further, increased expression of the CS1β (MLCP catalytic subunit) also reduced LPS-induced lung inflammation, whereas the inactive CS1β mutant increased vascular leak. We next examined the role of the cytoskeletal targets of MLCP, the ERM proteins (Ezrin/Radixin/Moesin), in mediating barrier dysfunction. LPS-induced increase in EC permeability was accompanied by PKC-mediated increase in ERM phosphorylation, which was more prominent in CS1β-depleted cells. Depletion of Moesin and Ezrin, but not Radixin attenuated LPS-induced increases in permeability. Further, delivery of a Moesin phospho-null mutant into murine lung endothelium attenuated LPS-induced lung inflammation and vascular leak suggesting that MLCP opposes LPS-induced ALI by mediating the dephosphorylation of Moesin and Ezrin. PMID:27976727

  4. The protective role of MLCP-mediated ERM dephosphorylation in endotoxin-induced lung injury in vitro and in vivo.

    PubMed

    Kovacs-Kasa, Anita; Gorshkov, Boris A; Kim, Kyung-Mi; Kumar, Sanjiv; Black, Stephen M; Fulton, David J; Dimitropoulou, Christiana; Catravas, John D; Verin, Alexander D

    2016-12-15

    The goal of this study was to investigate the role of MLC phosphatase (MLCP) in a LPS model of acute lung injury (ALI). We demonstrate that ectopic expression of a constitutively-active (C/A) MLCP regulatory subunit (MYPT1) attenuates the ability of LPS to increase endothelial (EC) permeability. Down-regulation of MYPT1 exacerbates LPS-induced expression of ICAM1 suggesting an anti-inflammatory role of MLCP. To determine whether MLCP contributes to LPS-induced ALI in vivo, we utilized a nanoparticle DNA delivery method to specifically target lung EC. Expression of a C/A MYPT1 reduced LPS-induced lung inflammation and vascular permeability. Further, increased expression of the CS1β (MLCP catalytic subunit) also reduced LPS-induced lung inflammation, whereas the inactive CS1β mutant increased vascular leak. We next examined the role of the cytoskeletal targets of MLCP, the ERM proteins (Ezrin/Radixin/Moesin), in mediating barrier dysfunction. LPS-induced increase in EC permeability was accompanied by PKC-mediated increase in ERM phosphorylation, which was more prominent in CS1β-depleted cells. Depletion of Moesin and Ezrin, but not Radixin attenuated LPS-induced increases in permeability. Further, delivery of a Moesin phospho-null mutant into murine lung endothelium attenuated LPS-induced lung inflammation and vascular leak suggesting that MLCP opposes LPS-induced ALI by mediating the dephosphorylation of Moesin and Ezrin.

  5. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells

    PubMed Central

    Wu, Hui-Mei; Jiang, Zi-Feng; Ding, Pei-Shan; Shao, Li-Jie; Liu, Rong-Yu

    2015-01-01

    Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α- dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation ‘was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis. PMID:26201611

  6. DIETARY FLAXSEED PREVENTS RADIATION-INDUCED OXIDATIVE LUNG DAMAGE, INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF THORACIC RADIATION INJURY

    PubMed Central

    Lee, James C.; Krochak, Ryan; Blouin, Aaron; Kanterakis, Stathis; Chatterjee, Shampa; Arguiri, Evguenia; Vachani, Anil; Solomides, Charalambos C.; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2009-01-01

    Flaxseed (FS) has high contents of omega-3 fatty acids and lignans with antioxidant properties. Its use in preventing thoracic X-ray radiation therapy (XRT)-induced pneumonopathy has never been evaluated. We evaluated FS supplementation given to mice given before and post-XRT. FS-derived lignans, known for their direct antioxidant properties, were evaluated in abrogating ROS generation in cultured endothelial cells following gamma radiation exposure. Mice were fed 10% FS or isocaloric control diet for three weeks and given 13.5 Gy thoracic XRT. Lungs were evaluated at 24 hours for markers of radiation-induced injury, three weeks for acute lung damage (lipid peroxidation, lung edema and inflammation), and at four months for late lung damage (inflammation and fibrosis). FS-Lignans blunted ROS generation in vitro, resulting from radiation in a dose-dependent manner. FS-fed mice had reduced expression of lung injury biomarkers (Bax, p21, and TGF-beta1) at 24 hours following XRT and reduced oxidative lung damage as measured by malondialdehyde (MDA) levels at 3 weeks following XRT. In addition, FS-fed mice had decreased lung fibrosis as determined by hydroxyproline content and decreased inflammatory cell influx into lungs at 4 months post XRT. Importantly, when Lewis Lung carcinoma cells were injected systemically in mice, FS dietary supplementation did not appear to protect lung tumors from responding to thoracic XRT. Dietary FS is protective against pulmonary fibrosis, inflammation and oxidative lung damage in a murine model. Moreover, in this model, tumor radioprotection was not observed. FS lignans exhibited potent radiation-induced ROS scavenging action. Taken together, these data suggest that dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic XRT by increasing the radiation tolerance of lung tissues. PMID:18981722

  7. Fluid Resuscitation in Sepsis: Reexamining the Paradigm

    PubMed Central

    Tirupakuzhi Vijayaraghavan, Bharath Kumar; Cove, Matthew Edward

    2014-01-01

    Sepsis results in widespread inflammatory responses altering homeostasis. Associated circulatory abnormalities (peripheral vasodilation, intravascular volume depletion, increased cellular metabolism, and myocardial depression) lead to an imbalance between oxygen delivery and demand, triggering end organ injury and failure. Fluid resuscitation is a key part of treatment, but there is little agreement on choice, amount, and end points for fluid resuscitation. Over the past few years, the safety of some fluid preparations has been questioned. Our paper highlights current concerns, reviews the science behind current practices, and aims to clarify some of the controversies surrounding fluid resuscitation in sepsis. PMID:25180196

  8. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

    PubMed Central

    Phan, Carole; Seferian, Andrei; Huertas, Alice; Thuillet, Raphaël; Sattler, Caroline; Le Hiress, Morane; Tamura, Yuichi; Jutant, Etienne-Marie; Chaumais, Marie-Camille; Bouchet, Stéphane; Manéglier, Benjamin; Molimard, Mathieu; Rousselot, Philippe; Sitbon, Olivier; Simonneau, Gérald; Montani, David; Humbert, Marc

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development. PMID:27482885

  9. Influenza Infection in Mice Induces Accumulation of Lung Mast Cells through the Recruitment and Maturation of Mast Cell Progenitors

    PubMed Central

    Zarnegar, Behdad; Mendez-Enriquez, Erika; Westin, Annika; Söderberg, Cecilia; Dahlin, Joakim S.; Grönvik, Kjell-Olov; Hallgren, Jenny

    2017-01-01

    Mast cells (MCs) are powerful immune cells that mature in the peripheral tissues from bone marrow (BM)-derived mast cell progenitors (MCp). Accumulation of MCs in lung compartments where they are normally absent is thought to enhance symptoms in asthma. The enrichment of lung MCs is also observed in mice subjected to models of allergic airway inflammation. However, whether other types of lung inflammation trigger increased number of MCp, which give rise to MCs, is unknown. Here, mouse-adapted H1N1 influenza A was used as a model of respiratory virus infection. Intranasal administration of the virus induced expression of VCAM-1 on the lung vascular endothelium and an extensive increase in integrin β7hi lung MCp. Experiments were performed to distinguish whether the influenza-induced increase in the number of lung MCp was triggered mainly by recruitment or in situ cell proliferation. A similar proportion of lung MCp from influenza-infected and PBS control mice were found to be in a proliferative state. Furthermore, BM chimeric mice were used in which the possibility of influenza-induced in situ cell proliferation of host MCp was prevented. Influenza infection in the chimeric mice induced a similar number of lung MCp as in normal mice. These experiments demonstrated that recruitment of MCp to the lung is the major mechanism behind the influenza-induced increase in lung MCp. Fifteen days post-infection, the influenza infection had elicited an immature MC population expressing intermediate levels of integrin β7, which was absent in controls. At the same time point, an increased number of toluidine blue+ MCs was detected in the upper central airways. When the inflammation was resolved, the MCs that accumulated in the lung upon influenza infection were gradually lost. In summary, our study reveals that influenza infection induces a transient accumulation of lung MCs through the recruitment and maturation of MCp. We speculate that temporary augmented numbers of lung MCs

  10. Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor.

    PubMed

    Goldkorn, Tzipora; Filosto, Simone; Chung, Samuel

    2014-11-20

    Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer.

  11. Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis.

    PubMed

    Yildirim, Alper; Ersoy, Yasemin; Ercan, Feriha; Atukeren, Pinar; Gumustas, Koray; Uslu, Unal; Alican, Inci

    2010-06-01

    Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis. Lung fibrosis was induced by intratracheal administration of 0.1 ml of bleomycin hydrochloride (5 mg/kg in 0.9% NaCl) under anesthesia to Sprague-Dawley rats (200-250 g; n = 7-8 per group). Control rats received an equal volume of saline intratracheally. In the treatment groups, the rats were treated with either sildenafil citrate (10 mg/kg per day; subcutaneously) or saline for 14 days. Another group of rats were administered subcutaneously with N(G)-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg in 0.9% NaCl) 5 min after sildenafil injections. After decapitation, the lungs were excised and taken for microscopic evaluation or stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity, and for the assessment of apoptosis. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. In the group with lung fibrosis, the lung tissue was characterized by microscopic lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and apoptosis. Serum TNF-alpha and IL-1beta levels were higher in the lung fibrosis group compared to control values. Sildenafil reversed tissue MDA levels, MPO activity and serum pro-inflammatory cytokine levels, and preserved GSH content although its effect on the extent of tissue lesion and apoptosis was not statistically significant. Treatment with l-NAME reversed

  12. Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures.

    PubMed

    Proctor, Deborah M; Suh, Mina; Campleman, Sharan L; Thompson, Chad M

    2014-11-05

    Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m(3)), for which clear exposure-response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose-response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation of particulate chromium in the bifurcations of the lung resulting in exceedance of clearance mechanisms and cellular absorption of Cr(VI). Once inside the cell, reduction of Cr(VI) results in oxidative stress and the formation of Cr ligands. Subsequent protein and DNA damage lead to tissue irritation, inflammation, and cytotoxicity. These effects, concomitant with increased cell proliferation, result in changes to DNA sequences and/or methylation status

  13. A MALDI-MSI approach to the characterization of radiation-induced lung injury and medical countermeasure development

    PubMed Central

    Carter, Claire L.; Jones, Jace W.; Barrow, Kory; Kieta, Kaitlyn; Taylor-Howell, Cheryl; Kearney, Sean; Smith, Cassandra P.; Gibbs, Allison; Farese, Ann M.; MacVittie, Thomas J.; Kane, Maureen A.

