The epidemiology of blast lung injury during recent military conflicts: a retrospective database review of cases presenting to deployed military hospitals, 2003-2009

Blast injuries are becoming increasingly common in military conflicts as the nature of combat changes from conventional to asymmetrical warfare and counter-insurgency. This article describes a retrospective database review of cases from the UK joint theatre trauma registry from 2003 to 2009, containing details of over 3000 patients, mainly injured in Iraq and Afghanistan. During this period, 1678 patients were injured by explosion of whom 113 had evidence of blast lung injury. Of the 50 patients who survived to reach a medical facility, 80 per cent required ventilatory support. Injuries caused by explosion are increasing when compared with those caused by other mechanisms, and blast lung represents a significant clinical problem in a deployed military setting. Management of these patients should be optimized from point of wounding to definitive care.     

Characterization of the response to primary blast injury

Lung injuries, predominantly arising from blast exposure, are a clinical problem in a significant minority of current military casualties. This special feature consists of a series of articles on lung injury. This first article examines the mechanism of the response to blast lung (primary blast injury to the lung). Subsequent articles examine the incidence of blast lung, clinical consequences and current concepts of treatment, computer (in silico) modelling of lung injury and finally chemical injuries to the lungs. Blast lung is caused by a shock wave generated by an explosion causing widespread damage in the lungs, leading to intrapulmonary haemorrhage. This, and the ensuing inflammatory response in the lung, leads to a compromise in pulmonary gas exchange and hypoxia that can worsen over several hours. There is also a characteristic cardio-respiratory effect mediated via an autonomic reflex causing apnoea (or rapid shallow breathing), bradycardia and hypotension (the latter possibly also due to the release of nitric oxide). An understanding of this response, and the way it modifies other reflexes, can help the development of new treatment strategies for this condition and for the way it influences the patient's response to concomitant injuries.     

Blast injury research models

Blast injuries are an increasing problem in both military and civilian practice. Primary blast injury to the lungs (blast lung) is found in a clinically significant proportion of casualties from explosions even in an open environment, and in a high proportion of severely injured casualties following explosions in confined spaces. Blast casualties also commonly suffer secondary and tertiary blast injuries resulting in significant blood loss. The presence of hypoxaemia owing to blast lung complicates the process of fluid resuscitation. Consequently, prolonged hypotensive resuscitation was found to be incompatible with survival after combined blast lung and haemorrhage. This article describes studies addressing new forward resuscitation strategies involving a hybrid blood pressure profile (initially hypotensive followed later by normotensive resuscitation) and the use of supplemental oxygen to increase survival and reduce physiological deterioration during prolonged resuscitation. Surprisingly, hypertonic saline dextran was found to be inferior to normal saline after combined blast injury and haemorrhage. New strategies have therefore been developed to address the needs of blast-injured casualties and are likely to be particularly useful under circumstances of enforced delayed evacuation to surgical care.     

冲击波负压对大鼠肺致伤效应的初步观察

观察了不同的冲击波负压峰值对大鼠肺的影响。各种条件下的冲击波负压值可由负压发生装置来模拟调节,这种装置可满足化爆、核爆和爆炸性减压下负压参数的一般要求,参数稳定,重复性好。冲击波负压峰值范围为-13～-90kPa,下降时间为1～90ms,持续时间为14～2 000ms。6组Wistar系大鼠,分别暴露在-47.2～-84.0kPa的冲击波负压环境中,伤后立即解剖动物,重点观察肺伤情。实验结果显示,在上述冲击波负压环境中,肺可出现从无伤至极重度伤;出血、充血以及肺表面压痕酷似肺冲击伤的病理表现。随着冲击波负压峰值的变化,各组肺伤情亦随着变化,冲击波负压峰值(△P)和减压倍数(P_i/P_a)分别与肺出血面积和动物死亡率相关显著或非常显著。本实验提示,一定条件下的冲击波负压具有明显的致伤作用,且伤情变化范围与超压所致肺伤情变化范围相同,超压和冲击波负压在一定条件下可通过伤情指标等效。     

