Smoke Inhalation-induced Lung Injury Research Articles

Colonic oxygen microbubbles augment systemic oxygenation and CO2 removal in a porcine smoke inhalation model of severe hypoxia

Inhalation injury can lead to pulmonary complications resulting in the development of respiratory distress and severe hypoxia. Respiratory distress is one of the major causes of death in critically ill patients with a reported mortality rate of up to 45%. The present study focuses on the effect of oxygen microbubble (OMB) infusion via the colon in a porcine model of smoke inhalation-induced lung injury. Juvenile female Duroc pigs (n = 6 colonic OMB, n = 6 no treatment) ranging from 39 to 51 kg in weight were exposed to smoke under general anesthesia for 2 h. Animals developed severe hypoxia 48 h after smoke inhalation as reflected by reduction in SpO2 to 66.3 ± 13.1% and PaO2 to 45.3 ± 7.6 mmHg, as well as bilateral diffuse infiltrates demonstrated on chest X-ray. Colonic OMB infusion (75–100 mL/kg dose) resulted in significant improvements in systemic oxygenation as demonstrated by an increase in PaO2 of 13.2 ± 4.7 mmHg and SpO2 of 15.2 ± 10.0% out to 2.5 h, compared to no-treatment control animals that experienced a decline in PaO2 of 8.2 ± 7.9 mmHg and SpO2 of 12.9 ± 18.7% over the same timeframe. Likewise, colonic OMB decreased PaCO2 and PmvCO2 by 19.7 ± 7.6 mmHg and 7.6 ± 6.7 mmHg, respectively, compared to controls that experienced increases in PaCO2 and PmvCO2 of 17.9 ± 11.7 mmHg and 18.3 ± 11.2 mmHg. We conclude that colonic delivery of OMB therapy has potential to treat patients experiencing severe hypoxemic respiratory failure.

RhKGF-2 Attenuates Smoke Inhalation Lung Injury of Rats via Activating PI3K/Akt/Nrf2 and Repressing FoxO1-NLRP3 Inflammasome.

Smoke inhalation injury is an acute pathological change caused by thermal stimulation or toxic substance absorption through respiratory epithelial cells. This study aims to probe the protective effect and mechanism of recombinant human keratinocyte growth factor 2 (rhKGF-2) against smoke inhalation-induced lung injury (SILI) in rats. The SILI was induced in rats using a smoke exposure model, which were then treated with rhKGF-2. The rat blood was collected for blood-gas analysis, and the levels of inflammatory factors and oxidative stress markers in the plasma were measured. The rat lung tissues were collected. The pathological changes and cell apoptosis were determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP nick end labeling (TUNEL) assay, and the PI3K/Akt/Nrf2/HO-1/NQO1, and FoxO1-NLRP3 inflammasome expression were verified by western blot (WB). Both of the human alveolar epithelial cell (HPAEpiC) and primary rat alveolar epithelial cell were exposed to lipopolysaccharide (LPS) for making in-vitro alveolar epithelial cell injury model. After treatment with rhKGF-2, GSK2126458 (PI3K inhibitor) and AS1842856 (FoxO1 inhibitor), the cell viability, apoptosis, inflammation, oxidative stress, reactive oxygen species (ROS), PI3K/Akt/Nrf2, HO-1/NQO1, and FoxO1-NLRP3 in HPAEpiC and primary rat alveolar epithelial cell were examined. The data suggested that rhKGF-2 reduced LPS-induced HPAEpiC cell and primary rat alveolar epithelial cell apoptosis and the expression of inflammatory factors and oxidative stress factors. Moreover, rhKGF-2 improved the blood gas and alleviated SILI-induced lung histopathological injury in vivo via repressing inflammation, NLRP3 inflammasome activation and oxidative stress. Mechanistically, rhKGF-2 activated PI3K/Akt pathway, enhanced Nrf2/HO-1/NQO1 expression, and attenuated FoxO1-NLRP3 inflammasome both in vitro and in vivo. However, pharmaceutical inhibition of PI3K/Akt pathway attenuated rhKGF-2-mediated protective effects against SILI, while suppressing FoxO1 promoted rhKGF-2-mediated protective effects. Taken together, this study demonstrated that rhKGF-2 mitigated SILI by regulating the PI3K/Akt/Nrf2 pathway and the FoxO1-NLRP3 axis, which provides new reference in treating SILI.