    2016-01-01

    Radiation-induced lung injury is highly complex and characterized by multiple pathologies, which occur over time, and sporadically throughout the lung. This complexity makes biomarker investigations and medical countermeasure screenings challenging. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has the ability to spatially resolve differences in molecular profiles within the lung following radiation exposure and can aid in biomarker identification and pharmaceutical efficacy investigations. MALDI-MSI was applied to the investigation of a whole-thorax lung irradiation model in non-human primates (NHP) for lipidomic analysis and medical countermeasure distribution. PMID:26425906

  14. Analysis of the activation routes induced by different metal oxide nanoparticles on human lung epithelial cells

    PubMed Central

    Simón-Vázquez, Rosana; Lozano-Fernández, Tamara; Dávila-Grana, Angela; González-Fernández, África

    2016-01-01

    Nanoparticles (Nps) can induce toxicity in the lung by accidental or intentional exposure. The main objective of the study reported here was to characterize the effect that four metal oxide Nps (CeO2, TiO2, Al2O3 and ZnO) had at the cellular level on a human lung epithelial cell line. This goal was achieved by studying the capacity of the Nps to activate the main mitogen-activated protein kinases (MAPKs) and the nuclear factor NFκB. Only ZnO Nps were able to activate all of the MAPKs and the release of Zn2+ ions was the main cause of activation. ZnO and Al2O3 Nps activated the NFκB pathway and induced the release of inflammatory cytokines. CeO2 and TiO2 Nps were found to have safer profiles. The graphical abstract was obtained using Servier Medical Art. PMID:28031965

  15. Genetic damage induced by benzo[a]pyrene diol epoxide and risk of lung cancer

    SciTech Connect

    Wei, Q.; Cheng, L.; Li, D.

    1997-10-01

    Lung cancer is the paradigm of carcinogen-induced disease. A chemical carcinogen, benzo[a]pyrene, commonly found in tobacco, is both mutagenic and carcinogenic. It is hypothesized that individuals have varying responses to exposure to environmental carcinogens. In this study, we used benzo[a]pyrene diol epoxide (BPDE) as the test mutagen to investigate three in-vitro susceptibility markers in lymphocytes from 51 patients with lung cancer and 172 cancer-free controls. These markers were: BPDE-induced chromosomal aberrations, BPDE-induced DNA adducts, and DNA repair capacity using host cell reactivation assay with BPDE-damaged plasmid. Using the medians of the controls as the cutoff values, increased risk of lung cancer was associated with increased frequency of chromosomal aberrations (OR=6.53; 95% confidence interval (C.I.), 3.74-11.4), increased BPDE-DNA adduct level (odds ratio (OR)=4.7; 95% C.I., 1.2-18.5), and reduced DNA repair capacity (OR=5.7; 95% C.I., 2.1-15.7). In correlation analyses, cellular ability to repair BPDE-induced DNA damage was found to be inversely correlated with the levels of BPDE-induced DNA adducts (n=34; r=0.34; p=0.048) and the levels of BPDE-DNA adducts correlated significantly with the frequency of chromosomal aberrations (n=62; r=0.42; p=0.001). However, cellular ability to repair BPDE-induced DNA damage was not correlated significantly with the frequency of chromosomal aberrations (n=47; r=0.06; p=0.677). These biomarkers have differing sensitivities in measuring repair of damage induced by chemical carcinogens; therefore, the complementary use of these assays should increase the probability of identifying individuals with susceptibility to smoking-related cancers.

  16. Pyruvate enhances neurological recovery following cardiopulmonary arrest and resuscitation

    PubMed Central

    Sharma, Arti B.; Barlow, Matthew A.; Yang, Shao-Hua; Simpkins, James W.; Mallet, Robert T.

    2009-01-01

    Purpose Cerebral oxidative stress and metabolic dysfunction impede neurological recovery from cardiac arrest-resuscitation. Pyruvate, a potent antioxidant and energy-yielding fuel, has been shown to protect against oxidant- and ischemia-induced neuronal damage. This study tested whether acute pyruvate treatment during cardiopulmonary resuscitation can prevent neurological dysfunction and cerebral injury following cardiac arrest. Methods Anesthetized, open-chest mongrel dogs underwent 5 min cardiac arrest, 5 min open chest cardiac compression (OCCC), defibrillation and 3 day recovery. Pyruvate (n = 9) or NaCl volume control (n = 8) were administered (0.125 mmol/kg/min iv) throughout OCCC and the first 55 min recovery. Sham dogs (n = 6) underwent surgery and recovery without cardiac arrest-resuscitation. Results Neurological deficit score (NDS), evaluated at 2 day recovery, was sharply increased in NaCl-treated dogs (10.3 ± 3.5) vs. shams (1.2 ± 0.4), but pyruvate treatment mitigated neurological deficit (NDS = 3.3 ± 1.2; P < 0.05 vs. NaCl). Brain samples were taken for histological examination and evaluation of inflammation and cell death at 3 d recovery. Loss of pyramidal neurons in the hippocampal CA1 subregion was greater in the NaCl controls than in pyruvate treated dogs (11.7 ± 2.3% vs. 4.3 ± 1.2%; P < 0.05). Cardiac arrest increased caspase 3 activity, matrix metalloproteinase activity, and DNA fragmentation in the CA1 subregion; pyruvate prevented caspase-3 activation and DNA fragmentation, and suppressed matrix metalloproteinase activity. Conclusion Intravenous pyruvate therapy during cardiopulmonary resuscitation prevents initial oxidative stress and neuronal injury and enhances neurological recovery from cardiac arrest. PMID:17618729

  17. Oxidative Lung Injury in Virus-Induced Wheezing

    DTIC Science & Technology

    2011-05-01

    tract infections in children, for which no specific treat- ment or vaccine is currently available. We have previously shown that RSV induces reactive...benzamidine, 5 mg/ml leupeptin, 25% glycerol ), incubated on ice for 20 minutes, and centrifuged (6,000 3 g, 48C, 2 min). A lysis-lavage method...6 M urea, 2% SDS, 50 mM Tris-HCl [pH 8.8], 20% glycerol ) containing 10 ml of 0.5 M TCEP [Tris(2-carboxyethyl) phosphine] for 15 minutes at 228C with

  18. Ultrastructural changes in the lung following exposure to perfluoroisobutylene (PFIB) and potentiation of PFIB-induced lung injury by post-exposure exercise

    SciTech Connect

    Lehnert, B.E.; Stavert, D.M.

    1990-01-01

    The authors investigated the kinetics of development of the injurious effects of perfluoroisobutylene (PFIB) in the lower respiratory tract of the rat as a function of inhaled mass concentration. We additionally examined if exercise performed after exposure to PFIB can potentiate the severity of expression of PFIB-induced lung injury, while also assessing how PFIB exposure may result in reductions in work performance capacity. The severity of PFIB-induced lung injury was found to be directly proportional to inhaled PFIB mass concentration whereas the post-exposure kinetics of development of the injurious response was inversely proportional to the mass concentration of PFIB, with post-exposure latency periods prior to the onset of detectable injury increasing with decreasing inhaled mass concentration. Exercise was found to potentiate PFIB-induced lung injury only after pulmonary edema was demonstrably present using lung gravimetric and light histopathologic criteria, even though ultrastructural observations indicated significant cellular changes occur during the latency period. Our collective findings suggest that pre-existing permeability changes in the lung are a necessary prerequisite for post-exposure exercise to exert a potentiating effect. Reductions in work performance capacity occurred only after the latency period, and such reductions proportionately scaled with the severity of pulmonary edema. 9 refs., 5 figs.

  19. Mechanical advances in cardiopulmonary resuscitation.

    PubMed

    Lurie, K; Plaisance, P; Sukhum, P; Soleil, C

    2001-06-01

    Challenged by the continued high mortality rates for patients in cardiac arrest, the American Heart Association and the European Resuscitation Council developed a new set of guidelines in 2000 to help advance several new and promising cardiopulmonary resuscitation (CPR) techniques and devices. This is the first time these organizations have taken such a bold move, in part because of the poor results with standard closed-chest cardiac massage. The new techniques, interposed abdominal counterpulsation and active compression decompression CPR, each provide greater blood flow to the vital organs in animal models of CPR and lead to higher blood pressures in patients in cardiac arrest. In some clinical studies, both techniques have resulted in a significant increase in survival after cardiac arrest in comparison with standard CPR. Three of the four new CPR devices that were recommended in the new guidelines also provide superior vital organ blood flow and increased blood pressures in comparison with standard CPR. The three devices that improve the efficiency of CPR are the circumferential vest, an active compression decompression CPR device, and an inspiratory impedance valve used in combination with the active compression decompression CPR device. The fourth device type, one that compresses the thorax using an automated mechanical piston compression mechanism, was recommended to reduce the number of personnel required to perform CPR. However, no studies on the automated mechanical compression devices have showed an improvement in hemodynamic variables or survival in comparison with standard CPR. Taken together, these new technologies represent an important step forward in the evolution of CPR from a pair of hands to devices designed to enhance CPR efficiency. Each of these advances is described, and the recent literature about each of them is reviewed.

  20. Myeloid-Specific Fos-Related Antigen-1 Regulates Cigarette Smoke–Induced Lung Inflammation, Not Emphysema, in Mice

    PubMed Central

    Vaz, Michelle; Rajasekaran, Subbiah; Potteti, Haranatha R.

    2015-01-01

    Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow–derived Fra-1–null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD. PMID:25489966

  1. Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein δ pathway

    PubMed Central

    Yan, Chunguang; Ward, Peter A.; Wang, Ximo; Gao, Hongwei

    2013-01-01

    Although uncontrolled inflammatory response plays a central role in the pathogenesis of acute lung injury (ALI), the precise molecular mechanisms underlying the development of this disorder remain poorly understood. SOCS3 is an important negative regulator of IL-6-type cytokine signaling. SOCS3 is induced in lung during LPS-induced lung injury, suggesting that generation of SOCS3 may represent a regulatory product during ALI. In the current study, we created mice lacking SOCS3 expression in macrophages and neutrophils (LysM-cre SOCS3fl/fl). We evaluated the lung inflammatory response to LPS in both LysM-cre SOCS3fl/fl mice and the wild-type (WT) mice (SOCS3fl/fl). LysM-cre SOCS3fl/fl mice displayed significant increase of the lung permeability index (lung vascular leak of albumin), neutrophils, lung neutrophil accumulation (myeloperoxidase activity), and proinflammatory cytokines/chemokines in bronchial alveolar lavage fluids compared to WT mice. These phenotypes were consistent with morphological evaluation of lung, which showed enhanced inflammatory cell influx and intra-alveolar hemorrhage. We further identify the transcription factor, CCAAT/enhancer-binding protein (C/EBP) δ as a critical downstream target of SOCS3 in LPS-induced ALI. These results indicate that SOCS3 has a protective role in LPS-induced ALI by suppressing C/EBPδ activity in the lung. Elucidating the function of SOCS3 would represent prospective targets for a new generation of drugs needed to treat ALI.—Yan, C., Ward, P. A., Wang, X., Gao, H. Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein δ pathway. PMID:23585399

  2. Mechanism of Tissue Remodeling in Sepsis-Induced Acute Lung Injury

    DTIC Science & Technology

    2006-04-01

    identified (e.g., infection, trauma ), little is known about the factors that control the tissue remodeling response. This project addresses this very...induced fibronectin expression in fibroblasts. This suggests that the main player in this process is acetaldehyde . To test this, we exposed cells...to acetaldehyde and found that this molecule indeed stimulated fibronectin expression. The latter observation suggests that lung fibroblasts contain

  3. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury.

