Curcumin Modulates the Inflammatory Response and Inhibits Subsequent Fibrosis in a Mouse Model of Viral-induced Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or non-infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 10⁷ pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNγ, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFκB p65. While the expression of TGFß1 was not modulated by curcumin, TGFß Receptor II, which is required for TGFß signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of α-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation.     

细胞因子在ARDS发病机制中的作用

细胞因子是由多种细胞产生的多肽或低分子糖蛋白,在人体内含量极微,在pg水平就发挥作用。作为特异性免疫反应和非特异性免疫反应的蛋白质,细胞因子以自分泌、旁分泌、或内分泌方式产生,与相应的细胞表面受体结合,在局部或全身发挥复杂的生物学效应,它们的代谢异常和疾病的发生、发展有着密切的关系。有些细胞因子已应用于临床的生物学治疗,具有深远的临床应用价值,故对细胞因子的研究将是一个越来越重要的课题。急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)发病机制错综复杂,大量临床和实验室研究证明多种效应细胞释放的炎症介质是造成ARDS的"中心环节",其中TNF-α、IL-1、IL-8、IL-10、CXC趋化因子等细胞因子在ARDS发病中的作用尤为重要。本文就细胞因子在ARDS发病机制中的作用做一综述。     

Predictors of Acute Respiratory Distress Syndrome in Patients with Paraquat Intoxication

Introduction

Paraquat poisoning is characterized by acute lung injury, pulmonary fibrosis, respiratory failure, and multi-organ failure, resulting in a high rate of mortality and morbidity. The objectives of this study were to identify predictors of acute respiratory distress syndrome (ARDS) in cases of paraquat poisoning and determine the association between these parameters.

Materials and Methods

In total, 187 patients were referred for management of intentional paraquat ingestion between 2000 and 2010. Demographic, clinical, and laboratory data were recorded. Sequential organ failure assessment (SOFA) and Acute Kidney Injury Network (AKIN) scores were collected, and predictors of ARDS were analyzed.

Results

The overall mortality rate for the entire population was 54% (101/187). Furthermore, the mortality rate was higher in the ARDS patients than in the non-ARDS patients (80% vs. 43.80%, P<0.001). Additionally, the ARDS patients not only had higher AKIN_48-h scores (P<0.009), SOFA_48-h scores (P<0.001), and time to ARDS/nadir PaO₂ (P=0.008) but also suffered from lower nadir PaO₂ (P<0.001), nadir AaDO₂ (P<0.001), and nadir eGFR (P=0.001) compared to those in the non-ARDS patients. Moreover, pneumomediastinum episodes were more frequent in the ARDS patients than in the non-ARDS patients (P<0.001). A multivariate Cox regression model revealed that blood paraquat concentrations (P<0.001), SOFA_48-h scores (P=0.001), and steroid and cyclophosphamide pulse therapies (P=0.024) were significant predictors of ARDS. The cumulative survival rates differed significantly (P<0.001) between patients with SOFA_48-h scores <3 and SOFA_48-h scores ≥3, with a sensitivity of 95.8%, specificity of 58.4%, and overall correctness of 67.6%. Finally, the area under the receiver operating characteristic (AUROC) analysis showed that SOFA_48-h scores (P<0.001) had a better discriminatory power than blood paraquat concentrations (P=0.01) for predicting ARDS.

Conclusions

The analytical results indicate that SOFA_48-h scores, blood paraquat concentrations, and steroid and cyclophosphamide pulse therapies are significantly associated with ARDS complications after paraquat intoxication.     

乌司他丁在急性呼吸窘迫综合征的临床应用研究

目的:观察乌司他丁(UTI)对急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)的临床应用。方法:选择我院ICU自2008年1月至2011年1月收治的160例ARDS患者作为研究对象,采用随机对照的方法,并且经患者或患者家属知情并签字同意分组。分为UTI组(A组)和对照组(B组)。两组均给予相同综合治疗措施,A组除综合治疗外还给予注射用乌司他丁,每次30万U,每日2次。分别记录两组患者开始治疗、治疗后第3天、治疗第7天的生命体征,动脉血气分析、血生化检查结果、并且记录患者在ICU治疗的转归,应用SPSS13.0软件对结果进行统计学分析。结果:经治疗3天A组呼吸频率低于B组,动脉血气分析提示两组PO2、PO2/FiO2、SaO2均有上升。比较后发现A组PO2、PO2/FiO2、SaO2高于B组(P<0.05),两组PO2、SaO2比较有统计学差异。经治疗3天A组与B组生化指标比较、白细胞计数、肾功及血乳酸均有下降,有统计学差异,P<0.05。全部治疗结束后A组与B组死亡率比较(UTI组34.29%,对照组38.26%,P=0.0097)及机械通气时间比较(UTI组7.54±3.27天,对照组11.78±2.69天,P=0.0086),均有统计学差异。结论:大剂量UTI用于ARDS的临床治疗可有效改善患者氧合指数,减少机械通气时间,降低患者的病死率。     