Effect of sivelestat sodium on early inflammatory reaction and pulmonary edema in rats with smoke inhalation induced lung injury

Objective To investigate the effects of sivelestat sodium on early inflammatory response and pulmonary edema in rats with smoke inhalation-induced lung injury. Methods Seventy-five Sprague-Dawley rats were randomly divided into control group, model group, low-dose group, middle-dose group and high-dose group. The smoke inhalation model was continued except for the control group. The rats were given intraperitoneal injection of normal saline, cevicell sodium 10 mg/kg, 20 mg/kg and 30 mg/kg. The general condition and lung tissue were observed after 24 hours. Results Compared with the control group, rats in each group had a certain degree of lung injury, alveolar wall thickening, alveolar interstitial hyperemia, etc. The alveolar septal thickness, lung tissue wet-dry (W/D) level, the incidence of edema and the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), neutrophil elastase (NE) and myeloperoxidase (MPO) in the model group were significantly higher than those of the other 4 groups. The lung function recovery was highest in the low dose group and the alveolar septal thickness was the highest among the dose group. The alveolar wall thickening incidence of W/D level and pulmonary edema in lung tissue in the low dose group were (6.76±0.40)μm, (5.18±0.13) and 40.00%, respectively, and the levels of TNF-α, IL-6, NE and MPO were (19.62±0.83)pg/L, (9.41±0.25)pg/L, (6.23±0.18)μg/L and (30.64±0.87)pg/L, significantly better than the middle dose group and high dose group (P<0.05). Conclusions Sivelestat sodium can significantly affect the smoke inhalation lung injury, and improve the recovery of liver function, which can significantly reduce the incidence of inflammation and pulmonary ede-ma in the lung, but its therapeutic effect and drug delivery. There was a significant association between doses and therapeutic effect, in the case of rats, a dose of 10 mg/kg was the best for treatment. Key words: Lung injury; Smoke inhalation injury; Sivelestat sodium; Inflammation; Pulmonary edema; Rats

The impact of glucocorticoid on coagulation of smoke inhalation induced lung injury

Objective To explore the impact of glucocorticoid on coagulation through administrating on rats with smoke inhalation. Methods Totally 150 male S-D rats were randomly (random number) divided into 5 groups: control group (ambient air inhalation), smoke group (smoke inhalation for 30 min), smoke+high dosage methyl prednisolone group(MP 40 mg/kg, intraperitoneal injection, s+HMP group), smoke+medium dosage MP (4 mg/kg) group (s+MMP group), smoke+low dosage MP (0.4 mg/kg) group (s+LMP group) (all n=30). Survival rates were calculated 24 h after smoke inhalation. Lung tissues were collected for histopathology and wet to dry (W/D) ratio. Arterial blood was collected for blood gas test. Coagulation factors in lung and plasma were tested. Results Survival rates of three MP groups were markedly improved compared with the smoke group (all P<0.05), and was significantly higher in the medium dosage group(85.17%) than those in the low and high dosage groups (65.73% and 60.07%, all P<0.05). The W/D ratio and blood gas test were markedly improved in the high and medium groups (all P<0.05). Tissue factor (TF) and thrombin-antithrombin complex (TAT-c) in bronchoalveolar lavage fluid (BALF) increased dramatically after SI (P<0.01, P=0.005) with a remarkable drop of factor Ⅱ (FⅡ) (P=0.007), all of which were attenuated by MP with dosage dependence. The mRNA expression of TF increased dramatically after SI and recovered significantly with MP administration, while the expression of thrombomodulin (TM) recovered in the opposite direction with MP, all of which were in a dosage dependent manner. TF, fibrinogen (FIB), TAT-c increased significantly in plasma after smoke inhalation (P<0.01, P=0.027, P=0.005). FⅧ% increased with MP administration and TF was raised by high dosage MP compared with the smoke group. FIB and TAT-c were decreased in all MP groups, which were significant higher in the high and middle dosage groups. The change of TM and endothelial cell protein C receptor (EPCR) in circulation were similar with FIB or TAT-c with or without MP. Protein C (PC%) and antithrombin (ATⅢ%) dropped dramatically after SI, high and middle dosages of MP could restore the activity significantly, while low dosage would restore ATⅢ% but not PC%. Conclusions Glucocorticoid can significantly improve local and systemical coagulation disorder caused by smoke inhalation, and high- and medium-dosage hormones are effective. The regulation of hormones on the coagulation system is an important mechanism in the treatment of smoke inhalation induced lung injury. Key words: Smoke inhalation; Acute lung injury; Coagulation; Glucocorticoid; Thrombomodulin

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.