    PubMed

    Hu, Yue; Lou, Jian; Mao, Yuan-Yuan; Lai, Tian-Wen; Liu, Li-Yao; Zhu, Chen; Zhang, Chao; Liu, Juan; Li, Yu-Yan; Zhang, Fan; Li, Wen; Ying, Song-Min; Chen, Zhi-Hua; Shen, Hua-Hao

    2016-12-01

    MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both MTOR and autophagy have been suggested to be involved in lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI). In the present study, we observed that lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure. Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through downregulation of autophagy and the subsequent activation of NFKB. Thus, inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.

  4. The common anesthetic, sevoflurane, induces apoptosis in A549 lung alveolar epithelial cells.

    PubMed

    Wei, Gui-Hua; Zhang, Juan; Liao, Da-Qing; Li, Zhuo; Yang, Jing; Luo, Nan-Fu; Gu, Yan

    2014-01-01

    Lung alveolar epithelial cells are the first barrier exposed to volatile anesthetics, such as sevoflurane, prior to reaching the targeted neuronal cells. Previously, the effects of volatile anesthetics on lung surfactant were studied primarily with physicochemical models and there has been little experimental data from cell cultures. Therefore it was investigated whether sevoflurane induces apoptosis of A549 lung epithelial cells. A549 cells were exposed to sevoflurane via a calibrated vaporizer with a 2 l/min flow in a gas‑tight chamber at 37˚C. The concentration of sevoflurane in Dulbecco's modified Eagle's medium was detected with gas chromatography. Untreated cells and cells treated with 2 µM daunorubicin hydrochloride (DRB) were used as negative and positive controls, respectively. Apoptosis factors, including the level of ATP, apoptotic‑bodies by terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling (TUNEL) assay, DNA damage and the level of caspase 3/7 were analyzed. Cells treated with sevoflurane showed a significant reduction in ATP compared with untreated cells. Effects in the DRB group were greater than in the sevoflurane group. The difference of TUNEL staining between the sevoflurane and untreated groups was statistically significant. DNA degradation was observed in the sevoflurane and DRB groups, however this was not observed in the untreated group. The sevoflurane and DRB groups induced increased caspase 3/7 activation compared with untreated cells. These results suggest that sevoflurane induces apoptosis in A549 cells. In conclusion, 5% sevoflurane induced apoptosis of A549 lung alveolar epithelial cells, which resulted in decreased cell viability, increased apoptotic bodies, impaired DNA integrality and increased levels of caspase 3/7.

  5. Hypoxic preconditioning with cobalt attenuates hypobaric hypoxia-induced oxidative damage in rat lungs.

    PubMed

    Shukla, Dhananjay; Saxena, Saurabh; Jayamurthy, Purushotman; Sairam, Mustoori; Singh, Mrinalini; Jain, Swatantra Kumar; Bansal, Anju; Ilavazaghan, Govindaswamy

    2009-01-01

    Shukla, Dhananjay, Saurabh Saxena, Purushotman Jayamurthy, Mustoori Sairam, Mrinalini, Singh, Swatantra Kumar Jain, Anju Bansal, and Govindaswamy Ilavazaghan. High Alt. Med. Biol. 10:57-69, 2009.-Hypoxic preco759nditioning (HPC) provides robust protection against injury from subsequent prolonged hypobaric hypoxia, which is a characteristic of high altitude and is known to induce oxidative injury in lung by increasing the generation of reactive oxygen species (ROS) and decreasing the effectiveness of the antioxidant defense system. We hypothesize that HPC with cobalt might protect the lung from subsequent hypobaric hypoxia-induced lung injury. HPC with cobalt can be achieved by oral feeding of CoCl(2) (12.5 mg kg(-1)) in rats for 7 days. Nonpreconditioned rats responded to hypobaric hypoxia (7619 m) by increased reactive oxygen species (ROS) generation and a decreased GSH/GSSG ratio. They also showed a marked increase in lipid peroxidation, heat-shock proteins (HSP32, HSP70), metallothionins (MT), levels of inflammatory cytokines (TNF-alpha, IFN-gamma, MCP-1), and SOD, GPx, and GST enzyme activity. In contrast, rats preconditioned with cobalt were far less impaired by severe hypobaric hypoxia, as observed by decreased ROS generation, lipid peroxidation, and inflammatory cytokine release and an inceased GSH/GSSG ratio. Increased expression of antioxidative proeins Nrf-1, HSP-32, and MT was also observed in cobalt- preconditioned animals. A marked increase in the protein expression and DNA binding activity of hypoxia-inducible transcriptional factor (HIF-1alpha) and its regulated genes, such as erythropoietin (EPO) and glucose transporter-1 (glut-1), was observed after HPC with cobalt. We conclude that HPC with cobalt enhances antioxidant status in the lung and protects from subsequent hypobaric hypoxia-induced oxidative stress.

  6. Cantharidin induces apoptosis of H460 human lung cancer cells through mitochondria-dependent pathways.

    PubMed

    Hsia, Te-Chun; Yu, Chien-Chih; Hsu, Shu-Chun; Tang, Nou-Ying; Lu, Hsu-Feng; Huang, Yi-Ping; Wu, Shin-Hwar; Lin, Jaung-Geng; Chung, Jing-Gung

    2014-07-01

    Lung cancer is one of the leading causes of death in cancer-related diseases. Cantharidin (CTD) is one of the components of natural mylabris (Mylabris phalerata Pallas). Numerous studies have shown that CTD induced cytotoxic effects on cancer cells. However, there is no report to demonstrate that CTD induced apoptosis in human lung cancer cells. Herein, we investigated the effect of CTD on the cell death via the induction of apoptosis in H460 human lung cancer cells. Flow cytometry assay was used for examining the percentage of cell viability, sub-G1 phase of the cell cycle, reactive oxygen species (ROS) and Ca²⁺ productions and the levels of mitochondrial membrane potential (∆Ψm). Annexin V/PI staining and DNA gel electrophoresis were also used for examining cell apoptosis. Western blot analysis was used to examine the changes of apoptosis associated protein expression and confocal microscopy for examining the translocation apoptosis associated protein. Results indicated that CTD significantly induced cell morphological changes and decreased the percentage of viable H460 cells. CTD induced apoptosis based on the occurrence of sub-G1 phase and DNA fragmentation. We found that CTD increased gene expression (mRNA) of caspase-3 and -8. Moreover, CTD increased ROS and Ca2+ production and decreased the levels of ∆Ψm. Western blot analysis results showed that CTD increased the expression of cleavage caspase-3 and -8, cytochrome c, Bax and AIF but inhibited the levels of Bcl-xL. CTD promoted ER stress associated protein expression such as GRP78, IRE1α, IRE1β, ATF6α and caspase-4 and it also promoted the expression of calpain 2 and XBP-1, but inhibited calpain 1 that is associated with apoptosis pathways. Based on those observations, we suggest that CTD may be used as a novel anticancer agent for the treatment of lung cancer in the future.

  7. Perinatal Nicotine Exposure Induces Myogenic Differentiation, But Not Epithelial–Mesenchymal Transition in Rat Offspring Lung

    PubMed Central

    Sakurai, Reiko; Liu, Jie; Gong, Ming; Bo, Ji; Rehan, Virender K.

    2016-01-01

    Summary Objective Perinatal nicotine exposure alters offspring lung structure and function; however, the underlying mechanisms remain incompletely understood. Whether epithelial– mesenchymal transition (EMT), a known contributor to pulmonary pathology, occurs following moderate perinatal nicotine exposure is not known. Methods Pregnant, pair-fed Sprague Dawley rat dams received either placebo (diluent) or nicotine [1 mg/kg, subcutaneously] once daily from embryonic day (e) 6 to postnatal day (PND) 21. Generation 1 (F1) and 3 (F3) offspring lungs were isolated at PND 21, and using Western analysis, q-RT-PCR and immunohistochemistry examined for evidence of EMT. To gain further supportive evidence for nicotine-induced EMT, embryonic day 19 primary rat lung alveolar type II (ATII) cells were cultured and treated with nicotine for 24 hr. Results Protein levels of α-smooth muscle actin, fibronectin, and calponin (myogenic differentiation markers) increased significantly. However, surfactant proteins B and C, and cholinephosphate cytidylyltransferase- α (epithelial cell markers), as well as the typical markers of EMT, E-cadherin, N-cadherin, and fibroblast specific protein (FSP)-1, in both F1 and F3 generation lungs, showed no significant change between the nicotine exposed and control dams. Immunostaining of lung sections and data from in vitro treated ATII cells strongly supported the Western data. Conclusions Enhanced myogenic molecular profile, without evidence of EMT, as evidenced by the absence of the loss of E-cadherin or gains in N-cadherin and FSP-1, suggest that perinatal nicotine exposure does not result in EMT, but it leads to myogenesis, which predominantly accounts for the lung phenotype seen in perinatally nicotine exposed rat offspring. PMID:27183179

  8. Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

    PubMed Central

    Pope-Varsalona, Hannah; Concel, Vincent J.; Liu, Pengyuan; Bein, Kiflai; Berndt, Annerose; Martin, Timothy M.; Ganguly, Koustav; Jang, An Soo; Brant, Kelly A.; Dopico, Richard A.; Upadhyay, Swapna; Di, Y. P. Peter; Hu, Zhen; Vuga, Louis J.; Medvedovic, Mario; Kaminski, Naftali; You, Ming; Alexander, Danny C.; McDunn, Jonathan E.; Prows, Daniel R.; Knoell, Daren L.

    2012-01-01

    The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using ≥ 10% allelic frequency and ≥ 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4. PMID:22447970

  9. Choosing the frequency of deep inflation in mice: balancing recruitment against ventilator-induced lung injury.

    PubMed

    Allen, Gilman B; Suratt, Benjamin T; Rinaldi, Lisa; Petty, Joseph M; Bates, Jason H T

    2006-10-01

    Low tidal volume (Vt) ventilation is protective against ventilator-induced lung injury but can promote development of atelectasis. Periodic deep inflation (DI) can open the lung, but if delivered too frequently may cause damage via repeated overdistention. We therefore examined the effects of varying DI frequency on lung mechanics, gas exchange, and biomarkers of injury in mice. C57BL/6 males were mechanically ventilated with positive end-expiratory pressure (PEEP) of 2 cmH2O for 2 h. One high Vt group received a DI with each breath (HV). Low Vt groups received 2 DIs after each hour of ventilation (LV) or 2 DIs every minute (LVDI). Control groups included a nonventilated surgical sham and a group receiving high Vt with zero PEEP (HVZP). Respiratory impedance was measured every 4 min, from which tissue elastance (H) and damping (G) were derived. G and H rose progressively during LV and HVZP, but returned to baseline after hourly DI during LV. During LVDI and HV, G and H remained low and gas exchange was superior to that of LV. Bronchoalveolar lavage fluid protein was elevated in HV and HVZP but was not different between LV and LVDI. Lung tissue IL-6 and IL-1beta levels were elevated in HVZP and lower in LVDI compared with LV. We conclude that frequent DI can safely improve gas exchange and lung mechanics and may confer protection from biotrauma. Differences between LVDI and HV suggest that an optimal frequency range of DI exists, within which the benefits of maintaining an open lung outweigh injury incurred from overdistention.

