Cytoprotection of heme oxygenase-1/carbon monoxide in lung injury

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) have been the major cause of morbidity and mortality in intensive care units (ICU) over the past decades despite advances in therapeutic modalities. This syndrome is characterized by noncardiogenic pulmonary edema, and pulmonary and systemic inflammation resulting in respiratory failure (1, 2). Both exudative and proliferative organizing phases of ARDS/ALI have been described pathologically (3, 4). The exudative phase is often called diffuse alveolar damage (DAD) characterized by inflammation and hyaline membrane composed of fibrin and cellular debris (3--5). Pulmonary alveolar cell death is the major pathologic change during the exudative phase in DAD. Repair and remodeling of injured lung cells occur during the proliferative phase, characterized by hyperplasia of alveolar type II cells and fibroblast proliferation (3-5). A variety of cellular insults can cause ALI/ARDS including but not limited to sepsis, trauma, drugs, high concentration of oxygen therapy, and mechanical ventilation (1, 2, 5). The broad spectrum of insults that potentially cause ARDS highlights the complexity of pathogenesis of this syndrome.     

Serum 7S collagen levels in diffuse interstitial lung diseases--an index of the destruction of alveolar structure]

To examine whether alteration of 7S collagen in the alveolar basement membrane is related to the condition and prognosis of diffuse interstitial lung diseases (idiopathic interstitial pneumonia: IIP, collagen vascular diseases, sarcoidosis, and hypersensitivity pneumonitis), we measured serum 7S collagen levels in 123 patients with diffuse interstitial lung disease and other lung diseases. Patients with diffuse lung diseases (diffuse interstitial lung disease, pulmonary emphysema, and diffuse panbronchiolitis: DPB) showed significantly higher serum levels of 7S collagen than healthy normal controls. Serum 7S collagen levels in IIP and collagen vascular diseases were significantly higher than those in pulmonary emphysema and DPB. In cases of IIP, serum 7S collagen levels in the active stage were significantly higher than those in the inactive stage. Furthermore, the prognosis of patients with higher serum 7S collagen levels was significantly poorer than those of patients with lower serum 7S collagen levels. In infectious pulmonary diseases, serum 7S collagen levels of patients with adult respiratory distress syndrome (ARDS) were significantly higher than those of patients without ARDS. Autopsy specimens obtained from patients with positive serum 7S collagen showed diffuse alveolar damage and/or diffuse pulmonary hemorrhage in the alveolar areas. Immunohistochemical staining for 7S collagen showed disruption and/or loss of the alveolar basement membrane. The authors conclude that serum level of 7S collagen is useful for estimating the activity of diffuse interstitial lung diseases as an index of the destruction of alveolar structure.     

Fatal pneumopathy after cytostatic treatment for leukemia in children

Summary Two cases of fatal pneumopathy during cytostatic therapy for acute lymphatic leukemia of childhood, are reported with pathoanatomical lung findings and general clinical features. Histology revealed massed atypical epithelial proliferation in the bronchiolar terminal pathways (tumourlets) with multinucleated polymorphic giant cells beside pulmonary fibrosis. As causative factors for pulmonary changes hypersensitivity reactions, direct toxicity, or pharmacologic effects are discussed. Formal pathogenesis is explained by an impairment of endothelial cells in alveolar capillaries followed by permeability disorders and interstitial edema with disturbed perfusion. Disseminated intravasal microthrombl are frequent. Restitution to integrity appears possible only under favorable conditions. If the exsudative turns into the proliferative phase, intraalveolar and interstitial pulmonary fibrosis may develop with atypical epithelial proliferations. The prognosis of cytostatics-induced pneumopathies depends essentially on the time when it is diagnosed.     

Acute respiratory failure after interferon-gamma therapy of end-stage pulmonary fibrosis

Interferon (IFN)-gamma was recently proposed as a treatment for idiopathic pulmonary fibrosis. We report on four patients who developed acute respiratory failure with new alveolar opacities after 2 (two patients), 6, and 35 injections of IFN-gamma-1b. All four patients had advanced idiopathic pulmonary fibrosis (total lung capacity less than 45% predicted or carbon monoxide diffusion capacity less than 30% predicted), and two patients had familial pulmonary fibrosis. No other cause of deterioration was found. Refractory hypoxemia led to death in three cases and to lung transplantation in one case. Pathologic studies in two patients showed diffuse alveolar damage lesions with preexisting usual interstitial pneumonia. These cases suggest that IFN-gamma therapy can induce an acute respiratory failure in patients with end-stage idiopathic pulmonary fibrosis.     