大鼠急性呼吸窘迫综合征动物模型的建立

目的　建立大鼠急性呼吸窘迫综合征动物模型 (ARDS)。方法　选取KM小鼠SD大鼠 (雌雄不限 ) ,分为正常对照组及百草枯组 ,小鼠按每公斤体重 10 0mg ,大鼠按每公斤体重 12 0mg一次灌胃给药。再分 2 4h、4 8h、72h组 ,小鼠每组 10只股动脉采血用于血气分析 ,取肺测定肺系数 ,全肺拍照进行对照 ,大鼠每组 10只取肺石腊包埋 ,病理切片。结果　①整体外观变化　随着给药时间延长 ,呼吸变得越来越困难、消瘦、咳嗽 ,2 4h后鼻腔有淡红色分泌物 ,食欲渐进性下降。②肺外观观察炎症渐进性发展 ,从正常粉红色发展到最后呈肝样变。③血气变化　随染毒时间延长 ,血液pH值逐渐降低 ,PaCO2 逐渐升高 ,PaO2 逐渐下降 ,肺系数逐渐增大 ,组间数据进行t检验p <0 0 1,差异有显著性。④病理切片观察肺部呈典型炎症病理变化过程 ,最终肺泡内形成典型透明膜。结论　百草枯染毒成功制造鼠ARDS模型。     

急性呼吸窘迫综合征临床治疗观察及预后影响因素分析

目的:观察急性呼吸窘迫综合征临床治疗效果,并对预后影响因素进行分析。方法:回顾性分析2006年3月~2011年10月在我院接受治疗的56例急性呼吸窘迫综合征患者的临床资料,使用SPSS12.0进行统计分析,并进行多因素Logistic回归分析。结果:采用以PEEP为主的综合治疗,并联合使用血必净注射液和乌司他丁,治疗ARDS病死率为26.8%;预后影响因素中ARDS并发MODS、APACHEⅡ评分和发病至接受治疗时间具有显著意义。结论:该治疗方法病死率较低,效果良好;ARDS并发并发MODS、APACHEⅡ评分和发病至接受治疗时间是影响ARDS患者的病死预后主要因素。     

Protective and Pathologic Roles of the Immune Response to Mouse Hepatitis Virus Type 1: Implications for Severe Acute Respiratory Syndrome