A murine model of sepsis following smoke inhalation injury

Acute lung injury (ALI) by smoke inhalation with subsequent pneumonia and sepsis represents a major cause of morbidity and mortality in burn patients. The aim of the present study was to develop a murine model of ALI and sepsis to enhance the knowledge of mechanistic aspects and pathophysiological changes in patients with these injuries. In deeply anesthetized female C57BL/6 mice, injury was induced by four sets of cotton smoke using an inhalation chamber. Afterward, live Pseudomonas aeruginosa (3.2 × 10⁷ colony-forming units) was administered intranasally. The indicated dose of bacteria was determined based on the results of a dose-response study (n = 47). The following study groups were monitored for survival over 96 h: (1) sham injury group, (2) only smoke inhalation group, (3) only bacteria group, and (4) smoke inhalation plus bacteria group. Each group included 10 mice. The survival rates were 100%, 90%, 30%, and 10%, respectively. The double hit injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, and enhanced neutrophil accumulation, increased lipid peroxidation, and excessive formation of reactive nitrogen species in the lung. In mice receiving only smoke inhalation injury, no systemic cytokine release and increased lung tissue lipid peroxidation were observed. However, smoke alone significantly increased neutrophil accumulation and formation of reactive nitrogen species in lung tissue. In conclusion, bacterial pneumonia is predominantly responsible for mortality and morbidity in this novel murine model of smoke inhalation and pulmonary sepsis. Reactive oxygen and nitrogen species mediate the severity of lung injury.     

The dynamic changes in autophagy activity and its role in lung injury after deep hypothermic circulatory arrest

Deep hypothermic circulatory arrest (DHCA) can cause acute lung injury (ALI), and its pathogenesis mimics ischaemia/reperfusion (I/R) injury. Autophagy is also involved in lung I/R injury. The present study aimed to elucidate whether DHCA induces natural autophagy activation and its role in DHCA‐mediated lung injury. Here, rats were randomly assigned to the Sham or DHCA group. The sham group (n = 5) only received anaesthesia and air intubation. DHCA group rats underwent cardiopulmonary bypass (CPB) followed by the DHCA procedure. The rats were then sacrificed at 3, 6 and 24 h after the DHCA procedure (n = 5) to measure lung injury and autophagy activity. Chloroquine (CQ) was delivered to evaluate autophagic flux. DHCA caused lung injury, which was prominent 3–6 h after DHCA, as confirmed by histological examination and inflammatory cytokine quantification. Lung injury subsided at 24 h. Autophagy was suppressed 3 h but was exaggerated at 6 h. At both time points, autophagic flux appeared uninterrupted. To further assess the role of autophagy in DHCA‐mediated lung injury, the autophagy inducer rapamycin and its inhibitor 3‐methyladenine (3‐MA) were applied, and lung injury was reassessed. When rapamycin was administered at an early time point, lung injury worsened, whereas administration of 3‐MA at a late time point ameliorated lung injury, indicating that autophagy contributed to lung injury after DHCA. Our study presents a time course of lung injury following DHCA. Autophagy showed adaptive yet protective suppression 3 h after DHCA, as induction of autophagy caused worsening of lung tissue. In contrast, autophagy was exaggerated 6 h after DHCA, and autophagy inhibition attenuated DHCA‐mediated lung injury.     

Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight- to ten-week-old WT (C57BL/6) or Cyp1a2^−/− mice were exposed to hyperoxia (>95% O₂) or maintained in room air for 24–72 h. Lung injury was assessed by determining the ratio of lung weight/body weight (LW/BW) and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2^−/− mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, and IL-6 and TNF-α levels and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde– and 4-hydroxynonenal–protein adducts and pulmonary isofurans compared to WT mice. In vitro experiments showed that the F₂-isoprostane PGF₂-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F₂-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation of hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.     

食管癌调强放疗并发放射性肺损伤的危险因素分析

目的:分析食管癌调强放疗并发放射性肺损伤的危险因素。方法:以2015年2月-2018年2月于青海医学院附属医院接受调强放疗的食管癌患者100例为研究对象。分别收集患者年龄、性别、吸烟史、同步化疗情况、卡氏评分、肿瘤分期等资料以及放射剂量学因素V5、V10、V20、V30、Dmean情况,并采用单因素和多因素Logistic回归分析分析食管癌调强放疗并发放射性肺损伤的危险因素。结果:100例患者中发生放射性肺损伤人数为27例,发生率为27.00%。其中1级20例,2级7例。经单因素分析可得:食管癌调强放疗并发放射性肺损伤与卡氏评分、V5、V10、V20、V30以及Dmean有关(P0.05);与性别、年龄、吸烟史、同步化疗、肿瘤分期无关(P0.05)。经多因素Logistic回归分析可得:卡氏评分80分、V5≥60%、V10≥40%、V20≥25%、V30≥20%、Dmean≥10%均是食管癌调强放疗患者并发放射性肺损伤的独立危险因素(P0.05)。结论:食管癌调强放疗并发放射性肺损伤的发生率较高,且与卡氏评分以及放射剂量学因素V5、V10、V20、V30、Dmean密切相关。临床工作中可通过控制肺组织的照射剂量,减少放射性肺损伤发生风险。     