The chest roentgenogram in pulmonary edema

It has been shown that the chest roentgenogram is a sensitive and accurate pool for detecting and quantitating cardiogenic pulmonary edema. This can be done at the interstitial stage, when it cannot be detected by physical examination. At the same time the chest film can provide useful information about the circulating blood volume. In patients with the ARDS, a characteristic peripheral and patchy distribution of alveolar edema associated with an absence of peribronchial cuffing, septal lines and effusions has been shown. Enlargement of the right side of the heart and main pulmonary artery may precede actual development of edema in ARDS and provide the opportunity for early diagnosis. Radiographic "scoring" in cases of ARDS correlates well with PO2 (measured with an F1O2 = .21) standardized to a PCO2 of 40 mm Hg. The three main forms of lung edema (that is, cardiogenic, renal or overhydration, and injury edema) appear to have radiographic features that can be used to separate them. The accuracy and objectivity of this approach has been confirmed by taking the radiographic signs as input variables for discriminant analysis. Different hemodynamic conditions and changes of the extravascular protein osmotic forces may be the main factors underlying the radiographic patterns in the various types of pulmonary edema.     

Lung injury in acute experimental pancreatitis in rats I. Morphological Studies

The pathogenesis of pancreatitis-related pulmonary injury was studied at the light- and electronmicroscopic level. Experimental pancreatitis was induced in rats by infusion of supramaximal doses of cerulein for 12 h. Investigations were carried out 3, 6, and 12 h after the start of infusion and 12, 48, and 72 h after the end of pancreatitis induction. Initial manifestations of pancreatitis-associated lung injury revealed a pronounced clustering of polymorphonuclear leukocytes in pulmonary microvessels, followed by severe damage of alveolar endothelial cells. Consecutively, the increase in vascular permeability of the lung resulted in interstitial edema formation. Structural changes were maximal after 12 h and reversed completely after 84 h. In conclusion, the structural appearance of pulmonary injury in cerulein-induced pancreatitis was similar to that reported in early stages of the adult respiratory distress syndrome (ARDS). It is suggested that polymorphonuclear granulocytes play a crucial role in the pathogenesis of pancreatitis-related lung injury.     

Two fatal cases of methotrexate-induced interstitial pneumonitis]

We report two cases of methotrexate-induced pneumonitis. Both patients died despite steroid pulse therapy. Postmortem lung tissue revealed diffuse alveolar damage, and focal lung fibrosis. Physicians should be aware of the possibility of MTX-induced interstitial pneumonitis in diagnosing RA patients with MTX when diffuse pulmonary infiltration is present.     

Ultrastructural abnormalities in increased-permeability pulmonary edema

A general clinical impression is that increased microvascular permeability following acute lung injury always leads to pulmonary edema. The ARDS is a final pathway of acute lung injury. A number of agents may initiate acute lung injury, either directly or indirectly, via cellular and humoral mediators. Clinical and experimental animal studies indicate that both the microvascular and alveolar-airway barriers are susceptible to injury. Unfortunately, the spectrum of cellular damage is nonspecific and quite uniform, regardless of the injurious agent. Thus pathologic examination often reveals little about the exact underlying etiology of the lung injury. This situation has minimized the diagnostic value of lung biopsies in clinical cases of increased-permeability pulmonary edema. Nonetheless, the pathologic information has been, and will continue to be, invaluable to understanding the structural and functional relationships present in experimental models of increased-permeability pulmonary edema.     

A case of polymyositis with concomitant diffuse alveolar damage following interstitial pneumonia]

A 68-year-old woman had been given a diagnosis of interstitial pneumonia (NSIP pattern) and followed up at our hospital for 3 years. She was admitted to our hospital because of dyspnea, lower limb edema and myalgia. On admission, serum CPK and CRP levels were elevated and an electromyogram suggested inflammatory myopathy. We diagnosed polymyositis (PM) with progressive interstitial pneumonia (IP). Although methylprednisolone pulse therapy and immunosuppressive agents were administered, pulmonary lesions became aggravated. The patient died due to respiratory failure as a result of the progress of IP. The autopsy lung revealed diffuse alveolar damage (DAD) at the both acute and fibrotic phases, suggesting that DAD could coincide with PM. We report here a rare case of polymyositis with diffuse alveolar damage (DAD).     

Lung injury in acute experimental pancreatitis in rats. I. Morphological studies.

The pathogenesis of pancreatitis-related pulmonary injury was studied at the light- and electronmicroscopic level. Experimental pancreatitis was induced in rats by infusion of supramaximal doses of cerulein for 12 h. Investigations were carried out 3, 6, and 12 h after the start of infusion and 12, 48, and 72 h after the end of pancreatitis induction. Initial manifestations of pancreatitis-associated lung injury revealed a pronounced clustering of polymorphonuclear leukocytes in pulmonary microvessels, followed by severe damage of alveolar endothelial cells. Consecutively, the increase in vascular permeability of the lung resulted in interstitial edema formation. Structural changes were maximal after 12 h and reversed completely after 84 h. In conclusion, the structural appearance of pulmonary injury in cerulein-induced pancreatitis was similar to that reported in early stages of the adult respiratory distress syndrome (ARDS). It is suggested that polymorphonuclear granulocytes play a crucial role in the pathogenesis of pancreatitis-related lung injury.     