  10. 4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells

    SciTech Connect

    Cheng Yahsin; Chang, Louis W.; Cheng Lichuan; Tsai, M.-H.; Lin Pinpin . E-mail: pplin@nhri.org.tw

    2007-05-01

    Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased liver tumors and promoted lung metaplasia in females. Metabolic changes in 17{beta}-estradiol (E{sub 2}) resulted from an interaction between TCDD and E{sub 2} could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE{sub 2}), especially 4-MeOE{sub 2}, accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E{sub 2}. In the present study, we demonstrate unique accumulation of 4-MeOE{sub 2}, as a result of TCDD/E{sub 2} interaction and revealed its bioactivity in human lung epithelial cell line (H1355). 4-Methoxyestradiol treatment significantly decreased cell growth and increased mitotic index. Elevation of ROS and SOD activity, with a concomitant decrease in the intracellular GSH/GSSG ratio, was also detected in 4-MeOE{sub 2}-treated cells. Quantitative comet assay showed increased oxidative DNA damage in the 4-MeOE{sub 2}-treated H1355 cells, which could be significantly reduced by the anti-oxidant N-acetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4-MeOE{sub 2} were unaffected by NAC. We concluded that 4-MeOE{sub 2} accumulation resulting from TCDD and E{sub 2} interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD.

  11. Permissive hypotension does not reduce regional organ perfusion compared to normotensive resuscitation: animal study with fluorescent microspheres

    PubMed Central

    2012-01-01

    Introduction The objective of this study was to investigate regional organ perfusion acutely following uncontrolled hemorrhage in an animal model that simulates a penetrating vascular injury and accounts for prehospital times in urban trauma. We set forth to determine if hypotensive resuscitation (permissive hypotension) would result in equivalent organ perfusion compared to normotensive resuscitation. Methods Twenty four (n=24) male rats randomized to 4 groups: Sham, No Fluid (NF), Permissive Hypotension (PH) (60% of baseline mean arterial pressure - MAP), Normotensive Resuscitation (NBP). Uncontrolled hemorrhage caused by a standardised injury to the abdominal aorta; MAP was monitored continuously and lactated Ringer’s was infused. Fluorimeter readings of regional blood flow of the brain, heart, lung, kidney, liver, and bowel were obtained at baseline and 85 minutes after hemorrhage, as well as, cardiac output, lactic acid, and laboratory tests; intra-abdominal blood loss was assessed. Analysis of variance was used for comparison. Results Intra-abdominal blood loss was higher in NBP group, as well as, lower hematocrit and hemoglobin levels. No statistical differences in perfusion of any organ between PH and NBP groups. No statistical difference in cardiac output between PH and NBP groups, as well as, in lactic acid levels between PH and NBP. NF group had significantly higher lactic acidosis and had significantly lower organ perfusion. Conclusions Hypotensive resuscitation causes less intra-abdominal bleeding than normotensive resuscitation and concurrently maintains equivalent organ perfusion. No fluid resuscitation reduces intra-abdominal bleeding but also significantly reduces organ perfusion. PMID:23531188

  12. Endothelial Nitric Oxide Synthase Deficient Mice Are Protected from Lipopolysaccharide Induced Acute Lung Injury

    PubMed Central

    Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham III, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen M.

    2015-01-01

    Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID:25786132

  13. Effect of chemical stabilizers of hypoxia-inducible factors on early lung development.

    PubMed

    Groenman, Freek A; Rutter, Martin; Wang, Jinxia; Caniggia, Isabella; Tibboel, Dick; Post, Martin

    2007-09-01

    Low oxygen stimulates pulmonary vascular development and airway branching and involves hypoxia-inducible factor (HIF). HIF is stable and initiates expression of angiogenic factors under hypoxia, whereas normoxia triggers hydroxylation of the HIF-1alpha subunit by prolyl hydroxylases (PHDs) and subsequent degradation. Herein, we investigated whether chemical stabilization of HIF-1alpha under normoxic (20% O(2)) conditions would stimulate vascular growth and branching morphogenesis in early lung explants. Tie2-LacZ (endothelial LacZ marker) mice were used for visualization of the vasculature. Embryonic day 11.5 (E11.5) lung buds were dissected and cultured in 20% O(2) in the absence or presence of cobalt chloride (CoCl(2), a hypoxia mimetic), dimethyloxalylglycine (DMOG; a nonspecific inhibitor of PHDs), or desferrioxamine (DFO; an iron chelator). Vascularization was assessed by X-gal staining, and terminal buds were counted. The fine vascular network surrounding the developing lung buds seen in control explants disappeared in CoCl(2)- and DFO-treated explants. Also, epithelial branching was reduced in the explants treated with CoCl(2) and DFO. In contrast, DMOG inhibited branching but stimulated vascularization. Both DFO and DMOG increased nuclear HIF-1alpha protein levels, whereas CoCl(2) had no effect. Since HIF-1alpha induces VEGF expression, the effect of SU-5416, a potent VEGF receptor (VEGFR) blocker, on early lung development was also investigated. Inhibition of VEGFR2 signaling in explants maintained under hypoxic (2% O(2)) conditions completely abolished vascularization and slightly decreased epithelial branching. Taken together, the data suggest that DMOG stabilization of HIF-1alpha during early development leads to a hypervascular lung and that airway branching proceeds without the vasculature, albeit at a slower rate.

  14. Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.

    PubMed

    Zychowski, Katherine E; Lucas, Selita N; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J

    2016-08-15

    Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability.

  15. Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress

    SciTech Connect

    Cheng, Ya-Hsin; Huang, Su-Chin; Lin, Chun-Ju; Cheng, Li-Chuan; Li, Lih-Ann

    2012-03-15

    Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53–p21–Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity. -- Highlights: ► AhR expression level influences cigarette sidestream smoke-induced ROS production. ► AhR reduces oxidative stress by coordinate regulation of

  16. Anti-Inflammatory Effects of Adrenomedullin on Acute Lung Injury Induced by Carrageenan in Mice

    PubMed Central

    Elena, Talero; Rosanna, Di Paola; Emanuela, Mazzon; Esposito, Emanuela; Virginia, Motilva; Salvatore, Cuzzocrea

    2012-01-01

    Adrenomedullin (AM) is a 52 amino acid peptide that has shown predominant anti-inflammatory activities. In the present study, we evaluated the possible therapeutic effect of this peptide in an experimental model of acute inflammation, the carrageenan- (CAR-) induced pleurisy. Pleurisy was induced by injection of CAR into the pleural cavity of mice. AM (200 ng/kg) was administered by intraperitoneal route 1 h after CAR, and the animals were sacrificed 4 h after that. AM treatment attenuated the recruitment of leucocytes in the lung tissue and the generation and/or the expression of the proinflammatory cytokines as well as the expression of the intercellular cell adhesion molecules. Moreover, AM inhibited the induction of inducible nitric oxide synthase (iNOS), thereby abating the generation of nitric oxide (NO) and prevented the oxidative and nitroxidative lung tissue injury, as shown by the reduction of nitrotyrosine, malondialdehyde (MDA), and poly (ADP-ribose) polymerase (PARP) levels. Finally, we demonstrated that these anti-inflammatory effects of AM were associated with the inhibition of nuclear factor-κB (NF-κB) activation. All these parameters were markedly increased by intrapleural CAR in the absence of any treatment. We report that treatment with AM significantly reduces the development of acute lung injury by downregulating a broad spectrum of inflammatory factors. PMID:22685374

  17. Carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE-inhibitory protein.

    PubMed

    Pongrakhananon, Varisa; Luanpitpong, Sudjit; Stueckle, Todd A; Wang, Liying; Nimmannit, Ubonthip; Rojanasakul, Yon

    2015-02-01

    Chronic exposure to single-walled carbon nanotubes (SWCNT) has been reported to induce apoptosis resistance of human lung epithelial cells. As resistance to apoptosis is a foundation of neoplastic transformation and cancer development, we evaluated the apoptosis resistance characteristic of the exposed lung cells to understand the pathogenesis mechanism. Passage control and SWCNT-transformed human lung epithelial cells were treated with known inducers of apoptosis via the intrinsic (antimycin A and CDDP) or extrinsic (FasL and TNF-α) pathway and analyzed for apoptosis by DNA fragmentation, annexin-V expression, and caspase activation assays. Whole-genome microarray was performed to aid the analysis of apoptotic gene signaling network. The SWCNT-transformed cells exhibited defective death receptor pathway in association with cellular FLICE-inhibitory protein (c-FLIP) overexpression. Knockdown or chemical inhibition of c-FLIP abrogated the apoptosis resistance of SWCNT-transformed cells. Whole-genome expression signature analysis confirmed these findings. This study is the first to demonstrate carbon nanotube-induced defective death receptor pathway and the role of c-FLIP in the process.

  18. Pulmonary epithelial CCR3 promotes LPS-induced lung inflammation by mediating release of IL-8.

    PubMed

    Li, Bo; Dong, Chunling; Wang, Guifang; Zheng, Huiru; Wang, Xiangdong; Bai, Chunxue

    2011-09-01

    Interleukin (IL)-8 from pulmonary epithelial cells has been suggested to play an important role in the airway inflammation, although the mechanism remains unclear. We envisioned a possibility that pulmonary epithelial CCR3 could be involved in secretion and regulation of IL-8 and promote lipopolysaccharide (LPS)-induced lung inflammation. Human bronchial epithelial cell line NCI-H292 and alveolar type II epithelial cell line A549 were used to test role of CCR3 in production of IL-8 at cellular level. In vivo studies were performed on C57/BL6 mice instilled intratracheally with LPS in a model of acute lung injury (ALI). The activity of a CCR3-specific inhibitor (SB-328437) was measured in both in vitro and in vivo systems. We found that expression of CCR3 in NCI-H292 and A549 cells were increased by 23% and 16%, respectively, 24 h after the challenge with LPS. LPS increased the expression of CCR3 in NCI-H292 and A549 cells in a time-dependent manner, which was inhibited significantly by SB-328437. SB-328437 also diminished neutrophil recruitment in alveolar airspaces and improved LPS-induced ALI and production of IL-8 in bronchoalveolar lavage fluid. These results suggest that pulmonary epithelial CCR3 be involved in progression of LPS-induced lung inflammation by mediating release of IL-8. CCR3 in pulmonary epithelia may be an attractive target for development of therapies for ALI.