Fire smoke inhalation induced lung injury：an update

Fire smoke inhalation induced lung injury：an update

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.

Dynamic Tracking Human Mesenchymal Stem Cells Tropism following Smoke Inhalation Injury in NOD/SCID Mice.

Multiple preclinical evidences have supported the potential value of mesenchymal stem cells (MSCs) for treatment of acute lung injury (ALI). However, few studies focus on the dynamic tropism of MSCs in animals with acute lung injury. In this study, we track systemically transplanted human bone marrow-derived mesenchymal stem cells (hBMSCs) in NOD/SCID mice with smoke inhalation injury (SII) through bioluminescence imaging (BLI). The results showed that hBMSCs systemically delivered into healthy NOD/SCID mouse initially reside in the lungs and then partially translocate to the abdomen after 24 h. Compared with the uninjured control group treated with hBMSCs, higher numbers of hBMSCs were found in the lungs of the SII NOD/SCID mice. In both the uninjured and SII mice, the BLI signals in the lungs steadily decreased over time and disappeared by 5 days after treatment. hBMSCs significantly attenuated lung injury, elevated the levels of KGF, decreased the levels of TNF-α in BALF, and inhibited inflammatory cell infiltration in the mice with SII. In conclusion, our findings demonstrated that more systemically infused hBMSCs localized to the lungs in mice with SII. hBMSC xenografts repaired smoke inhalation-induced lung injury in mice. This repair was maybe due to the effect of anti-inflammatory and secreting KGF of hMSCs but not associated with the differentiation of the hBMSCs into alveolar epithelial cells.

Role of angiotensin-converting enzyme (ACE) and ACE2 in a rat model of smoke inhalation induced acute respiratory distress syndrome

Smoke inhalation induced acute respiratory distress syndrome (ARDS) has become more and more common throughout the world and it is hard to improve the outcome. The present research was to investigate possible roles of angiotensin-converting enzyme (ACE) and ACE2 in lung injury resulted from smoke exposure. Rats were exposed to dense smoke to induce ARDS. Histological changes, blood gases, bronchoalveolar lavage fluids (BALF) and wet-to-dry weight were analyzed to evaluate lung injury after smoke inhalation; beside, we also measured the expression of ACE and ACE2 at different time points to explore the possible mechanism of those changes. The results showed that pH of arterial blood, partial blood oxygen (PaO2) and blood oxygen saturation (SO2) decreased after smoke inhalation at different time points (P<0.01); while, partial blood carbon dioxide (PaCO2), wet-to-dry weight ratio, leukocytes count, protein concentration and inflammatory cytokines in BALF increased after smoke exposure (P<0.01). More importantly, both immunohistochemical staining and Western blot results showed that ACE and ACE2 expression in lungs from the experimental groups significantly increased compared with that of the control group (P<0.05). This study indicated that inflammation pulmonary edema and histological changes resulted from smoke inhalation induced lung injury were possibly attributed to abnormal expression of ACE and ACE2 related pathway.

Protective effects of hydrogen sulfide inhalation on oxidative stress in rats with cotton smoke inhalation-induced lung injury.

