Acute postembolic pulmonary edema in vagotomized rats

1. In the rat, pulmonary embolism induced by intravenous administration of gaseous carbon dioxide increases intrapulmonary water content. When the rat is vagotomized before emboli are produced, an important lung edema is found. 2. Strong respiratory stimulation with lung hyperinflation seems to be the cause of this facilitated alveolar transudation. 3. Mechanical factors operating after pulmonary embolism are those which explain transudation after inhalation of hypercapnic gas mixtures in vagotomized rats.     

New Developments in the Pathogenesis of Smoke Inhalation-Induced Pulmonary Edema

Smoke inhalation causes most of the deaths in fire-related injuries, with pulmonary edema as a major determinant in the outcome of smoke-inhalation injury. The pathophysiology of pulmonary edema is thought to be related to the products of incomplete combustion. Damage to the integrity of the alveolar epithelium is one of the determinants of the development of smoke-induced pulmonary edema. In recent studies using lung clearance of aerosolized pentetic acid (DTPA [diethylenetriaminepentaacetic acid]) labeled with technetium Tc 99m to assess the permeability of the alveolar epithelium, several factors were identified that may increase a person''s susceptibility to smoke-induced acute lung injury. These are increased initial alveolar permeability and alterations in the number and activity of alveolar macrophages. Clinical measurement of ^99mTcDTPA clearance may provide a sensitive and convenient method for the early detection and serial assessment of smoke-induced alveolar epithelial permeability changes.     

人工饲养条件下死亡恒河猴肺脏病理改变分析

目的观察人工饲养条件下实验恒河猴肺脏病理改变,探讨实验猴呼吸系统疾病分布规律和病理改变特点,丰富实验猴自发病变基本研究资料。方法对1998～2008年云南地区饲养的自然死亡的155只恒河猴（年龄2～20岁）的肺脏进行病理检查,按年龄分为幼年组、成年组、老年组,并对观察结果进行统计学分析。结果实验猴肺脏主要病变有大叶性肺炎、支气管肺炎、间质性肺炎、肺气肿、支气管扩张症、胸膜炎、肺肉芽肿性炎等12种,出现率最高的为支气管肺炎（18.71%）和大叶性肺炎（16.74%）。恒河猴肺脏病变在不同年龄阶段均有发生,老年猴组肺脏病变发生率最高,疾病类型和发生率在不同年组中分布不相同,统计学分析显示：支气管炎病变成年组发病率明显高于幼年组;肺气肿病变老年组明显高于成年组和幼年组,（P〈0.05）。结论人工饲养条件下死亡实验猴肺脏病变检出率较高,实验猴肺脏病变在不同年龄阶段存在差异,实验猴肺脏病理改变结果丰富了实验猴的基本研究资料,对实验猴的质量控制和相关动物实验有重要价值。     

Pulmonary Complications of Drug Abuse

Complications resulting from drug abuse more frequently affect the lung than any other organ. The spectrum of pulmonary complications associated with drug abuse is wide. The current practice of using mixtures of drugs is mainly responsible for the increase in pulmonary complications. The chief complications observed in a series of 241 drug abuse patients were aspiration pneumonitis (12.9 percent), pulmonary edema (10.0 percent), and pneumonia (7.5 percent).     

Invited review: lung edema clearance: role of Na(+)-K(+)-ATPase.

Acute hypoxemic respiratory failure is a consequence of edema accumulation due to elevation of pulmonary capillary pressures and/or increases in permeability of the alveolocapillary barrier. It has been recognized that lung edema clearance is distinct from edema accumulation and is largely effected by active Na(+) transport out of the alveoli rather than reversal of the Starling forces, which control liquid flux from the pulmonary circulation into the alveolus. The alveolar epithelial Na(+)-K(+)-ATPase has an important role in regulating cell integrity and homeostasis. In the last 15 yr, Na(+)-K(+)-ATPase has been localized to the alveolar epithelium and its contribution to lung edema clearance has been appreciated. The importance of the alveolar epithelial Na(+)-K(+)-ATPase function is reflected in the changes in the lung's ability to clear edema when the Na(+)-K(+)-ATPase is inhibited or increased. An important focus of the ongoing research is the study of the mechanisms of Na(+)-K(+)-ATPase regulation in the alveolar epithelium during lung injury and how to accelerate lung edema clearance by modulating Na(+)-K(+)-ATPase activity.     