  19. Thromboxane synthase suppression induces lung cancer cell apoptosis via inhibiting NF-{kappa}B

    SciTech Connect

    Leung, Kin Chung; Li, Ming-Yue; Leung, Billy C.S.; Hsin, Michael K.Y.; Mok, Tony S.K.; Underwood, Malcolm J.; Chen, George G.

    2010-12-10

    Accumulating evidence shows that the inhibition of thromboxane synthase (TXS) induced apoptosis in cancer cells. TXS inhibitor 1-Benzylimidzole (1-BI) can trigger apoptosis in lung cancer cells but the mechanism is not fully defined. In this study, lung cancer cells were treated with 1-BI. In this study, the level of reactive oxygen species (ROS) was measured and NF-{kappa}B activity was determined in human lung cancer cells. The roles of ROS and NF-{kappa}B in 1-BI-mediated cell death were analyzed. The results showed that 1-BI induced ROS generation but decreased the activity of NF-{kappa}B by reducing phosphorylated I{kappa}B{alpha} (p-I{kappa}B{alpha}) and inhibiting the translocation of p65 into the nucleus. In contrast to 1-BI, antioxidant N-acetyl cysteine (NAC) stimulated cell proliferation and significantly protected the cells from 1-BI-mediated cell death by neutralizing ROS. Collectively, apoptosis induced by 1-BI is associated with the over-production of ROS and the reduction of NF-{kappa}B. Antioxidants can significantly block the inhibitory effect of 1-BI.

  20. Oral recombinant human or mouse lactoferrin reduces Mycobacterium tuberculosis TDM induced granulomatous lung pathology.

    PubMed

    Hwang, Shen-An; Kruzel, Marian L; Actor, Jeffrey K

    2017-02-01

    Trehalose 6'6-dimycolate (TDM) is the most abundant glycolipid on the cell wall of Mycobacterium tuberculosis (MTB). TDM is capable of inducing granulomatous pathology in mouse models that resembles those induced by MTB infection. Using the acute TDM model, this work investigates the effect of recombinant human and mouse lactoferrin to reduce granulomatous pathology. C57BL/6 mice were injected intravenously with TDM at a dose of 25 μg·mouse(-1). At day 4 and 6, recombinant human or mouse lactoferrin (1 mg·(100 μL)(-1)·mouse(-1)) were delivered by gavage. At day 7 after TDM injection, mice were evaluated for lung pathology, cytokine production, and leukocyte populations. Mice given human or mouse lactoferrin had reduced production of IL-12p40 in their lungs. Mouse lactoferrin increased IL-6 and KC (CXCL1) in lung tissue. Increased numbers of macrophages were observed in TDM-injected mice given human or mouse lactoferrin. Granulomatous pathology, composed of mainly migrated leukocytes, was visually reduced in mice that received human or mouse lactoferrin. Quantitation of granulomatous pathology demonstrated a significant decrease in mice given human or mouse lactoferrin compared with TDM control mice. This report is the first to directly compare the immune modulatory effects of both heterologous recombinant human and homologous mouse lactoferrin on the development of TDM-induced granulomas.

  1. Exogenous Fibroblast Growth Factor-10 Induces Cystic Lung Development with Altered Target Gene Expression in the Presence of Heparin in Cultures of Embryonic Rat Lung

    PubMed Central

    Hashimoto, Shuichi; Nakano, Hiroshi; Suguta, Yuko; Irie, Seiko; Jianhua, Luo; Katyal, Sikardar L.

    2012-01-01

    Objectives Signaling by fibroblast growth factor (FGF) receptor (FGFR) 2IIIb regulates branching morphogenesis in the mammalian lung. FGFR2IIIb is primarily expressed in epithelial cells, whereas its ligands, FGF-10 and keratinocyte growth factor (KGF; FGF-7), are expressed in mesenchymal cells. FGF-10 null mice lack lungs, whereas KGF null animals have normal lung development, indicating that FGF-10 regulates lung branching morphogenesis. In this study, we determined the effects of FGF-10 on lung branching morphogenesis and accompanying gene expression in cultures of embryonic rat lungs. Methods Embryonic day 14 rat lungs were cultured with FGF-10 (0–250 ng/ml) in the absence or presence of heparin (30 ng/ml) for 4 days. Gene expression profiles were analyzed by Affymetrix microchip array including pathway analysis. Some of these genes, functionally important in FGF-10 signaling, were further analyzed by Northern blot, real-time PCR, in situ hybridization and immunohistochemistry. Results Exogenous FGF-10 inhibited branching and induced cystic lung growth only in cultures containing heparin. In total, 252 upregulated genes and 164 downregulated genes were identified, and these included Spry1 (Sprouty-1), Spry2 (Sprouty-2), Spred-1, Bmp4 (bone morphogenetic protein-4, BMP-4), Shh(sonic hedgehog, SHH), Pthlh (parathyroid hormone-related protein, PTHrP), Dusp6 (MAP kinase phosphatase-3, MKP-3) and Clic4 (chloride intracellular channel-4, CLIC-4) among the upregulated genes and Igf1 (insulin-like growth factor-1, IGF-1), Tcf21 (POD), Gyg1 (glycogenin 1), Sparc (secreted protein acidic and rich in cysteine, SPARC), Pcolce (procollagen C-endopeptidase enhancer protein, Pro CEP) and Lox (lysyl oxidase) among the downregulated genes. Gsk3β and Wnt2, which are involved in canonical Wnt signaling, were up- and downregulated, respectively. Conclusions Unlike FGF-7, FGF-10 effects on lung branching morphogenesis are heparin-dependent. Sprouty-2, BMP-4, SHH, IGF-1, SPARC

  2. Teaching Cardiopulmonary Resuscitation in the Schools.

    ERIC Educational Resources Information Center

    Carveth, Stephen W.

    1979-01-01

    Cardiopulmonary resuscitation is a key part of emergency cardiac care. It is a basic life support procedure that can be taught in the schools with the assistance of the American Heart Association. (JMF)

  3. Advance Directives and Do Not Resuscitate Orders

    MedlinePlus

    ... an advance directive. For example, someone who has terminal cancer might write that she does not want ... education, patient information, power of attorney, resuscitate, state, terminal care, wishes End-of-Life Issues, Healthcare Management, ...

  4. Smad7 is a TGF-beta-inducible attenuator of Smad2/3-mediated inhibition of embryonic lung morphogenesis.

    PubMed

    Zhao, J; Crowe, D L; Castillo, C; Wuenschell, C; Chai, Y; Warburton, D

    2000-05-01

    Smad7 was recently shown to antagonize TGF-beta-induced activation of signal-transducing Smad2 and Smad3 proteins. However, the biological function of Smad7 in the process of lung organogenesis is not known. Since Smad2/3-mediated TGF-beta signaling is known to inhibit embryonic lung branching morphogenesis, we tested the hypothesis that Smad7 regulates early lung development by modulating TGF-beta signal transduction. An antisense oligodeoxynucleotide (ODN) was designed to specifically block endogenous Smad7 gene expression at both transcriptional and translational levels in embryonic mouse lungs in culture. TGF-beta-mediated inhibition of lung branching morphogenesis was significantly potentiated in cultured embryonic lungs in the absence of Smad7 gene expression: abrogation of Smad7 potentiated TGF-beta-mediated inhibition of lung branching morphogenesis from 76 to 52% of the basal level in lungs cultured in the presence of 5 ng/ml TGF-beta1 ligand. Likewise, TGF-beta1 EC(50) (concentration of TGF-beta1 that induced half maximal branching inhibition) was reduced from 5 to 1 ng/ml when Smad7 gene expression was abrogated in lung culture, indicating an enhanced level of TGF-beta signaling in lung tissue with abolished Smad7 gene expression. By immunocytochemistry, Smad7 protein was co-localized with both Smad2 and Smad3 in distal bronchial epithelial cells, supporting the concept that Smad7 inhibits TGF-beta signaling by competing locally with Smad2 and Smad3 for TGF-beta receptor complex binding during lung morphogenesis. Furthermore, antisense Smad7 ODN increased the negative effect of TGF-beta1 on epithelial cell growth in developing lungs in culture. We also demonstrated that Smad7 mRNA levels were rapidly and potently induced upon TGF-beta1 stimulation of lungs in culture, suggesting that Smad7 regulates TGF-beta responses in a negative feedback loop. These studies define a novel function for Smad7 as an intracellular antagonist of TGF-beta-induced, Smad2

  5. Burn Resuscitation Decision Support System (BRDSS)

    DTIC Science & Technology

    2013-09-01

    CONTRACTING ORGANIZATION: Arcos , Inc. HoustonTX77018-5308 REPORT DATE: September 2013 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical... Arcos , Inc. 866 W. 41st St. Houston TX 77018-5308 The Burn Resuscitation Decision Support System (BRDSS) is a medical device designed to guide and...project: The Burn Resuscitation Decision Support System (BRDSS) Tablet project will be broken into four major phases. Throughout the project Arcos will

  6. Gastrointestinal Fluid Resuscitation of Thermally Injured Patients

    DTIC Science & Technology

    2006-10-01

    remains to be determined. Therefore, the purpose of this article is to review the history and current status of gastroin- testinal resuscitation and...progress in this field occurred until Frank Underhill’s report on the Rialto Theater fire of 1921. In this article , the author recognized...featured a shift to the use of intravenous plasma as the primary resuscitation fluid.17 Still, it is worth recalling that the landmark article by Reiss

  7. The US Department of Defense Hemorrhage and Resuscitation Research and Development Program

    DTIC Science & Technology

    2015-08-01

    Biomedical Advanced Re- search and Development Authority, the National Heart Lung and Blood Institute, and the US Food and Drug Administration Office of...conflicts demonstrate the continuing need for research and development focusing on hemorrhage control, fluid resuscitation, blood products, transfusion...often received blood transfusions at forward-positioned hospitals and surgical teams. The magnitude of this requirement is evidenced by the fact that more

  8. [Mechanisms of psychological adaptation of anesthesiologists-resuscitators to the stress-induced conditions of professional occupation and possibilities of their correction within a teaching process].

    PubMed

    Shchelkova, O Iu; Mazurok, V A

    2007-01-01

    High psychological tension results in the development of specific coping behavior. Ninety-six anesthesiologists, including 62 (64.6%) males and 34 (35.4%) females, were examined to reveal the mechanisms of psychological adaptation to stress-induced conditions of professional occupation. The respondents were ascertained to most frequently use cognitive, emotional, and behavioral constructive copings in settling stress situations. Nonadaptive copings most commonly contemplate a refusal to get over difficulties due to the lack of faith in power, to the underestimation of the importance of negative events, to passivity, isolation, etc., which is traditionally considered to be a manifestation of the emotional burnout syndrome in attendants. Psychological training within a teaching process may be regarded as a help to physicians in developing constructive coping strategies, training in self-diagnosis and self-help in the early manifestations of emotional burnout.