Intranasal mouse hepatitis virus type 1 (MHV-1) infection of mice induces lung pathology similar to that observed in severe acute respiratory syndrome (SARS) patients. However, the severity of MHV-1-induced pulmonary disease varies among mouse strains, and it has been suggested that differences in the host immune response might account for this variation. It has also been suggested that immunopathology may represent an important clinical feature of SARS. Little is known about the host immune response to MHV-1 and how it might contribute to some of the pathological changes detected in infected mice. In this study we show that an intact type I interferon system and the adaptive immune responses are required for controlling MHV-1 replication and preventing morbidity and mortality in resistant C57BL/6J mice after infection. The NK cell response also helps minimize the severity of illness following MHV-1 infection of C57BL/6J mice. In A/J and C3H/HeJ mice, which are highly susceptible to MHV-1-induced disease, we demonstrate that both CD4 and CD8 T cells contribute to morbidity during primary infection, and memory responses can enhance morbidity and mortality during subsequent reexposure to MHV-1. However, morbidity in A/J and C3H/HeJ mice can be minimized by treating them with immune serum prior to MHV-1 infection. Overall, our findings highlight the role of the host immune response in contributing to the pathogenesis of coronavirus-induced respiratory disease.Severe acute respiratory syndrome (SARS) is caused by a zoonotic coronaviral infection that reached epidemic proportions beginning in late 2002 (37, 52, 55, 76, 84, 86). The etiologic agent, SARS-coronavirus (CoV), is a novel group 2 CoV that emerged in the human population exposed to infected animals that were present in wet markets in various provinces of southern China (16, 22, 35, 45, 57, 61). Although the outbreak was quickly contained by the application of aggressive public health measures, it highlighted the deadly potential of this novel pathogen as more than 8,000 people in more than 25 countries were affected, and almost 800 infected individuals died (37, 76, 84, 86). Although there have not been additional outbreaks of this disease in the general population since 2003, due to the continued presence of related viruses in bats and other animals and to cultural practices prevalent in the local population in southern China, the reemergence of this pathogen in the human population may occur in the future (40).Currently, there are no rigorously tested efficacious prophylactic or therapeutic agents targeting this pathogen. Given the lethal potential of this virus, it is imperative to develop specific antiviral therapies that can be rapidly and universally applied. One of the serious drawbacks in the field is the paucity of appropriate animal models that faithfully reproduce the clinical features of SARS (52, 60). Although a mouse-adapted strain of this virus is available, studies with this strain need to be performed in biosafety level 3 facilities (48, 59). Logistical issues associated with such requirements hamper the rapidity and ease with which one can perform a comprehensive and detailed systemic examination of the dynamics of host-pathogen interactions. Recently, it was reported that intranasal infection of certain strains of mice with a related group 2 respiratory CoV, mouse hepatitis virus type 1 (MHV-1), induced pulmonary disease that was very similar to that observed in human subjects infected with SARS-CoV (11). In addition to the phylogenetic proximity of MHV-1 and SARS-CoV, they also share similarities in genome organization and in mechanisms of replication (63, 68). Hence, it is likely that the pathophysiology observed in MHV-1-infected mice mimics important pathological features associated with SARS-CoV infection in humans. A dysregulated immune response characterized by aberrant cytokine production is postulated to contribute to clinical disease in patients with SARS (8, 26, 55, 58, 72, 75, 82, 83). MHV-1 infection of susceptible strains of mice is also associated with an altered cytokine profile, and published reports suggest that the host immune response to the virus is an important contributor to the pathology observed in susceptible strains of mice (11). Examination of the immune response to a pathogen is critical for the purpose of designing rational and effective vaccination approaches. In addition, it also helps identify potentially deleterious effects of the immune response that can subsequently be manipulated to the advantage of the host, thereby maximizing recovery and minimizing morbidity.In the present study we have carried out a comprehensive analysis of the immune response to MHV-1 following intranasal infection of both resistant and susceptible strains of inbred mice. Our observations in alpha/beta interferon (type I IFN) receptor-knockout (IFN-αβR-KO) mice and NK cell-depleted mice shed light on the protective role of these components of the innate immune response in resistant C57BL/6J (B6) mice. And our examination of the adaptive immune responses to MHV-1 shows that they function as a double-edged sword, mediating protection in resistant strains and contributing to pathology in susceptible strains of mice.     

丙戊酸钠对LPS诱导的急性呼吸窘迫综合征小鼠的治疗作用

为了探讨丙戊酸钠(valproic acid,VPA)对急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)小鼠治疗作用及分子机制,本研究将30只雌性C57BL/6小鼠分为空白组、LPS组、LPS+VPA组,LPS+VPA组小鼠造模前腹腔预注射VPA,以LPS气管内注射诱导ARDS小鼠模型,6 h后检测各组小鼠肺水肿(湿重/干重),检测各组小鼠血液SOD和MDA水平;通过ELISA检测各组小鼠肺泡灌洗液中TNFα和IL-1β水平,Western blotting检测各组小鼠NF-κB p65和p-H2A.X蛋白表达水平。研究结果表明:与空白组相比,LPS组小鼠肺水肿显著升高,与LPS组比较,LPS+VPA组和阳性组小鼠肺水肿显著降低,差异具有统计学意义(p<0.01)。ELISA结果显示,与空白组比较,LPS组小鼠肺组织TNFα和IL-1β含量显著升高,与LPS组比较,LPS+VPA组小鼠肺组织TNFα和IL-1β含量显著降低,差异具有统计学意义(p<0.01)。与空白组比较,LPS组小鼠血液SOD活性显著降低,MDA含量显著升高,与LPS组比较,LPS+VPA组和阳性组小鼠血液SOD活性显著升高,MDA含量显著降低。Western blotting结果显示,与空白组比较,LPS组小鼠肺NF-κB p65和p-H2A.X蛋白表达显著升高,与LPS组比较,LPS+VPA组和阳性组小鼠肺NF-κB p65和p-H2A.X蛋白表达显著降低,差异具有统计学意义(p<0.01)。本研究初步表明:VPA能够抑制NF-κB通路,抑制小鼠氧化应激和炎症反应,保护ARDS小鼠肺组织。     