Mechanisms of alveolar protein clearance in the intact lung

Transport of protein across the alveolar epithelial barrier is a critical process in recovery from pulmonary edema and is also important in maintaining the alveolar milieu in the normal healthy lung. Various mechanisms have been proposed for clearing alveolar protein, including transport by the mucociliary escalator, intra-alveolar degradation, or phagocytosis by macrophages. However, the most likely processes are endocytosis across the alveolar epithelium, known as transcytosis, or paracellular diffusion through the epithelial barrier. This article focuses on protein transport studies that evaluate these two potential mechanisms in whole lung or animal preparations. When protein concentrations in the air spaces are low, e.g., albumin concentrations <0.5 g/100 ml, protein transport demonstrates saturation kinetics, temperature dependence indicating high energy requirements, and sensitivity to pharmacological agents that affect endocytosis. At higher concentrations, the protein clearance rate is proportional to protein concentration without signs of saturation, inversely related to protein size, and insensitive to endocytosis inhibition. Temperature dependence suggests a passive process. Based on these findings, alveolar albumin clearance occurs by receptor-mediated transcytosis at low protein concentrations but proceeds by passive paracellular mechanisms at higher concentrations. Because protein concentrations in pulmonary edema fluid are high, albumin concentrations of 5 g/100 ml or more, clearance of alveolar protein occurs by paracellular pathways in the setting of pulmonary edema. Transcytosis may be important in regulating the alveolar milieu under nonpathological circumstances. Alveolar degradation may become important in long-term protein clearance, clearance of insoluble proteins, or under pathological conditions such as immune reactions or acute lung injury. acute respiratory distress syndrome; endocytosis; diffusion; protein transport pulmonary edema     

Morphological changes in lung tissue of victims associated with the 2009 A H1N1/v09 influenza pandemic in Colombia

Introduction. Influenza is an acute respiratory infection that may be seasonal or pandemic. In 2009 The World Health Organization (WHO) declared an influenza pandemia; 3,876 cases and 239 deaths were reported in Colombia. Objective. The morphological changes in lung tissues associated with virus infection H1N1/v09 were described from autopsied victims. Materials and methods. Seventy-five cases were diagnosed by RT-PCR for influenza A H1N1/v09, of which the lungs of 20 were selected for morphological study by light microscopy, optical microscopy, high-resolution transmission electron microscopy and immunohistochemistry. Results. Of the 75 cases, 83% had viral pneumonitis and 17% alveolitis. Complications included intra-alveolar hemorrhage (66%), edema (89%), diffuse alveolar damage (2%), and bacterial co-infection (32%). Morphological changes were as follows: destruction of the alveolar epithelium and interstitium, edema, macrophages with vacuolated cytoplasm,and infiltration of polymorphonuclear leukocytes in the alveolar lumen and interstitium, vacuolization cytoplasmic type I pneumocytes and electronedense bodies in cellular debris in the alveolar lumen, and immunoreactivity of viral antigens in bronchiolar epithelial cells and alveolar infiltrate. Conclusion. The low percentage of bacterial co-infection observed in these cases was a prominent feature, and suggested that the fatal result was probably not associated with secondary bacterial disease (Indicated by previous reports). The tissue lesions were attributed to tissue damage due to viral lesion, as well as the cellular and humoral inflammatory response associated with infiltration by polymorphonucleocytes and macrophages in the interstitium and alveolar lumen.     

Nasal potential difference to detect Na+ channel dysfunction in acute lung injury

Pulmonary fluid clearance is regulated by the active transport of Na(+) and Cl(-) through respiratory epithelial ion channels. Ion channel dysfunction contributes to the pathogenesis of various pulmonary fluid disorders including high-altitude pulmonary edema (HAPE) and neonatal respiratory distress syndrome (RDS). Nasal potential difference (NPD) measurement allows an in vivo investigation of the functionality of these channels. This technique has been used for the diagnosis of cystic fibrosis, the archetypal respiratory ion channel disorder, for over a quarter of a century. NPD measurements in HAPE and RDS suggest constitutive and acquired dysfunction of respiratory epithelial Na(+) channels. Acute lung injury (ALI) is characterized by pulmonary edema due to alveolar epithelial-interstitial-endothelial injury. NPD measurement may enable identification of critically ill ALI patients with a susceptible phenotype of dysfunctional respiratory Na(+) channels and allow targeted therapy toward Na(+) channel function.     

Eight cases of Legionnaires' disease.

Eight patients with Legionnaires'' disease were seen at one hospital in the summer of 1979. They presented in the same 12-day period with an illness of rapid onset characterized by fever, chills, malaise, profuse sweating and neurologic symptoms. Neutrophilia, a high erythrocyte sedimentation rate, proteinuria, hypoalbuminemia, hyponatremia, hypochloremia and abnormal liver enzyme levels in the serum were usually noted. The roentgenographic findings in the lungs ranged from segmental interstitial infiltration to panlobar pneumonia. Seven patients responded to erythromycin treatment, though one died suddenly, presumably of unrelated cardiac disease. The other patient died of a combination of renal and respiratory failure, with pulmonary edema.     