  9. Oleic-acid-induced lung injury in the rat. Failure of indomethacin treatment or complement depletion to ablate lung injury.

    PubMed Central

    Dickey, B. F.; Thrall, R. S.; McCormick, J. R.; Ward, P. A.

    1981-01-01

    The purpose of this study was to establish a rat animal model of acute respiratory distress syndrome using the intravenous injection of oleic acid. Further, we attempted to inhibit the development of lung injury by pretreatment of the rats with indomethacin or cobra venom factor. Histologic evidence of lung injury was apparent within hours after the administration of a single intravenous injection of oleic acid. By 24 hours, interstitial and intraalveolar edema and hemorrhage were noted with vascular congestion and an extensive interstitial infiltrate. The lungs appeared virtually normal by 12 days, with no evidence of chronic lung injury. Multiple injections of oleic acid also did not progress into chronic pulmonary inflammation. Treatment of the rats with indomethacin or cobra venom factor had no effect on ablating acute lung injury. An animal model of adult respiratory distress syndrome is presented which does not progress to chronic lung injury. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7234970

  10. Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene.

    PubMed

    Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

    2015-01-01

    Rocket kerosene (RK) is a new rocket propellant. Toxicity occurs if a high level of RK is inhaled. To study the toxicity of RK in lung and the mechanisms of RK-induced lung jury, a total of 72 male ICR mice (1.5 months, adult) were randomly assigned to the RK exposure group (RKEG) and normal control group (NCG). Mice were whole-body exposed to room air or aerosol of 18000 mg/m3 RK for 4 hours. Histopathological analysis was performed to evaluate the pulmonary lesions. Oxidative stress was assessed by assay of MDA, SOD, GSH-PX and TAOC. Inflammatory response was estimated by detecting inflammatory cell counts, TNF-α and IL-6 protein levels in serum. The results showed that after 2 to 6 hours of RK exposure, pulmonary vascular dilatation, congestion and edematous widening of the alveolar septum were noted. After 12 to 24 hours post-exposure, diffuse hemorrhage in alveolar space were found, along with the progressive pulmonary vascular dilatation and edematous widening of alveolar septum. During 3 to 7 days of RK-exposure, inflammatory cells were scattered in the lung tissue. The pathological alterations of the lung were alleviated after 14 days post-exposure, and showed significant improvement after 21 days post-exposure. After 30 days of RK exposure, the pathological changes in the lung tissue were nearly recovered except the local thickening of the alveolar wall. Compared with NCG, RK inhalation produced a significant increase of MDA levels and a significant decrease of SOD, GSH-Px and TAOC activity in the lung after 2 hours post-exposure (P<0.05). There were significant increases of TNF-α and IL-6 protein levels in serum of mice in RKEG after 2, 6 and 12 hours and 1, 4 and 7 days post-exposure compared with NCG (P<0.05). TNF-α protein levels had a sharp increase after 4 days of exposure. IL-6 protein level was increased at early phase of experiment and then gradually decreased along with the prolonged course of exposure. Considering that the RK-induced lung

  11. Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene

    PubMed Central

    Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

    2015-01-01

    Rocket kerosene (RK) is a new rocket propellant. Toxicity occurs if a high level of RK is inhaled. To study the toxicity of RK in lung and the mechanisms of RK-induced lung jury, a total of 72 male ICR mice (1.5 months, adult) were randomly assigned to the RK exposure group (RKEG) and normal control group (NCG). Mice were whole-body exposed to room air or aerosol of 18000 mg/m3 RK for 4 hours. Histopathological analysis was performed to evaluate the pulmonary lesions. Oxidative stress was assessed by assay of MDA, SOD, GSH-PX and TAOC. Inflammatory response was estimated by detecting inflammatory cell counts, TNF-α and IL-6 protein levels in serum. The results showed that after 2 to 6 hours of RK exposure, pulmonary vascular dilatation, congestion and edematous widening of the alveolar septum were noted. After 12 to 24 hours post-exposure, diffuse hemorrhage in alveolar space were found, along with the progressive pulmonary vascular dilatation and edematous widening of alveolar septum. During 3 to 7 days of RK-exposure, inflammatory cells were scattered in the lung tissue. The pathological alterations of the lung were alleviated after 14 days post-exposure, and showed significant improvement after 21 days post-exposure. After 30 days of RK exposure, the pathological changes in the lung tissue were nearly recovered except the local thickening of the alveolar wall. Compared with NCG, RK inhalation produced a significant increase of MDA levels and a significant decrease of SOD, GSH-Px and TAOC activity in the lung after 2 hours post-exposure (P < 0.05). There were significant increases of TNF-α and IL-6 protein levels in serum of mice in RKEG after 2, 6 and 12 hours and 1, 4 and 7 days post-exposure compared with NCG (P < 0.05). TNF-α protein levels had a sharp increase after 4 days of exposure. IL-6 protein level was increased at early phase of experiment and then gradually decreased along with the prolonged course of exposure. Considering that the RK-induced lung

  12. Carbon black nanoparticle instillation induces sustained inflammation and genotoxicity in mouse lung and liver

    PubMed Central

    2012-01-01

    Background Widespread occupational exposure to carbon black nanoparticles (CBNPs) raises concerns over their safety. CBNPs are genotoxic in vitro but less is known about their genotoxicity in various organs in vivo. Methods We investigated inflammatory and acute phase responses, DNA strand breaks (SB) and oxidatively damaged DNA in C57BL/6 mice 1, 3 and 28 days after a single instillation of 0.018, 0.054 or 0.162 mg Printex 90 CBNPs, alongside sham controls. Bronchoalveolar lavage (BAL) fluid was analyzed for cellular composition. SB in BAL cells, whole lung and liver were assessed using the alkaline comet assay. Formamidopyrimidine DNA glycosylase (FPG) sensitive sites were assessed as an indicator of oxidatively damaged DNA. Pulmonary and hepatic acute phase response was evaluated by Saa3 mRNA real-time quantitative PCR. Results Inflammation was strongest 1 and 3 days post-exposure, and remained elevated for the two highest doses (i.e., 0.054 and 0.162 mg) 28 days post-exposure (P < 0.001). SB were detected in lung at all doses on post-exposure day 1 (P < 0.001) and remained elevated at the two highest doses until day 28 (P < 0.05). BAL cell DNA SB were elevated relative to controls at least at the highest dose on all post-exposure days (P < 0.05). The level of FPG sensitive sites in lung was increased throughout with significant increases occurring on post-exposure days 1 and 3, in comparison to controls (P < 0.001-0.05). SB in liver were detected on post-exposure days 1 (P < 0.001) and 28 (P < 0.001). Polymorphonuclear (PMN) cell counts in BAL correlated strongly with FPG sensitive sites in lung (r = 0.88, P < 0.001), whereas no such correlation was observed with SB (r = 0.52, P = 0.08). CBNP increased the expression of Saa3 mRNA in lung tissue on day 1 (all doses), 3 (all doses) and 28 (0.054 and 0.162 mg), but not in liver. Conclusions Deposition of CBNPs in lung induces inflammatory and genotoxic effects in mouse lung that persist considerably after the

  13. Bronchoscopic Investigation of Atypical Drug-induced Hypersensitivity Syndrome Showing Viral Lung Involvement.

    PubMed

    Hase, Isano; Arakawa, Hiroaki; Sakuma, Hideo; Kaneko, Fumio; Watanabe, Yuzuru; Fujiu, Koichi; Miyamoto, Hideaki; Ishii, Yoshiki

    We herein report a case of atypical drug-induced hypersensitivity syndrome (DIHS) involving serological reactivation of cytomegalovirus induced by carbamazepine with pulmonary and skin manifestations. These lesions were not present on admission, but developed on virus reactivation as indicated by the presence of inclusion bodies and multinucleated giant cells in alveolar cells with CD8(+) T lymphocyte infiltration on a transbronchial lung biopsy. Although the precise mechanism of DIHS remains unknown, this case suggests the crucial role of viral reactivation in pulmonary lesions in DIHS.

  14. Inhaled asbestos fibers induce p53 expression in the rat lung.

    PubMed

    Mishra, A; Liu, J Y; Brody, A R; Morris, G F

    1997-04-01

    Humans and rodents exposed to an aerosol of asbestos fibers develop lung injury that can lead to a fibroproliferative response culminating in excessive scarring and impaired lung function. To define the early events that precede asbestos-induced fibrotic lung disease, rats were exposed to an aerosol of chrysotile asbestos fibers for 5 h. At various times after exposure, the lungs of the asbestos-exposed animals were evaluated immunohistochemically for expression of the p53 tumor suppressor protein, a growth regulatory protein. p53 became detectable by immunostaining at the predicted sites of fiber deposition (the bronchiolar-alveolar duct bifurcations) by 24 h after exposure. The number of cells positive for p53 immunostaining increased to a maximal level at 8 days after exposure, decreased by 14 days and returned to a low basal level at the 30-day time point. Control groups of rats that were unexposed or exposed to an aerosol of iron beads were negative for p53 immunostaining throughout the 30-day assessment period. Simultaneous detection of the proliferating cell nuclear antigen (PCNA) at the sites of fiber deposition in the asbestos-exposed animals agrees with our previous finding that p53 binds and regulates the PCNA promoter.

  15. Simvastatin Reduces Endotoxin-Induced Acute Lung Injury by Decreasing Neutrophil Recruitment and Radical Formation

    PubMed Central

    Grommes, Jochen; Vijayan, Santosh; Drechsler, Maik; Hartwig, Helene; Mörgelin, Matthias; Dembinski, Rolf; Jacobs, Michael; Koeppel, Thomas Andreas; Binnebösel, Marcel; Weber, Christian; Soehnlein, Oliver

    2012-01-01

    Introduction Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. Methods C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. Results Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. Conclusion Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI. PMID:22701728

  16. Increased surface tension of the lung and surfactant in bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Horiuchi, T; Ikegami, M; Cherniack, R M; Mason, R J

    1996-10-01

    The increased elastic recoil of the lung in bleomycin-induced pulmonary fibrosis in the rat is due in part to increased surface forces. This study was designed to determine the role of surface tension in situ and in vitro 21 d after instillation of bleomycin. Using sequentially measured pressure-volume curves generated with air, saline, air after lavage with Tween 20, and saline, surface tension was significantly higher in bleomycin-treated lungs than in untreated lungs (4.7 +/- 1.1 versus 1.8 +/- 0.2 dyne/cm, p < 0.01). Surface tension was determined in vitro with a Wilhelmy balance using bronchoalveolar lavage fluid, surfactant, and organic solvent lipid extracts of surfactant. Bleomycin treatment resulted in elevated minimal surface tensions: BALF (20.7 +/- 0.6 versus 13.6 +/- 3.8 dyne/cm, p < 0.02), isolated surfactant (12.0 +/- 1.3 versus 3.0 +/- 0.5 dyne/cm, p < 0.02), and the organic solvent lipid extracted surfactant (11.0 versus 3.2 dyne/cm). These results indicate that the physical properties of surfactant in lungs of rats treated with bleomycin are abnormal and contribute to the increased elastic recoil in this model of pulmonary fibrosis.