The central role of Fas-ligand cell signaling in inflammatory lung diseases

Following inflammation and injury in the lung, loss of epithelial cell precursors could determine the balance between tissue regeneration and fibrosis. This review discusses evidence that proapoptotic Fas-Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis. FasL signaling induces inflammatory apoptosis in epithelial cells and alveolar macrophages, with concomitant IL-1 beta and chemokine release, leading to neutrophil infiltration. FasL signaling plays a critical role in models of acute lung injury, idiopathic pulmonary fibrosis and silicosis; blockade of Fas-FasL interactions either prevents or attenuates pulmonary inflammation and fibrosis. Serologic and immunohistochemical studies in patients support a major pathogenic role of Fas and FasL molecules in inflammatory lung diseases. Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases.     

Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation

Background

Mortality from severe acute respiratory distress syndrome exceeds 40% and there is no available pharmacologic treatment. Mechanical ventilation contributes to lung dysfunction and mortality by causing ventilator-induced lung injury. We explored the utility of simvastatin in a mouse model of severe ventilator-induced lung injury.

Methods

Male C57BL6 mice (n = 7/group) were pretreated with simvastatin or saline and received protective (8 mL/kg) or injurious (25 mL/kg) ventilation for four hours. Three doses of simvastatin (20 mg/kg) or saline were injected intraperitoneally on days −2, −1 and 0 of the experiment. Lung mechanics, (respiratory system elastance, tissue damping and airway resistance), were evaluated by forced oscillation technique, while respiratory system compliance was measured with quasi-static pressure-volume curves. A pathologist blinded to treatment allocation scored hematoxylin-eosin-stained lung sections for the presence of lung injury. Pulmonary endothelial dysfunction was ascertained by bronchoalveolar lavage protein content and lung tissue expression of endothelial junctional protein Vascular Endothelial cadherin by immunoblotting. To assess the inflammatory response in the lung, we determined bronchoalveolar lavage fluid total cell content and neutrophil fraction by microscopy and staining in addition to Matrix-Metalloprotease-9 by ELISA. For the systemic response, we obtained plasma levels of Tumor Necrosis Factor-α, Interleukin-6 and Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was undertaken using one-way analysis of variance and Tukey’s post hoc tests.

Results

Ventilation with high tidal volume (HVt) resulted in significantly increased lung elastance by 3-fold and decreased lung compliance by 45% compared to low tidal volume (LVt) but simvastatin abrogated lung mechanical alterations of HVt. Histologic lung injury score increased four-fold by HVt but not in simvastatin-pretreated mice. Lavage pleocytosis and neutrophilia were induced by HVt but were significantly attenuated by simvastatin. Microvascular protein permeability increase 20-fold by injurious ventilation but only 4-fold with simvastatin. There was a 3-fold increase in plasma Tumor Necrosis Factor-α, a 7-fold increase in plasma Interleukin-6 and a 20-fold increase in lavage fluid Matrix-Metalloprotease-9 by HVt but simvastatin reduced these levels to control. Lung tissue vascular endothelial cadherin expression was significantly reduced by injurious ventilation but remained preserved by simvastatin.

Conclusion

High-dose simvastatin prevents experimental hyperinflation lung injury by angioprotective and anti-inflammatory effects.     

Stromal cell-derived factor-1α attenuates oleate-induced acute lung injury in rabbits