Respiratory distress and surfactant inhibition following vagotomy in rabbits

We used the model of bilateral cervical vagotomy of adult rabbits to cause respiratory failure characterized by pulmonary edema, decreased lung compliance, and atelectasis. We documented an 18-fold increase in radiolabeled albumin leak from the vascular space into alveolar washes of vagotomy vs. sham-operated rabbits (P less than 0.01). Despite a twofold increase in percent of prelabeled saturated phosphatidylcholine secreted (P less than 0.01), the alveolar wash saturated phosphatidylcholine pool sizes were not different. The minimum surface tensions were 19.6 +/- 2.5 vs. 9.4 +/- 2.2 dyn/cm for alveolar washes from vagotomy and control rabbits, respectively (P less than 0.01). The soluble proteins from alveolar washes inhibited the surface tension lowering properties of natural surfactant, whereas those from the control rabbits did not (P less than 0.01). When vagotomy rabbits in respiratory failure were treated with 50 mg natural surfactant lipid per kilogram arterial blood gas values and compliances improved relative to control rabbits. Vagotomy results in alveolar pulmonary edema, and surfactant dysfunction despite normal surfactant pool sizes and respiratory failure. A surfactant treatment can improve the respiratory failure.     

Macrophage-expressed IFN-β Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia

Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.     

Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice

Bronchodilators (such as ipratropium bromide), steroids (such as fluticasone propionate), and newly developed anti-inflammatory drugs (such as roflumilast) are used for patients with chronic obstructive pulmonary disease (COPD). We recently reported that lecithinized superoxide dismutase (PC-SOD) confers a protective effect in mouse models of COPD. We here examined the therapeutic effect of the combined administration of PC-SOD with ipratropium bromide on pulmonary emphysema and compared the effect of PC-SOD to other types of drugs. The severity of emphysema in mice was assessed by various criteria. Lung mechanics (elastance) and respiratory function (ratio of forced expiratory volume in the first 0.05 s to forced vital capacity) were assessed. Administration of PC-SOD by inhalation suppressed elastase-induced pulmonary emphysema, alteration of lung mechanics, and respiratory dysfunction. The concomitant intratracheal administration of ipratropium bromide did not alter the ameliorating effects of PC-SOD. Administration of ipratropium bromide, fluticasone propionate, or roflumilast alone did not suppress the elastase-induced increase in the pulmonary level of superoxide anion, pulmonary inflammatory response, pulmonary emphysema, alteration of lung mechanics, or respiratory dysfunction as effectively as did PC-SOD. PC-SOD, but not the other drugs, showed a therapeutic effect even when the drug was administered after the development of emphysema. PC-SOD also suppressed the cigarette smoke-induced pulmonary inflammatory response and increase in airway resistance. Based on these results, we consider that the inhalation of PC-SOD would be therapeutically beneficial for COPD.     

Reduced activity of the epithelial sodium channel in malaria-induced pulmonary oedema in mice

Lung complications during malaria infection can range from coughs and impairments in gas transfer to the development of acute respiratory distress syndrome (ARDS). Infecting C57BL/6 mice with Plasmodium berghei K173 strain (PbK) resulted in pulmonary oedema, capillaries congested with leukocytes and infected red blood cells (iRBCs), and leukocyte infiltration into the lungs. This new model of malaria-associated lung pathology, without any accompanying cerebral complications, allows the investigation of mechanisms leading to the lung disease. The activity of the amiloride-sensitive epithelial sodium channel (ENaC) in alveolar epithelial cells is decreased by several respiratory tract pathogens and this is suggested to contribute to pulmonary oedema. We show that PbK, a pathogen that remains in the circulation, also decreased the activity and expression of ENaC, suggesting that infectious agents can have indirect effects on ENaC activity in lung epithelial cells. The reduced ENaC activity may contribute to the pulmonary oedema induced by PbK malaria.     