  17. Group B Streptococcus Induces a Caspase-Dependent Apoptosis in Fetal rat Lung Interstitium

    PubMed Central

    Kling, David E.; Tsvang, Inna; Murphy, Miriam P.; Newburg, David S.

    2013-01-01

    Group B Streptococcus (GBS) is an important pathogen and is associated with sepsis and meningitis in neonates and infants. An ex vivo model that facilitates observations of GBS interactions with multiple host cell types over time was used to study its pathogenicity. GBS infections were associated with profound reductions in fetal lung; explant size, and airway branching. Elevated levels of apoptosis subsequent to GBS infections were observed by whole-mount confocal immunofluorescence using activated-caspase-3-antibodies and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assays. The caspase inhibitor Z-VAD-FMK abolished the increase in TUNEL-positive cells associated with GBS infections, indicating that the GBS-induced apoptosis was caspase-dependent. Digital image analyses revealed that both GBS and the active form of caspase-3 were distributed primarily within the lung interstitium, suggesting that these tissues are important targets for GBS. Antibodies to the active form of caspase-3 colocalized with both macrophage- and erythroblast-markers, suggesting that these hematopoietic cells are vulnerable to GBS-mediated pathogenesis. These studies suggest that GBS infections profoundly alter lung morphology and caspase-dependent hematopoietic cell apoptosis within the lung interstitium play roles in GBS pathophysiology in this model. PMID:23624260

  18. Acrolein induced both pulmonary inflammation and the death of lung epithelial cells.

    PubMed

    Sun, Yang; Ito, Sachiko; Nishio, Naomi; Tanaka, Yuriko; Chen, Nana; Isobe, Ken-Ichi

    2014-09-02

    Acrolein, a compound found in cigarette smoke, is a major risk factor for respiratory diseases. Previous research determined that both acrolein and cigarette smoke produced reactive oxygen species (ROS). As many types of pulmonary injuries are associated with inflammation, this study sought to ascertain the extent to which exposure to acrolein advanced inflammatory state in the lungs. Our results showed that intranasal exposure of mice to acrolein increased CD11c(+)F4/80(high) macrophages in the lungs and increased ROS formation via induction of NF-κB signaling. Treatment with acrolein activated macrophages and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. In in vitro studies, acrolein treatment of bone marrow-derived GM-CSF-dependent immature macrophages (GM-IMs), activated the cells and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. Acrolein treatment of macrophages induced apoptosis of lung epithelial cells. Inclusion of an inhibitor of ROS formation markedly decreased acrolein-mediated macrophage activation and reduced the extent of epithelial cell death. These results indicate that acrolein can cause lung damage, in great part by mediating the increased release of pro-inflammatory cytokines/factors by macrophages.

  19. Leukocyte transepithelial migration in lung induced by DMSA functionalized magnetic nanoparticles.

    PubMed

    Azevedo, Ricardo Bentes; Valois, Caroline Rodrigues Alves; Chaves, Sacha Braun; Silva, Jaqueline Rodrigues; Garcia, Monica Pereira

    2011-01-01

    Magnetic nanoparticles surface-covered with meso-2,3-dimercaptosuccinic acid (MNPs-DMSA) constitute a promising approach for tissue- and cell-targeted delivery of therapeutic drugs in the lung. However, they can also induce a transient transendothelial migration of leukocytes in the organ as a side effect after endovenous administration of MNPs-DMSA. We demonstrated that monocytes/macrophages constitute the main subpopulation of leukocytes involved in this process. Our recent research found that MNPs-DMSA up-regulated the mRNA expression of E-, L- and P-selectin and macrophage-1 antigen, and increased concentration of tumor necrosis factor-α in lung, in a time dependent manner. The critical relevance of the β2 integrin-dependent pathway in leukocyte transmigration elicited by MNPs-DMSA was demonstrated by use of knockout mice. Our work characterizes mechanisms of the pro-inflammatory effects of MNPs-DMSA in the lung, and identifies β2 integrin-targeted interventions as promising strategies to reduce pulmonary side effects of MNPs-DMSA during biomedical applications. In addition, MNPs-DMSA could be used as modulators of lung immune response.

  20. Cigarette smoke-induced lung emphysema in mice is associated with prolyl endopeptidase, an enzyme involved in collagen breakdown

    PubMed Central

    Koelink, Pim J.; Henricks, Paul A. J.; Jackson, Patricia L.; Nijkamp, Frans P.; Garssen, Johan; Kraneveld, Aletta D.; Blalock, J. Edwin; Folkerts, Gert

    2011-01-01

    There is increasing evidence that the neutrophil chemoattractant proline-glycine-proline (PGP), derived from the breakdown of the extracellular matrix, plays an important role in neutrophil recruitment to the lung. PGP formation is a multistep process involving neutrophils, metalloproteinases (MMPs), and prolyl endopeptidase (PE). This cascade of events is now investigated in the development of lung emphysema. A/J mice were whole body exposed to cigarette smoke for 20 wk. After 20 wk or 8 wk after smoking cessation, animals were killed, and bronchoalveolar lavage fluid and lung tissue were collected to analyze the neutrophilic airway inflammation, the MMP-8 and MMP-9 levels, the PE activity, and the PGP levels. Lung tissue degradation was assessed by measuring the mean linear intercept. Additionally, we investigated the effect of the peptide l-arginine-threonine-arginine (RTR), which binds to PGP sequences, on the smoke-induced neutrophil influx in the lung after 5 days of smoke exposure. Neutrophilic airway inflammation was induced by cigarette smoke exposure. MMP-8 and MMP-9 levels, PE activity, and PGP levels were elevated in the lungs of cigarette smoke-exposed mice. PE was highly expressed in epithelial and inflammatory cells (macrophages and neutrophils) in lung tissue of cigarette smoke-exposed mice. After smoking cessation, the neutrophil influx, the MMP-8 and MMP-9 levels, the PE activity, and the PGP levels were decreased or reduced to normal levels. Moreover, RTR inhibited the smoke-induced neutrophil influx in the lung after 5 days' smoke exposure. In the present murine model of cigarette smoke-induced lung emphysema, it is demonstrated for the first time that all relevant components (neutrophils, MMP-8, MMP-9, PE) involved in PGP formation from collagen are upregulated in the airways. Together with MMPs, PE may play an important role in the formation of PGP and thus in the pathophysiology of lung emphysema. PMID:21112944

  1. Heterozygosity in the glutathione synthesis gene Gclm increases sensitivity to diesel exhaust particulate induced lung inflammation in mice

    PubMed Central

    Weldy, Chad S.; White, Collin C.; Wilkerson, Hui-Wen; Larson, Timothy V.; Stewart, James A.; Gill, Sean E.; Parks, William C.; Kavanagh, Terrance J.

    2012-01-01

    Context Inhalation of ambient fine particulate matter (PM2.5) is associated with adverse respiratory and cardiovascular effects. A major fraction of PM2.5 in urban settings is diesel exhaust particulate (DEP), and DEP-induced lung inflammation is likely a critical event mediating many of its adverse health effects. Oxidative stress has been proposed to be an important factor in PM2.5-induced lung inflammation, and the balance between pro- and antioxidants is an important regulator of this inflammation. An important intracellular antioxidant is the tripeptide thiol glutathione (GSH). Glutamate cysteine ligase (GCL) carries out the first step in GSH synthesis. In humans, relatively common genetic polymorphisms in both the catalytic (Gclc) and modifier (Gclm) subunits of GCL have been associated with increased risk for lung and cardiovascular diseases. Objective This study was aimed to determine the effects of Gclm expression on lung inflammation following DEP exposure in mice. Materials and methods We exposed Gclm wild type, heterozygous, and null mice to DEP via intranasal instillation and assessed lung inflammation as determined by neutrophils and inflammatory cytokines in lung lavage, inflammatory cytokine mRNA levels in lung tissue, as well as total lung GSH, Gclc, and Gclm protein levels. Results The Gclm heterozygosity was associated with a significant increase in DEP-induced lung inflammation when compared to that of wild type mice. Discussion and conclusion This finding indicates that GSH synthesis can mediate DEP-induced lung inflammation and suggests that polymorphisms in Gclm may be an important factor in determining adverse health outcomes in humans following inhalation of PM2.5. PMID:21967497

  2. Pediatric trauma resuscitation: initial fluid management.

    PubMed

    Schweer, Lynn

    2008-01-01

    Fluid management is a vital component in the resuscitative care of the injured child. The goal of fluid resuscitation is to restore tissue perfusion without compromising the body's natural compensatory mechanism. Recent literature has questioned the timing, type, and amount of fluid administration during the resuscitative phase. When managing a pediatric resuscitation, it is imperative to use a variety of age-appropriate physiologic parameters because reliance on blood pressure alone will lead to delayed recognition of shock. Establishing vascular access, via peripheral intravenous, central venous, or intraosseous catheter, should be a high nursing priority. Hemorrhage control and fluid resuscitation of an injured child remains a top priority of trauma care. Early intravenous access with appropriate fluid administration continues to be a universal treatment for the hypotensive trauma patient. Fluid resuscitation in the early phase of care, whether in the field, emergency department, or operating room, should be targeted toward perfusing critical organs, such as the brain and heart. Once obvious bleeding is controlled, the overall goal for fluid management centers on maintaining oxygen delivery to perfuse vital structures with enough oxygen and energy substrates to maintain cellular function, thus avoiding tissue ischemia. However, specific issues around timing and type of fluid administration, once thought to be straightforward, have triggered increasing investigation of current beliefs.

  3. Transfusion of Human Platelets Treated with Mirasol Pathogen Reduction Technology Does Not Induce Acute Lung Injury in Mice.

    PubMed

    Caudrillier, Axelle; Mallavia, Beñat; Rouse, Lindsay; Marschner, Susanne; Looney, Mark R

    2015-01-01

    Pathogen reduction technology (PRT) has been developed in an effort to make the blood supply safer, but there is controversy as to whether it may induce structural or functional changes to platelets that could lead to acute lung injury after transfusion. In this study, we used a commercial PRT system to treat human platelets that were then transfused into immunodeficient mice, and the development of acute lung injury was determined. P-selectin expression was higher in the Mirasol PRT-treated platelets compared to control platelets on storage day 5, but not storage day 1. Transfusion of control vs. Mirasol PRT-treated platelets (day 5 of storage, 109 platelets per mouse) into NOD/SCID mice did not result in lung injury, however transfusion of storage day 5 platelets treated with thrombin receptor-activating peptide increased both extravascular lung water and lung vascular permeability. Transfusion of day 1 platelets did not produce lung injury in any group, and LPS priming 24 hours before transfusion had no effect on lung injury. In a model of transfusion-related acute lung injury, NOD/SCID mice were susceptible to acute lung injury when challenged with H-2Kd monoclonal antibody vs. isotype control antibody. Using lung intravital microscopy, we did not detect a difference in the dynamic retention of platelets in the lung circulation in control vs. Mirasol PRT-treated groups. In conclusion, Mirasol PRT produced an increase in P-selectin expression that is storage-dependent, but transfusion of human platelets treated with Mirasol PRT into immunodeficient mice did not result in greater platelet retention in the lungs or the development of acute lung injury.