The stromal cell-derived factor-1α/C-X-C chemokine receptor 4 (SDF-1/CXCR4) axis is involved in various aspects of tissue repair, regeneration and development. However, the role of SDF-1/CXCR4 in acute lung injury (ALI) remains largely unknown. The aim of the present investigation is to examine pathological changes in a rabbit model with ALI induced by oleic acid (OA) and to explore the protective effect of SDF-1α on ALI. Intravenous application (i.v.) of oleic acid (0.1 ml/kg/h for 2 h) provoked pulmonary hemorrhage, edema, and protein leakage, resulting in severe ALI. When the rabbit received an infusion of SDF-1α (20 μg/kg/24 h) for 30 min before OA treatment, SDF-1α seemed to significantly improve the pathologies associated with OA-induced ALI. While dissecting the molecular mechanisms underlying the beneficial effects of SDF-1α, we found that SDF-1/CXCR4 is expressed in uninjured lung tissues but is greatly reduced after OA treatment. Interestingly, intravenous delivery of SDF-1α could target an injured lung and rescue expression of CXCR4, which in turn activates anti-apoptotic proteins, Bcl-1 and Bcl-xl, but does not affect pro-apoptotic proteins, such as Bad and Bax. These data suggested that SDF-1α could protect rabbit lungs from AIL. The molecular mechanism might be associated with upregulating anti-apoptosis family expression through CXCR4. Thus, SDF-1/CXCR4 signaling pathway may be a promising target for treatment of patients with ALI.     

Increased isoprostane levels in oleic acid-induced lung injury

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 F2α). 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.     

SARS相关急性肺损伤与抗粘附免疫调节

SARS作为急性呼吸道传染病,其肺损伤的早期与急性呼吸窘迫综合征(ARDS)有关,后期表现为肺纤维化。患者体内免疫防御机制可出现针对SARS病毒的过度激活,造成肺部白细胞免疫炎性损伤。粘附分子及其介导的白细胞粘附可能参与了SARS的急性肺损伤。设想在病毒感染早期,通过抗粘附免疫调节,抑制患者过激的免疫防御机制,阻抑活化白细胞的粘附级联反应,进而减轻肺损伤,以减轻或延缓病变的进一步发展。     

Benzamil, a blocker of epithelial Na(+) channel-induced upregulation of artery oxygen pressure level in acute lung injury rabbit ventilated with high frequency oscillation

The epithelial Na(+) transport via an epithelial Na(+) channel (ENaC) expressed in the lung epithelium would play a key role in recovery from lung edema at acute lung injury by removing the fluid in lung luminal space. The lung edema causes dysfunction of gas exchange, decreasing oxygen pressure level of artery [P(aO(2))]. To study if ENaC plays a key role in recovering P(aO(2)) from a decreased level to a normal one in acute lung injury, we applied benzamil (20microM, a specific blocker of ENaC) to the lung luminal space in acute lung injury treated with high frequency oscillation ventilation (HFOV) that is a lung-protective ventilation with a lower tidal volume and a smaller pressure swing than conventional mechanical ventilation (CMV). Benzamil facilitated the recovery of P(aO(2)) in acutely injured lung with HFOV but not CMV. The observation suggests that in acutely injured lung treated with HFOV an ENaC blocker, benzamil, can be applied as a therapeutic drug for acute lung injury combing with HFOV.     

The injured lung: clinical issues and experimental models

Exposure of military and civilian populations to inhaled toxic chemicals can take place as a result of deliberate release (warfare, terrorism) or following accidental releases from industrial concerns or transported chemicals. Exposure to inhaled toxic chemicals can result in an acute lung injury, and in severe cases acute respiratory distress syndrome, for which there is currently no specific medical therapy, treatment remaining largely supportive. This treatment often requires intensive care facilities that may become overwhelmed in mass casualty events and may be of limited benefit in severe cases. There remains, therefore, a need for evidence-based treatment to inform both military and civilian medical response teams on the most appropriate treatment for chemically induced lung injury. This article reviews data used to derive potential clinical management strategies for chemically induced lung injury.     

The role of Toll-like receptors in non-infectious lung injury

The role of Toll-like receptors （TLRs） in pathogen recognition has been expeditiously advanced in recent years. However, investigations into the function of TLRs in non-infectious tissue injury have just begun. Previously, we and others have demonstrated that fragmented hyaluronan （HA） accumulates during tissue injury. CD44 is required to clear HA during tissue injury, and impaired clearance of HA results in unremitting inflammation. Additionally, fragmented HA stimulates the expression of inflammatory genes by inflammatory cells at the injury site. Recently, we identified that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines and cytokines. In a non-infectious lung injury model, mice deficient in both TLR2 and TLR4 show an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis, and decreased survival. Lung epithelial cell overexpression of high molecular mass HA protected mice against acute lung injury and apoptosis, in part through TLR-dependent basal activation of NF-κB. The exaggerated injury in TLR2 and TLR4 deficient mice appears to be due to impaired HA-TLR interactions on epithelial cells. These studies identify that host matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.     

