Smoke Inhalation-induced Acute Lung Injury Research Articles

INOS inhibitor S-methylisothiourea alleviates smoke inhalation-induced acute lung injury by suppressing inflammation and macrophage infiltration

ObjectiveWe investigated the effects of the inducible NO synthase (iNOS) inhibitor, S-methylisothiourea (SMT), in a mouse model of smoke inhalation-induced acute lung injury (ALI) and explored the underlying molecular mechanism. Methods and analysisA mouse model of smoke inhalation-induced ALI was established. RNA-sequencing (seq) analysis was conducted to identify the differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed for functional annotation of DEGs. Moreover, an immunofluorescence assay using macrophage marker F4/80 was performed to assess macrophage infiltration. A hypoxia-induced HUVEC model was used to mimic smoke inhalation-induced injury in endothelial cells. Finally, a transwell assay was used to analyze the chemoattractive effects of endothelial cells on macrophages. ResultsSMT markedly alleviated the pulmonary pathological symptoms, edema, and inflammatory response in the mouse smoke inhalation-induced ALI model. RNA-seq analysis revealed that SMT may diminish lung injury by regulating the levels of genes associated with inflammatory responses, cell chemokines, and adhesion. In vivo data revealed that the protective effects of SMT against smoke inhalation-induced ALI were partly achieved by inhibiting the production of adhesion molecules and infiltration of macrophages. Furthermore, in vitro data from the hypoxia-induced HUVEC model revealed that SMT reduced macrophage chemotaxis by inhibiting the production of chemokines and adhesion molecules in endothelial cells. ConclusioniNOS inhibitor SMT protects the lungs from smoke inhalation-induced ALI by reducing the production of pro-inflammatory cytokines, adhesion molecules, and chemokines in endothelial cells, thereby inhibiting inflammation and macrophage infiltration.

Vitexin attenuates smoke inhalation induced acute lung injury in rats by inhibiting oxidative stress via PKC β/p66Shc signaling pathway

Purpose: To investigate the protective effect of vitexin on smoke inhalation-induced acute lung injury (SI-ALI), and the underlying mechanism of action.Methods: The ALI rat model was established by inhalation of smoke in a closed smoke chamber. Survival rate, arterial blood gas analysis, wet-to-dry weight ratio of lung tissues, bronchoalveolar lavage fluid protein concentration, lung tissue histology, and oxidative stress and inflammation level were evaluated. Expressions of protein kinase C β (PKC β), p66Shc, and phosphorylated p66Shc were determined by western blot or quantitative reverse transcription-polymerase chain reaction.Results: Compared with smoke inhalation group, vitexin alleviated the decline in arterial partial pressure of oxygen (p < 0.05), reduced lung tissue exudation and pathological lung tissue damage, inhibited the expression of PKC β/p66Shc signaling pathway proteins, downregulated the level of oxidative stress and inflammation, and ultimately improved the survival rate in SI-ALI rats (p < 0.05).Conclusion: Vitexin attenuates SI-ALI in rats by alleviating oxidative stress via inhibition of PKC β/p66Shc signaling pathway. Thus, this compound is a potential agent for the treatment of SI-ALI.

Preparation of inhalable quercetin-β-cyclodextrin inclusion complexes using the supercritical antisolvent process for the prevention of smoke inhalation-induced acute lung injury

Quercetin (Que) is a natural flavonoid with good anti-inflammatory and anti-apoptosis activities, but its poor water solubility and low bioavailability restrict its clinical application. Cyclodextrin inclusion is one effective method to improve the solubility of Que. In this study, Que-β-cyclodextrin inclusion complexes (Que-β-CD) were prepared using the supercritical antisolvent (SAS) process with supercritical carbon dioxide (SCCO2) and the grinding method, called S-Que-β-CD and G-Que-β-CD, respectively. Que-β-CD was identified with Fourier transform infrared spectroscopy and the X-ray diffraction method. S-Que-β-CD powders had a higher loading efficiency (19.81%) and drug release (71.76%), the smaller mass median aerodynamic diameter (2.83 µm), and the larger fine particle fraction (48.74%) than G-Que-β-CD powders, indicating the SAS process suitable for the preparation of Que-β-CD and S-Que-β-CD suitable for pulmonary inhalation. Pulmonary delivery of S-Que-β-CD showed good protection of the mouse lung from smoke inhalation-induced acute lung injury (SI-ALI), which was indicated by reduced pulmonary edema, high percutaneous oxygen saturation, weak inflammation and apoptosis, and the recovery of body weight. The SAS process is the optimal preparation method to obtain inhalable S-Que-β-CD powders with accelerated drug release, high lung deposition and enhanced therapeutic efficiency.