Hamsters as a Model of Severe Acute Respiratory Syndrome Coronavirus-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), rapidly spread across the world in late 2019, leading to a pandemic. While SARS-CoV-2 infections predominately affect the respiratory system, severe infections can lead to renal and cardiac injury and even death. Due to its highly transmissible nature and severe health implications, animal models of SARS-CoV-2 are critical to developing novel therapeutics and preventatives. Syrian hamsters (Mesocricetus auratus) are an ideal animal model of SARS-CoV-2 infections because they recapitulate many aspects of human infections. After inoculation with SARS-CoV-2, hamsters become moribund, lose weight, and show varying degrees of respiratory disease, lethargy, and ruffled fur. Histopathologically, their pulmonary lesions are consistent with human infections including interstitial to broncho-interstitial pneumonia, alveolar hemorrhage and edema, and granulocyte infiltration. Similar to humans, the duration of clinical signs and pulmonary pathology are short lived with rapid recovery by 14 d after infection. Immunocompromised hamsters develop more severe infections and mortality. Preclinical studies in hamsters have shown efficacy of therapeutics, including convalescent serum treatment, and preventatives, including vaccination, in limiting or preventing clinical disease. Although hamster studies have contributed greatly to our understanding of the pathogenesis and progression of disease after SARS-CoV-2 infection, additional studies are required to better characterize the effects of age, sex, and virus variants on clinical outcomes in hamsters. This review aims to describe key findings from studies of hamsters infected with SARS-CoV-2 and to highlight areas that need further investigation.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel betacoronavirus that was first detected in Wuhan, China at the end of 2019.³¹ Coronavirus infections predominantly present with either respiratory or gastrointestinal manifestations, depending on the strain and host. While many coronavirus infections result in mild clinical symptoms, SARS-CoV-2 is highly pathogenic and poses significant health concerns.^31,58,78 Although initial clinical signs are attributed to the respiratory system, severe infections result in systemic complications, such as acute cardiac and renal injury, secondary infections, and shock.^31,58SARS-CoV-2 relies on a structural surface spike glycoprotein to establish infection. The spike protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells to gain entry in a receptor-mediated fashion. This interaction facilitates both human-to-human transmission and cross-species infection.⁷⁷ Species tropism is determined by the presence of ACE2 residues that recognize the SARS-CoV-2 spike protein. Animals permissive for SARS-CoV-2 infection include cats, ferrets, pigs, nonhuman primates, select genetically modified mice, and hamsters.^5,7,23,37,67 Susceptible species can be both intermediate hosts and sources of infection of SARS-CoV-2 for humans.⁷⁷ Rodents, such as mice and hamsters, are ideal models for the study of COVID-19 due to their small size, ready availability, low cost of care, SPF status, and in-depth characterization across a variety of translational models, including past and present betacoronavirus infections.^60,61 Although transgenic mice expressing human ACE2 are susceptible to SARS-CoV-2 infection, Syrian hamsters (Mesocricetus auratus) naturally express ACE2 residues that recognize the SARS-CoV-2 spike protein.^5,46,84 As such, Syrian hamsters are a valuable animal model for studying COVID-19.Syrian hamsters, commonly referred to as golden hamsters, belong to the family Cricetidae and have a natural geographic range of arid southeast Europe and Asia Minor. Additional members of the Cricetidae family used in biomedical research include Chinese hamsters (Cricetulus griseus), European hamsters (Cricetus cricetus), Armenian hamsters (Cricetulus migratorius), and dwarf hamsters (Phodopus species). Unless otherwise noted, any mention of hamsters in this overview refers to Syrian hamsters. Laboratory hamsters primarily originated from one Syrian litter captured in 1930. Progeny of this litter were first imported into the United States in 1938.⁵⁰ Outbred Syrian hamsters are widely available; recently developed transgenic hamsters are increasingly used in biomedical research and may provide unique insight into SARS-CoV-2 infections.^22,44 Syrian hamsters have a rich history in biomedical research and can be used to model cancer and infectious, metabolic, cardiovascular, and respiratory diseases.⁵⁰Hamsters play an important role in SARS-CoV-2 studies. This is due, in part, to their susceptibility to the first described highly pathogenic coronavirus infection in the 21st century, severe acute respiratory syndrome (SARS-CoV). SARS-CoV emerged in late 2002 in Southern China. Although individuals in more than 20 countries contracted SARS-CoV, the spread was quickly contained, with the last reported case in July 2003.^16,40 After experimental infection with SARS-CoV, hamsters developed high viral loads in the lungs and nasal turbinates.^{15,32,56,62,69} Pulmonary pathology included inflammation, cell necrosis, and consolidation without clinical signs of disease.⁶¹ Based on their susceptibility to SARS-CoV and natural expression of ACE2 capable of recognizing the SARS-CoV-2 spike protein, hamsters have been a preferred model of SARS-CoV-2. Hamster studies have replicated key aspects of SARS-CoV-2 infections in humans, including viral replication, transmission, and pathology. Furthermore, hamsters are a model organism for developing and testing novel preventions and therapeutics. However, using hamsters in biomedical research has several key limitations, including the lack of reagents, especially antibodies, suitable for use with hamster tissue and the relatively few established transgenic hamsters compared to mice. The purpose of this review is to describe key findings of hamster models of SARS-CoV-2 and to highlight gaps in our current understanding that will require further investigation.     