Autophagy maintains the integrity of endothelial barrier in LPS‐induced lung injury

Understanding the role and underlying regulation mechanism of autophagy in lipopolysaccharide‐induced lung injury (LPS‐LI) may provide potentially new pharmacological targets for treatment of acute lung injury. The aim of this study was to investigate the functional significance of autophagy in LPS‐LI. The autophagy of human pulmonary microvascular endothelial cells (HPMVECs) and mice was inhibited before they were challenged with LPS. In vitro, permeability, vitality, and the LDH release rate of the cells were detected, the zonula occluden‐1 (ZO‐1) expression and the stress fiber formation were determined. In vivo, the lung injury was assessed. We found LPS caused high permeability and increased lactate dehydrogenase (LDH) release rate, lowered viability of the cells, inhibited the ZO‐1 expression and induced stress fiber formation, these effects were further aggravated by prohibiting the level of autophagy. Consistently, in in vivo experiments, LPS‐induced serious lung injury, which was reflected as edema, leukocyte infiltration and hemorrhage in lung tissue, and the high concentration of pro‐inflammation cytokines tumor necrosis factor (TNF)‐α and interleukin (IL)‐1β in bronchoalveolar lavage fluid (BALF). Inhibiting autophagy further exacerbated LPS‐LI. It appears that autophagy played a protective role in LPS‐LI in part through restricting the injury of lung microvascular barrier.     

高碳酸血症对大鼠机械通气肺损伤时炎症因子和p38MAPK 表达的影响

目的:探讨高碳酸血症对大鼠机械通气性肺损伤(VILI)时炎症因子和p38MAPK表达的影响。方法:健康雄性Wistar大鼠30只,体重220～280g,采用随机数字表法,将大鼠随机分3组(n=10):对照组(C组)、机械通气肺损伤组(V组)和高碳酸血症组(H组)。C组保留自主呼吸,V组和H组行机械通气4 h。采用高气道压机械通气模式制备机械通气性肺损伤模型。H组通过调整吸入的CO2浓度来维持动脉血PaCO2分别为80～100mmHg。机械通气结束时,测定支气管肺泡灌洗液(BALF)中总蛋白、TNF-α和巨噬细胞炎症蛋白-2(MIP-2)的浓度;取肺组织,测定湿干重比(W/D比)、细胞间粘附分子(ICAM-1)和p38MAPK蛋白的表达水平以及p38MAPK的活性,并观察病理学结果,进行肺损伤评分。结果:与C组比较,V组肺损伤评分、W/D比、ICAM-1表达水平、BALF中总蛋白浓度、TNF-α和MIP-2浓度和肺组织p38MAPK活性升高,PaO2降低(P<0.05);与V组比较,H组肺损伤评分、W/D比、ICAM-1表达水平、BALF中总蛋白浓度、TNF-α和MIP-2浓度和肺组织p38MAPK活性降低,PaO2升高(P<0.05)。结论:高碳酸血症通过调节p38MAPK的表达,从而抑制炎症反应减轻大鼠机械通气肺损伤。     

Silencing of Paralemmin-3 Protects Mice from lipopolysaccharide-induced acute lung injury

Excessive inflammatory response induced by lipopolysaccharide (LPS) plays a critical role in the development of acute lung injury (ALI). Paralemmin-3 (PALM3) is a novel protein that can modulate LPS-stimulated inflammatory responses in alveolar epithelial A549 cells. However, it remains unclear whether it is involved in the progression of ALI in vivo. Therefore, we studied the role of PALM3 in the pathogenesis of ALI induced by LPS. ALI was induced by LPS peritoneal injection in C57BL/6J mice. Lentivirus-mediated small interfering RNA (siRNA) targeting the mouse PALM3 gene and a negative control siRNA were intranasally administered to the mice. We found that the expression of PALM3 was up-regulated in the lung tissues obtained from the mouse model of LPS-induced ALI. The LPS-evoked inflammatory response (neutrophils and the concentrations of proinflammatory cytokines [IL-6, IL-1β, TNF-α, MIP-2] in the bronchoalveolar lavage fluid [BALF]), histologic lung injury (lung injury score), permeability of the alveolar capillary barrier (lung wet/dry weight ratio and BALF protein concentration) and mortality rates were attenuated in the PALM3 siRNA-treated mice. These results indicate that PALM3 contributes to the development of ALI in mice challenged with LPS. Inhibiting PALM3 through the intranasal application of specific siRNA protected against LPS-induced ALI.