Dexamethasone up-regulates TNFAIP3 to attenuate inflammatory response with smoke inhalation-induced acute lung injury based on the GEO database

Dexamethasone up-regulates TNFAIP3 to attenuate inflammatory response with smoke inhalation-induced acute lung injury based on the GEO database

Rat model of smoke inhalation-induced acute lung injury

BackgroundAcute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a lethal disease with limited therapeutic options and an unacceptably high mortality rate. Understanding the complex pathophysiological processes involved in the...

Effects of different corticosteroid doses and durations on smoke inhalation-induced acute lung injury and pulmonary fibrosis in the rat

Excessive inflammation induced by cytokine storm and coagulation disorders is considered the primary characteristic of smoke inhalation-induced acute lung injury (SI-ALI). Glucocorticoids such as methylprednisolone (MP) are commonly used to treat patients with inflammatory diseases; however, the management of ALI or acute respiratory distress syndrome (ARDS) remains controversial. We explored the effects of different MP doses and durations in a rat SI-ALI model. SI-ALI model rats had a high mortality rate and severe lung injury with proinflammatory, procoagulant, and pro-fibrotic changes. We found that a medium MP dose (4 mg/kg) markedly improved survival rates compared with low (0.4 mg/kg) and high (40 mg/kg) doses in the acute phase. A medium dose significantly attenuated lung injury, and reduced proinflammatory cytokine production and neutrophil infiltration into alveoli. Both medium and high MP doses improved coagulation and fibrinolysis conditions compared with low-dose MP. We also explored the effect of different durations of MP treatment on attenuating fibrotic changes in late-phase SI-ALI. Pro-fibrotic chemokine levels were gradually increased, followed by an increase in collagen and fibrin deposition after smoke inhalation. Three and 7-day MP treatments significantly attenuated this process, which was reflected by a reduction in pro-fibrotic chemokine levels. There was no significant difference between 3- and 7-day treatments. We report that a medium MP (4 mg/kg) dose significantly reduced inflammation and coagulation disorders, as well as acute-phase mortality. Three-day MP treatment may sufficiently attenuate fibrotic changes in late-phase SI-ALI.

76 Nebulized Epinephrine Attenuates Lung Alveolar and Interstitial Edema Compared to Phenylephrine and Albuterol in Ovine Burn and Smoke Inhalation-Induced Acute Lung Injury

76 Nebulized Epinephrine Attenuates Lung Alveolar and Interstitial Edema Compared to Phenylephrine and Albuterol in Ovine Burn and Smoke Inhalation-Induced Acute Lung Injury

Preclinical and clinical studies of smoke-inhalation-induced acute lung injury: update on both pathogenesis and innovative therapy.

Smoke-inhalation-induced acute lung injury (SI-ALI) is a leading cause of morbidity and mortality in victims of fire tragedies. SI-ALI contributes to an estimated 30% of burn-caused patient deaths, and recently, more attention has been paid to the specific interventions for this devastating respiratory illness. In the last decade, much progress has been made in the understanding of SI-ALI patho-mechanisms and in the development of new therapeutic strategies in both preclinical and clinical studies. This article reviews the recent progress in the treatment of SI-ALI, based on pathophysiology, thermal damage, airway obstruction, the nuclear-factor kappa-B signaling pathway, and oxidative stress. Preclinical therapeutic strategies include use of mesenchymal stem cells, hydrogen sulfide, peroxynitrite decomposition catalysts, and proton-pump inhibitors. Clinical interventions include high-frequency percussive ventilation, perfluorohexane, inhaled anticoagulants, and nebulized epinephrine. The animal model, dose, clinical application, and pharmacology of these medications are summarized. Future directions and further needs for developing innovative therapies are discussed.