The aim of the present study was to investigate the mechanism by which hydrogen sulfide (H2S) inhalation protects against oxidative stress in rats with cotton smoke inhalation-induced lung injury. A total of 24 male Sprague-Dawley rats were separated randomly into four groups, which included the control, H2S, smoke and smoke + H2S groups. A rat model of cotton smoke inhalation-induced lung injury was established following inhalation of 30% oxygen for 6 h. In addition, H2S (80 ppm) was inhaled by the rats in the H2S and smoke + H2S groups for 6 h following smoke or sham-smoke inhalation. Enzyme-linked immunosorbent assays were performed to measure various indices in the rat lung homogenate, while the levels of nuclear factor (NF)-κBp65 in the lung tissue of the rats were determined and semiquantitatively analyzed using immunohistochemistry. In addition, quantitative fluorescence polymerase chain reaction was employed to detect the mRNA expression of inducible nitric oxide synthase (iNOS) in the rat lung tissue. The concentrations of malondialdehyde (MDA), nitric oxide (NO), inducible iNOS and NF-κBp65, as well as the sum-integrated optical density of NF-κBp65 and the relative mRNA expression of iNOS, in the rat lung tissue from the smoke + H2S group were significantly lower when compared with the smoke group. The concentrations of MDA, NO, iNOS and NF-κBp65 in the H2S group were comparable to that of the control group. Therefore, inhalation of 80 ppm H2S may reduce iNOS mRNA transcription and the production of iNOS and NO in rats by inhibiting NF-κBp65 activation, subsequently decreasing oxidative stress and cotton smoke inhalation-induced lung injury.

The therapeutic efficacy of glutamine 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. Glutamine (GLN) is considered a conditionally essential amino acid during critical illness and injury. However, whether GLN could attenuate lung injury caused by smoke inhalation is still unknown. The purpose of this study is to investigate whether GLN has a beneficial effect on smoke inhalation induced lung injury. In our present work, rats were equally randomized into three groups: Sham group (ambient air inhalation plus GLN treatment), Control group (smoke inhalation plus physiological saline) and GLN treatment group (smoke inhalation injury plus GLN treatment). At sampling, bronchoalveolar lavage fluid was performed to determine total protein concentration and pro-inflammatory cytokine levels. Lung tissues were collected for wet/dry ratio, histopathology, hydroxyproline and Western blotting measurement. Our results exhibited that GLN attenuated the lung histopathological alterations, improved pulmonary oxygenation, and mitigated pulmonary edema. At 28days post-injury, GLN mitigated smoke inhalation-induced excessive collagen deposition as evidence by Masson-Goldner trichrome staining and hydroxyproline content. GLN mitigated smoke inhalation-induced lung inflammatory response, and further prevented the activity of NF-kappa-B. More importantly, results from Western blotting and Immunohistochemistry exhibited that GLN enhanced the expression of HSF-1, HSP-70 and HO-1 in lung tissues. Our data demonstrated that GLN protected rats against smoke inhalation-induced lung injury and its protective mechanism seems to involve in inhibition inflammatory response and enhancing HSP expression.

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.

Predictive role of arterial carboxyhemoglobin concentrations in ovine burn and smoke inhalation-induced lung injury

ABSTRACTInhalation injury frequently occurs in burn patients and contributes to the morbidity and mortality of these injuries. Arterial carboxyhemoglobin has been proposed as an indicator of the severity of inhalation injury; however, the interrelation between arterial carboxyhemoglobin and histological alterations has not yet been investigated. Chronically instrumented sheep were subjected to a third degree burn of 40% of the total body surface area and inhalation of 48 breaths of cotton smoke. Carboxyhemoglobin was measured immediately after injury and correlated to clinical parameters of pulmonary function as well as histopathology scores from lung tissue harvested 24 hours after the injury. The injury was associated with a significant decline in pulmonary oxygenation and increases in pulmonary shunting, lung lymph flow, wet/dry weight ratio, congestion score, edema score, inflammation score, and airway obstruction scores. Carboxyhemoglobin was negatively correlated to pulmonary oxygenation and positively correlated to pulmonary shunting, lung lymph flow, and lung wet/dry weight ratio. No significant correlations could be detected between carboxyhemoglobin and histopathology scores and airway obstruction scores. Arterial carboxyhemoglobin in sheep with combined burn and inhalation injury are correlated with the degree of pulmonary failure and edema formation, but not with certain histological alterations including airway obstruction scores.

The complex role of fibrin in acute lung injury

in the last decade there have been many advances in our understanding of the pathogenesis of acute lung injury (ALI), but there have been frustratingly few successful therapeutic interventions. In fact, the only treatment proven to reduce mortality is low tidal volume lung-protective mechanical