Plasma Adiponectin,Clinical Factors,and Patient Outcomes during the Acute Respiratory Distress Syndrome

Objective

Adiponectin (APN) is an anti-inflammatory hormone derived from adipose tissue that attenuates acute lung injury in rodents. In this study, we investigated the association between circulating APN and outcomes among patients with acute respiratory distress syndrome (ARDS).

Methods

We performed a retrospective cohort study using data and plasma samples from participants in the multicenter ARDS Network Fluid and Catheter Treatment Trial.

Results

Plasma APN concentrations were measured in 816 (81.6%) trial participants at baseline and in 568 (56.8%) subjects at both baseline and day 7 after enrollment. Clinical factors associated with baseline APN levels in multivariable-adjusted models included sex, body mass index, past medical history of cirrhosis, and central venous pressure (model R² = 9.7%). We did not observe an association between baseline APN and either severity of illness (APACHE III) or extent of lung injury (Lung Injury Score). Among patients who received right heart catheterization (n = 384), baseline APN was inversely related to mean pulmonary artery pressure (β = −0.015, R² 1.5%, p = 0.02); however, this association did not persist in multivariable models (β = −0.009, R² 0.5%, p = 0.20). Neither baseline APN levels [HR per quartile1.04 (95% CI 0.91–1.18), p = 0.61], nor change in APN level from baseline to day 7 [HR 1.04 (95% CI 0.89–1.23), p = 0.62)] were associated with 60 day mortality in Cox proportional hazards regression models. However, subgroup analysis identified an association between APN and mortality among patients who developed ARDS from extra-pulmonary etiologies [HR per quartile 1.31 (95% CI 1.08–1.57)]. APN levels did not correlate with mortality among patients developing ARDS in association with direct pulmonary injury [HR 0.96 (95% CI 0.83–1.13)], p_interaction = 0.016.

Conclusions

Plasma APN levels did not correlate with disease severity or mortality in a large cohort of patients with ARDS. However, higher APN levels were associated with increased mortality among patients developing ARDS from extra-pulmonary etiologies.     

Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome

Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine MA-ALI/ARDS and possibly contribute to lung dysfunction.     

黄磷及其化合物急性吸入致大鼠急性肺损伤或急性呼吸窘迫综合征模型的制作

目的建立黄磷及其化合物急性吸入致大鼠急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）的模型。方法健康SD大鼠48只随机分为对照组以及实验组（0、4、12、24、48 h时间点处死）。采用自制染毒装置,间歇染毒形成ALI/ARDS模型。观察ALI/ARDS大鼠动脉血气分析以及肺系数和肺组织病理变化。结果肺损伤后大鼠动脉血气分析以及肺组织病理改变明显恶化,肺系数较对照组明显增大。结论成功地建立了黄磷及其化合物急性吸入致大鼠ALI/ARDS的模型,为黄磷及其化合物吸入中毒的防治研究提供良好实验基础,同时也适用于其他气体吸入致ARDS的实验研究。