Therapeutic effects of different doses of methylprednisolone on smoke inhalation-induced acute lung injury in rats

To investigate the therapeutic effect of different doses of methylprednisolone (MP) in smoke inhalation-induced acute lung injury (SI-ALI). Adult male Sprague-Dawley (SD) rats were divided into control group (group A, n = 6), smoke inhalation group (group B, smoke inhalation 30 minutes, n = 30) and smoke + MP 40, 4, 0.4 mg/kg intervention group (groups C, D, E; intraperitoneal injection of MP at 1 hour before smoke inhalation, n = 30) according to random number table method. The survival status of rats in each group was observed at 24 hours, and murine smoke inhalation induced trauma score (MSITS) according to the symptoms and signs of rats at 3 hours after smoke inhalation were scored. The blood of abdominal aorta of rats was collected. Then the rats were sacrificed to harvest bronchoalveolar lavage fluid (BALF) and lung tissue. The levels of interleukin (IL-6, IL-17a) in plasma and BALF were detected by enzyme linked immunosorbent assay (ELISA); the total number of white blood cells and the proportion of leukocytes or macrophages in BALF were calculated; the histopathological changes of lung were observed and the lung injury score was given; the expression of myeloperoxidase (MPO) and high mobility group protein B1 (HMGB1) in lung tissue were detected by Western Blot. The 24-hour survival rate of group B rats was 33.67%. The survival rate of groups C, D and E (65.73%, 85.17%, 60.07%) were significantly higher than that of group B (all P < 0.05), and the survival rate of group D was significantly higher than that of groups C and E. Diffuse inflammatory cell infiltration, intra-alveolar hemorrhage and a large amount of edema fluid were seen in the lung tissue of group B; and the lung injury score was significantly higher than that of group A. Compared with group B, the lung injury in different doses of MP group were decreased to different degrees, while the lung injury scores in groups C and D were significantly decreased (3.31±1.37, 2.62±0.98 vs. 5.52±0.97, both P < 0.01); correlation analysis showed that MSITS score was significantly and positively correlated with lung injury score (r = 0.862, P < 0.001). The levels of plasma inflammatory factors and BALF protein, inflammatory cells and inflammatory factors, and the expression of MPO, HMGB1 in group B were significantly higher than those in group A. Compared with group B, the levels of inflammatory factors in plasma, and protein content, inflammatory cells and inflammatory factors in BALF in different doses of MP group were decreased to different degrees, with significant differences in groups C and D [plasma: IL-17a (pg/L): 49.28±27.12, 36.57±16.52 vs. 191.79±88.21; IL-6 (ng/L): 206.47±109.96, 197.52±113.86 vs. 669.00±299.60; BALF: protein content (mg/L): 892.0±164.5, 566.1±120.9 vs. 1 838.0±145.8; white blood cell count (×109/L): 5.40±1.67, 2.81±1.20 vs. 9.02±2.06; neutrophil ratio: 0.315±0.081, 0.273±0.080 vs. 0.590±0.096; IL-17a (ng/L): 22.63±8.62, 18.92±8.43 vs. 43.31±19.17; IL-6 (ng/L): 156.49±46.94, 123.66±64.91 vs. 253.43±80.03; all P < 0.01]; in addition, the expression of MPO and HMGB1 protein in lung tissues of MP groups with different doses were significantly decreased, the expression of MPO in group D was significantly lower than that in group E [MPO/β-actin (fold increase from group A): 2.14±0.97 vs. 4.35±0.87, P < 0.01], the expression of HMGB1 in groups C and D were significantly lower than that in group E [HMGB1/β-actin (fold increase from group A): 1.77±0.73, 1.23±0.67 vs. 3.65±1.08, both P < 0.05]. MP can significantly improve the survival rate of SI-ALI rats and reduce the acute pulmonary and systemic inflammatory response. The MP effect of 4 mg/kg was better than 40 mg/kg and 0.4 mg/kg.

SOCS-1 Suppresses Inflammation Through Inhibition of NALP3 Inflammasome Formation in Smoke Inhalation-Induced Acute Lung Injury.

Smoke inhalation leads to acute lung injury (ALI), a devastating clinical problem associated with high mortality rates. Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of proinflammatory cytokine signaling. We have found that adenoviral gene transfer of SOCS-1 ameliorates smoke inhalation-induced lung injury in C57BL/6 mice. We also found that the release of adenosine triphosphate (ATP) was increased post smoke exposure, while oxidized ATP, an inhibitor of purinergic P2X7 receptor, suppressed smoke-induced NALP3 inflammasome assembly, caspase-1 activation, and K+ efflux. Similar to oxidized ATP, high protein level of SOCS-1 dampened the formation of NALP3 inflammasome and the activation of caspase-1 and IL-1β induced by smoke exposure in mouse alveolar macrophages. In conclusion, SOCS-1 relieves smoke inhalation-induced pulmonary inflammation and injury by inhibiting NALP3 inflammasome formation.