  4. ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells

    PubMed Central

    SHI, SHAOMIN; TAN, PING; YAN, BINGDI; GAO, RONG; ZHAO, JIANJUN; WANG, JING; GUO, JIA; LI, NING; MA, ZHONGSEN

    2016-01-01

    Cisplatin [cis-diamminedichloroplatinum II (CDDP)] is one of the most classical and effective chemotherapeutic drugs for the treatment of cancers including lung cancer. However, the presence of cisplatin resistance in cancer lowers its curative effect and limits its usage in the clinic. The aim of the present study was to investigate the underlying mechanisms of cisplatin resistance in lung cancer involving endoplasmic reticulum (ER) stress and autophagy. In the present study, we detected the effect of cisplatin on cell viability, ER stress and autophagy in lung cancer cell lines A549 and H460. We also tested the effects of ER stress and autophagy on apoptosis induced by cisplatin. The results showed that cisplatin induced apoptosis, ER stress and autophagy in lung cancer cell lines. In addition, the inhibition of ER stress by 4-phenylbutyric acid (4-PBA) or tauroursodeoxycholic acid sodium (TUDC) enhanced cisplatin-induced apoptosis in the human lung cancer cells. Meanwhile, combination treatment with the autophagic inhibitor 3-methyladenine (3-MA) or chloroquine (CQ) further increased the apoptosis induced by cisplatin in the human lung cancer cells. The present study provides a novel treatment strategy - cisplatin in combination with an autophagic inhibitor or an ER stress inhibitor leads to increased apoptosis in human lung cancer cells. PMID:26985651

  5. Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis.

    PubMed

    Nakanishi, Takeo; Hasegawa, Yoshitaka; Mimura, Reo; Wakayama, Tomohiko; Uetoko, Yuka; Komori, Hisakazu; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi; Tamai, Ikumi

    2015-01-01

    Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

  6. Local Correlation Between Monte-Carlo Dose and Radiation-Induced Fibrosis in Lung Cancer Patients

    SciTech Connect

    Stroian, Gabriela; Martens, Chandra; Souhami, Luis; Collins, D. Louis; Seuntjens, Jan

    2008-03-01

    Purpose: To present a new method of evaluating the correlation between radiotherapy (RT)-induced fibrosis and the local dose delivered to non-small-cell lung cancer patients. Methods and Materials: Treatment plans were generated using the CadPlan treatment planning system (pencil beam, no heterogeneity corrections), and RT delivery was based on these plans. Retrospective Monte-Carlo dose calculations were performed, and the Monte-Carlo distributions of dose to real tissue were calculated using the planning computed tomography (CT) images and the number of monitor units actually delivered. After registration of the follow-up CT images with the planning CT images, different grades of radiologic fibrosis were automatically segmented on the follow-up CT images. Subsequently, patient-specific fibrosis probabilities were studied as a function of the local dose and a function of time after RT completion. Results: A strong patient-specific variation in the fibrosis volumes was found during the follow-up period. For both lungs, the threshold dose for which the probability of fibrosis became significant coincided with the threshold dose at which significant volumes of the lung were exposed. At later stages, only fibrosis localized in the high-dose regions persisted for both lungs. Overall, the Monte-Carlo dose distributions correlated much better with the probability of RT-induced fibrosis than did the CadPlan dose distributions. Conclusion: The presented method allows for an accurate, systematic, patient-specific and post-RT time-dependent numeric study of the relationship between RT-induced fibrosis and the local dose.

  7. The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

    PubMed Central

    Wirsdörfer, Florian; Jendrossek, Verena

    2016-01-01

    Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein, lymphocytes represent a versatile and wide-ranged group of cells of the immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory, or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage-associated pulmonary diseases with a focus on T lymphocytes and B lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions as well as the interaction and the intercellular cross talk between cells from the innate and adaptive immune systems and (damaged) resident epithelial cells and stromal cells (e.g., endothelial cells, mesenchymal stem cells, and fibroblasts). Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease. PMID:28018357

  8. FGF4 induces epithelial-mesenchymal transition by inducing store-operated calcium entry in lung adenocarcinoma

    PubMed Central

    Qi, Lisha; Song, Wangzhao; Li, Lingmei; Cao, Lu; Yu, Yue; Song, Chunmin; Wang, Yalei; Zhang, Fei; Li, Yang; Zhang, Bin; Cao, Wenfeng

    2016-01-01

    Several fibroblast growth factor (FGF) isoforms act to stimulate epithelial-mesenchymal transition (EMT) during cancer progression. FGF4 and FGF7 are two ligands of FGF receptor 2 (FGFR2). Using two lung adenocarcinoma (ADC) cell lines, A549 and H1299, we showed that FGF4, but not FGF7, altered cell morphology, promoted EMT-associated protein expression, and enhanced cell proliferation, migration/invasion and colony initiation. In addition, FGF4 increased store-operated calcium entry (SOCE) and expression of the calcium signal-associated protein Orai1. The SOCE inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or Orai1 knockdown reversed all of the EMT-promoting effects of FGF4. BHQ also inhibited FGF4-induced EMT in a mouse xenograft model. Finally, 60 human lung ADC samples and 21 sets of matched specimens (primary and metastatic foci in lymph nodes from one patient) were used to confirm the clinicopathologic significance of FGF4 and its correlation with E-cadherin, Vimentin and Orai1 expression. Our study thus shows that FGF4 induces EMT by elevating SOCE in lung ADC. PMID:27677589

  9. ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6.

    PubMed

    Miller, Marina; Tam, Arvin B; Cho, Jae Youn; Doherty, Taylor A; Pham, Alexa; Khorram, Naseem; Rosenthal, Peter; Mueller, James L; Hoffman, Hal M; Suzukawa, Maho; Niwa, Maho; Broide, David H

    2012-10-09

    Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6-deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.

  10. Formaldehyde induces apoptosis through decreased Prx 2 via p38 MAPK in lung epithelial cells.

    PubMed

    Lim, Seul Ki; Kim, Jong Chun; Moon, Chang Jong; Kim, Gye Yeop; Han, Ho Jae; Park, Soo Hyun

    2010-05-27

    Formaldehyde (FA) is an important substance that induces sick house syndrome and diseases, such as asthma and allergies. Oxidative stress is involved in the development of respiratory disease, and diverse antioxidants may protect respiratory tract cells from apoptosis. Peroxiredoxin is a pivotal endogenous antioxidant. In the present study, FA induced death in A549 cells, a lung epithelial cell line, in a dose-dependent manner. FA also increased lipid peroxide formation (LPO) in A549 cells, suggesting a role for oxidative stress. Additionally, FA decreased peroxiredoxin 2 (Prx 2) protein levels after a 24 or 48h exposure to FA. We also examined whether the FA-induced decrease in Prx 2 was associated with apoptosis. Prx 2 overexpression protected against FA-induced cell apoptosis but not necrosis. Prx 2 overexpression blocked FA-induced increase in Bax, a pro-apoptotic molecule, and a decrease in Bcl-2, an anti-apoptotic molecule. Prx 2 overexpression also protected against FA-induced activation of some special apoptosis-associated proteins [caspase-3, caspase-9, and polypeptide poly (ADP-ribose) polymerase (PARP)]. Furthermore, we examined the signaling molecules involved in the FA-induced decrease in Prx 2 expression. The FA-induced decrease in Prx 2 and increase in cell apoptosis was restored by treatment with SB203580 [a p38 mitogen activated protein kinase (MAPK) inhibitor], but not by SP600125 [a c-jun-N-terminal kinase (JNK) inhibitor]. Also, FA-induced events were blocked by treatment with p38 siRNA, but not by scrambled siRNA. Indeed, FA increased p38 MAPK activation, suggesting a role for p38 MAPK in FA action. In conclusion, FA mediated apoptosis in lung epithelial cells by decreasing Prx 2 via p38 MAPK.

  11. Interleukin-17-induced EMT promotes lung cancer cell migration and invasion via NF-κB/ZEB1 signal pathway

    PubMed Central

    Gu, Kuo; Li, Ming-Ming; Shen, Jing; Liu, Fang; Cao, Jing-Yan; Jin, Shi; Yu, Yan

    2015-01-01

    Inflammatory cytokine interleukin-17 (IL-17) has been associated with the risk of progressive cancers including lung cancer. However, it remains unclear how IL-17 may contribute to the invasion and development of these inflammation-associated malignancies. Here we aimed to investigate the role of IL-17 in lung cancer cell development. Epithelial-mesenchymal transition (EMT) has been recently proposed as a developmental process which plays an important role in cancer progression and metastases. Here we show that IL-17 might promote EMT in lung cancer cells by inducing the transcriptional repressor ZEB1. Exposure to IL-17 upregulated the signature EMT phenotypic markers vimentin and E-cadherin in lung cancer cells, and compared with controls, increased cell migration was observed in IL-17-treated lung cancer cells. ZEB1 mRNA and protein expression was induced by IL-17, and IL-17 stimulated nuclear localization of phosphorylated ZEB1. Conversely, suppressing ZEB1 expression by ZEB1 siRNA abrogated IL-17-stimulated vimentin expression and cell migration. Moreover, the phosphorylation of IκBα was required for IL-17-induced expression of ZEB1, suggesting the involvement of canonical NF-κB signaling. To check this hypothesis, we used IKK inhibitor BAY 11-7028 to block NF-κB activity. We found that BAY 11-7028 abrogated IL-17-induced ZEB1 expression, cell migration, and EMT, thus confirming that NF-κB is required for IL-17 to induce these aggressive phenotypes in lung cancer cells. Taken together, our data support the idea that IL-17-induced EMT promotes lung cancer cell migration and invasion via NF-κB-mediated upregulation of ZEB1. This study reveals a new signaling axis through which the tumor microenvironment causes ZEB1 expression to promote cancer metastasis. We suggest that targeting IL-17-induced ZEB1 expression may offer an effective therapeutic strategy for lung cancer treatment. PMID:26045995

  12. SU-E-J-190: Characterization of Radiation Induced CT Number Changes in Tumor and Normal Lung During Radiation Therapy for Lung Cancer

    SciTech Connect

    Yang, C; Liu, F; Tai, A; Gore, E; Johnstone, C; Li, X

    2014-06-01

    Purpose: To measure CT number (CTN) changes in tumor and normal lung as a function of radiation therapy (RT) dose during the course of RT delivery for lung cancer using