光,电镜观察小鼠呼吸道合胞病毒性肺炎的免疫病理改变

Ｂａｌｂ／ｃ小鼠经鼻吸入呼吸道合胞病毒（ＲＳＶ）悬液感染成ＲＳＶ肺炎。于感染第５天后连续隔日取肺,光镜与透射电镜检查。感染第５～７天,肺组织病理改变最严重,多数小鼠表现为间质淋巴细胞（ＬＣ）套状浸润,肺泡隔增宽;少数小鼠出现间质内大量ＬＣ浸润与肺泡内大量单个核细胞渗出的两种病理改变。病毒包涵体出现于肺泡上皮细胞内,细胞受感染后发生肿胀、坏死。Ⅰ型细胞核周胞质内有核衣壳复制,表面病毒芽生形成长短不等的丝状体。第９天,肺泡隔增宽与间质ＬＣ浸润逐渐减轻。第１２天,病毒包涵体明显减少。     

Role and regulation of lung Na,K-ATPase.

The recognition that pulmonary edema is cleared from the alveolar airspace by active Na+ transport has led to studies of the role and regulation of alveolar epithelial Na,K-ATPases. In the lung these heterodimers are predominantly composed of alpha1 and beta1-subunits and are located on the basolateral aspect of alveolar type 2 epithelial cells (AT2). Working with apically positioned epithelial Na+ channels they generate a transepithelial osmotic gradient which causes the movement of fluid out of the alveolar airspace. Accumulating data indicates that in some forms of pulmonary edema alveolar Na,K-ATPases function is reduced suggesting that pulmonary edema may be due, in part, to impairment of edema clearance mechanisms. Other studies suggest that Na,K-ATPase dysfunction or inhibition may contribute to airway reactivity. It is now recognized that lung Na,K-ATPases are positively regulated by glucocorticoids, aldosterone, catecholamines and growth hormones. These findings have led to investigations that show that enhancement of Na,K-ATPase function can accelerate pulmonary edema clearance in vitro, in normal and injured animal lungs in vivo, and in human lung explants. This review focuses on Na,K-ATPase data from lung and lung cell experiments that highlight the importance of Na,K-ATPases in airway reactivity and in maintaining a dry alveolar airspace. Review of data that suggests that there may be a role for therapeutic modulation of alveolar Na,K-ATPases for the purpose of treating patients with respiratory failure are also included.     

The dysfunction of ATPases due to impaired mitochondrial respiration in phosgene-induced pulmonary edema

Phosgene is a toxic gas that is widely used in modern industry, and its inhalation can cause severe pulmonary edema. There is no effective clinical treatment because the mechanism of phosgene-induced pulmonary edema still remains unclear. Many studies have demonstrated that the Na⁺/K⁺-ATPase plays a critical role in clearing pulmonary edema and the inhibition of Na⁺/K⁺-ATPase protein expression has been found in many other pulmonary edema models. In the present study, after the mice were exposed to phosgene, there was serious pulmonary edema, indicating the dysfunction of the ATPases in mice. However, in vitro enzyme study showed that there were increases in the activities of the Na⁺/K⁺-ATPase and Ca²⁺-ATPase. Further investigation showed that the ATP content and mitochondrial respiratory control ratio (RCR) in the lungs decreased significantly. The oxidative stress product, malondialdehyde (MDA), increased while the antioxidants (GSH, SOD, and TAC) decreased significantly. These results indicate that mitochondrial respiration is the target of phosgene. The dysfunction of ATPases due to impaired mitochondrial respiration may be a new mechanism of phosgene-induced pulmonary edema.     

Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung

Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung injury. Statins exert beneficial effects in septic patients although the mechanisms remain elusive. This study examined effects of simvastatin on M1 protein-provoked pulmonary inflammation and tissue injury. Male C57BL/6 mice were pretreated with simvastatin or a CXCR2 antagonist before M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for determination of neutrophil infiltration, formation of edema, and CXC chemokines. Flow cytometry was used to determine Mac-1 expression on neutrophils. Gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative RT-PCR. M1 protein challenge caused massive infiltration of neutrophils, edema formation, and production of CXC chemokines in the lung as well as upregulation of Mac-1 on circulating neutrophils. Simvastatin reduced M1 protein-induced infiltration of neutrophils and edema in the lung. In addition, M1 protein-induced Mac-1 expression on neutrophils was abolished by simvastatin. Furthermore, simvastatin markedly decreased pulmonary formation of CXC chemokines and gene expression of CXC chemokines in alveolar macrophages. Moreover, the CXCR2 antagonist reduced M1 protein-induced neutrophil expression of Mac-1 and accumulation of neutrophils as well as edema formation in the lung. These novel findings indicate that simvastatin is a powerful inhibitor of neutrophil infiltration in acute lung damage triggered by streptococcal M1 protein. The inhibitory effect of simvastatin on M1 protein-induced neutrophil recruitment appears related to reduced pulmonary generation of CXC chemokines. Thus, simvastatin may be a useful tool to ameliorate acute lung injury in streptococcal infections.