SOCS-1 ameliorates smoke inhalation-induced acute lung injury through inhibition of ASK-1 activity and DISC formation

Smoke inhalation leads to acute lung injury (ALI), a devastating clinical problem associated with high mortality. Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of apoptosis and pro-inflammatory cytokine signaling, two major contributors to the pathogenesis of ALI. We have found that SOCS-1 protects lung epithelial cells from smoke-induced apoptosis through two mechanisms. One is that SOCS-1 enhances degradation of ASK-1 and diminishes cleavage of pro-caspase-3 to repress smoke-triggered apoptosis in lung epithelial cells. The other is that SOCS-1 represses smoke-triggered DISC formation through altering TRADD-caspase-8 interaction rather than TNFR-1-TRADD interaction or TNFR-1-TRAF-2 interaction. In conclusion, SOCS-1 relieves smoke inhalation-induced lung injury by repressing ASK-1 and DISC-mediated epithelium apoptosis.

Imbalance of Th17/Tregs in rats with smoke inhalation-induced acute lung injury.

T helper (Th) 17 cells and CD4+ CD25+ regulatory T (Treg) cells are supposed to be critically involved in regulating autoimmune and inflammatory diseases. The aim of this study was to investigate the Th17/Treg pattern in rats with gunpowder smog-induced acute lung injury. Wistar rats were equally randomized to three groups: normal control group, ALI 6 h group (smoke inhalation for 6 h) and ALI 24 h group (smoke inhalation for 24 h). We observed changes in cell counting in bronchoalveolar lavage fluid (BALF), alveolar-capillary membrane permeability and lung tissue pathology. Moreover, rats in ALI 6 h and ALI 24 h group showed increased expression of Th17 cell and related cytokines (IL-17 A, IL-6, TGF-β and IL-23). Meanwhile, Treg prevalence and related cytokines (IL-10, IL-2 and IL-35) were decreased. Consequently, the ratio of Th17/Treg was higher after smoke inhalation. Additionally, Th1 cell decreased while Th2 cell increased at 6 h and 24 h after smoke inhalation. In conclusion, Th17/Treg imbalance exists in rats with smoke inhalation-induced acute lung injury, suggesting its potential role in the pathogenesis of this disease.

Administration of a Peroxynitrite Decomposition Catalyst Into the Bronchial Artery Attenuates Pulmonary Dysfunction After Smoke Inhalation and Burn Injury in Sheep

Reactive nitrogen species such as peroxynitrite play a significant role in burn and smoke inhalation injury. The bronchial circulation increases more than 10-fold in response to this combination injury. We hypothesized that direct delivery of low-dose WW-85, a peroxynitrite decomposition catalyst, into the bronchial artery would attenuate burn- and smoke inhalation-induced acute lung injury. In adult female sheep (n = 17), the bronchial artery was cannulated in preparation surgery. After a 5- to 7-day recovery period, sheep were subjected to a burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, <40°C). The animals were divided into three groups following the injury: (i) WW-85 group: 1 h after injury, WW-85 (0.002 mg/kg per hour) was continuously infused into the bronchial artery, n = 5; (ii) control group: 1 h after injury, an equivalent amount of saline was injected into the bronchial artery, n = 6; (iii) sham group: no injury, no treatment, same operation and anesthesia, n = 6. All animals were mechanically ventilated and fluid resuscitated equally. In the control group, the injury induced a severe deterioration of pulmonary oxygenation and shunting and an increase in pulmonary microvascular permeability toward sham. The injury was further associated with an increase in reactive nitrogen species in lung tissues of the control group. All these alterations were significantly attenuated in the WW-85 group. We demonstrated that a low dosage of WW-85 directly administered into the bronchial artery attenuated pulmonary dysfunction to the same extent as higher systemically administered doses in previous experiments. Our data strongly suggest that local airway production of peroxynitrite contributes to pulmonary dysfunction following smoke inhalation and burn injury.

The therapeutic efficacy of Ulinastatin for rats with smoking inhalation injury

Smoke inhalation injury represents a major cause of mortality in burn patients and is associated with a high incidence of pulmonary complications. Ulinastatin (UTI) has been widely used as a drug for patients with severe burn, sepsis, severe acute pancreatitis, and multiple organ dysfunction syndrome. In view of the critical role of inflammatory response in pathogenesis of smoke inhalation-induced lung injury and the anti-inflammatory effects of UTI, we hypothesized that treatment with UTI could lessen smoke inhalation-induced lung injury. In this study, fifty-four rats were equally randomized to three groups: Sham group (ambient air inhalation), Control group (smoke inhalation injury) and UTI treatment group (UTI treatment plus smoke inhalation injury). At sampling, bronchoalveolar lavage fluid was performed to determine total protein concentration and pro-inflammatory cytokine levels. Lung tissues were collected for the measurement of wet/dry ratio, myeloperoxidase, histopathology, hydroxyproline, collagens I and III, and western blotting. Our present work exhibited that UTI attenuated the lung histopathological alterations, improved the pulmonary function, inhibited neutrophil accumulation and mitigated pulmonary edema. In addition, UTI mitigated the inflammatory response, and further prevented the initiation of downstream inflammatory cascades: NF-κB and p-JNK. Importantly, UTI also mitigated smoke inhalation-induced pulmonary fibrosis as evidenced by Masson–Goldner trichrome staining with the content of hydroxyproline and collagens I and III. In conclusion, our data demonstrated that UTI protected rat against smoke inhalation-induced acute lung injury and the subsequent development of pulmonary fibrosis.

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

BackgroundData from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.MethodWe performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.ResultsThe efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.ConclusionLocal anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.

Direct Delivery of Low-Dose 7-Nitroindazole Into the Bronchial Artery Attenuates Pulmonary Pathophysiology After Smoke Inhalation and Burn Injury in an Ovine Model

Bronchial circulation plays a critical role in the pathophysiology of burn and smoke inhalation-induced acute lung injury. A 10-fold increase in bronchial blood flow is associated with excessive production of nitric oxide (NO) following smoke inhalation and cutaneous burn. Because an increased release of neuropeptides from the airway has been implicated in smoke inhalation injury, we hypothesized that direct delivery into the bronchial artery of low-dose 7-nitroindazole (7-NI), a specific neuronal NO synthase inhibitor, would attenuate smoke/burn-induced acute lung injury. Eighteen adult female sheep were instrumented for chronic hemodynamic monitoring 5 to 7 days before the injury. The bronchial artery was cannulated via intercostal thoracotomy, while blood flow was preserved. Acute lung injury was induced by 40% total body surface area third-degree cutaneous burn and smoke inhalation (48 breaths of cotton smoke, <40°C) under deep anesthesia. Following injury, animals (35.4 ± 1.1 kg) were divided into three groups: (a) 7-NI group: 1 h after injury, 7-NI (0.01 mg · kg · h, 2 mL · h) was continuously infused into the bronchial artery, n = 6; (b) control group: 1 h after injury, same amount of saline was injected into the bronchial artery, n = 6; (c) sham group: no injury, no treatment, same operation and anesthesia, n = 6. After injury, all animals were ventilated and fluid resuscitated according to an established protocol. The experiment was conducted for 24 h. Injury induced severe pulmonary dysfunction, which was associated with increases in lung edema formation, airway obstruction, malondialdehyde, and nitrate/nitrite. 7-Nitroindazole injection into the bronchial artery reduced the degree of lung edema formation and improved pulmonary gas exchange. The increase in malondialdehyde and nitrate/nitrite in lung tissue was attenuated by treatment. Our data strongly suggest that local airway production of NO contributes to pulmonary dysfunction following smoke inhalation and burn injury. Most mechanisms that drive this pathophysiology reside in the airway.

Year in review 2010: Interstitial lung diseases, acute lung injury, sleep, physiology, imaging, bronchoscopic intervention and lung cancer

Year in review 2010: Interstitial lung diseases, acute lung injury, sleep, physiology, imaging, bronchoscopic intervention and lung cancer

Effects of intravenously administered recombinant human antithrombin (rhAT) and aerosolized heparin on burn and smoke inhalation-induced acute lung injury

Effects of intravenously administered recombinant human antithrombin (rhAT) and aerosolized heparin on burn and smoke inhalation-induced acute lung injury

Effects of Intravenously Administered Recombinant Human Antithrombin (rhAT) and Aerosolized Heparin on Burn and Smoke Inhalation-Induced Acute Lung Injury

Effects of Intravenously Administered Recombinant Human Antithrombin (rhAT) and Aerosolized Heparin on Burn and Smoke Inhalation-Induced Acute Lung Injury