The lung in systemic lupus erythematosus: Analysis of the pathologic changes in 120 patients

The nature and frequency of pulmonary involvement in systemic lupus erythematosus (SLE) is controversial. We reviewed the clinical and pathologic features of 120 patients with SLE described in autopsy records at The Johns Hopkins Hospital to determine the pulmonary parenchymal changes that could be attributed directly to SLE. Each case was reviewed to determine the extent of extrapulmonic SLE and possible alternative explanations for the observed lung pathology. Moderate or severe pulmonary parenchymal alterations that were attributed to SLE were found in 22 patients (18 percent). Five patients with interstitial fibrosis, two with pulmonary vasculitis, and one with pulmonary hematoxylin bodies were attributable only to SLE, as were 11 of 15 (73 percent) patients with interstitial pneumonitis. Alternative explanations for findings previously attributed to SLE included congestive heart failure, renal failure, infection, aspiration, oxygen toxicity and increased intracranial pressure. Alveolar hemorrhage, thought to be a feature of acute lupus pneumonitis, was unexplained in only two of 29 (7 percent) patients, alveolar wall necrosis was unexplained in one of seven (14 percent) and edema was unexplained in three of 70 (4 percent). Hyaline membranes, present in four patients, were always explained. Pleuritis and pleural effusions were attributed to SLE in 22 of 36 (61 percent) and three of 28 (11 percent) patients, respectively. The findings suggest that many nonspecific pulmonary lesions previously attributed to SLE, such as alveolar hemorrhage, alveolar wall necrosis, edema and hyaline membranes, are probably secondary to intercurrent infection, congestive heart failure, renal failure or oxygen toxicity.     

Pathologic mechanisms of drug-induced lung disorders

The pathology of drug-induced lung disease is approached on the basis of patterns of tissue reaction in this review. The entities described include various pathologic lesions, from diffuse alveolar damage to interstitial pneumonias and angiopathies. Because the histopathologic manifestations of drug injury are variable and nonspecific, pathogenetic mechanisms are emphasized. Drugs may cause injury by direct toxicity or by triggering immunologic responses, but often this neat distinction is blurred by the combined effects of preexisting lung injury and the concurrent administration of several drugs. Thus the identification of drug-induced lung disease requires thorough knowledge of the clinical history and rigorous analysis of histopathologic features.     

An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis

Fibroblasts in healthy adult lung are quiescent, synthesizing little collagen. We studied lung biopsies from 30 patients with pulmonary fibrosis, using immunohistochemistry with monoclonal antibodies against the propeptides of type I collagen to localize fibroblasts actively synthesizing collagen. Adjacent sections were stained with antibodies to type III and IV collagen, fibrin, cytokeratin, plasma fibronectin, or EDIIIa-containing "cellular" fibronectin (cFN). In rapid pulmonary fibrosis, including the proliferative phase of diffuse alveolar damage, organizing pneumonia, and subacute idiopathic fibrosis, collagen-synthesizing cells were numerous in organizing exudate filling airspaces but were also seen in the interstitium of the alveolar walls, interlobular septa, and walls of blood vessels. The new matrix deposited in the airspaces also contained type III collagen and EDIIIa-containing fibronectin. In chronic pulmonary fibrosis, more than half of the biopsies showed foci of collagen synthesis and cFN deposition near the air-tissue interface. The foci were consistently localized outside remnants of basal lamina and therefore within airspaces. The results indicate that (1) fibrosis in chronic idiopathic pulmonary fibrosis results mainly from organization of exudate within airspaces, just as it does after acute lung injury, and (2) during this process, fibroblasts increase their synthesis of collagen and fibronectin coordinately. Foci of active matrix deposition provide evidence for the progressive nature of chronic pulmonary fibrosis.     

Radiologic considerations in the adult respiratory distress syndrome

ARDS is the clinical consequence of acute lung injury that results in increased-permeability edema. Distinct pathophysiologic stages are reflected in the radiographic evolution of the syndrome. Diffuse microatelectasis, proteinaceous edema fluid, and multifocal in situ pulmonary vascular occlusions characterize the acute stages of injury and result in the appearance of diffuse consolidations and occasional pleural effusions on the radiograph. In the chronic organizing stage of ARDS, the physiologic consequences of subsiding edema and tissue repair may be reflected by a transition to stable interstitial patterns. There is a high frequency of complications related to the decreased compliance of the injured lung that lead to interstitial emphysema and other barotraumatic complications. Survivors of ARDS exhibit various degrees of physiologic impairment and radiographic abnormality that may improve during the first year after survival. The relations between various indices of the severity of ARDS and the ultimate outcome are emerging. Debate continues about the specificity of the chest radiograph in distinguishing increased-permeability edema from hydrostatic edema. In fact, interstitial patterns and pleural effusions are observed in both. Nonetheless, the chest radiograph is a pivotal tool for monitoring patients at risk of serious morbidity from nosocomial lung infection, barotrauma, and the complications accompanying the use of invasive devices. It is hoped that as we develop a more uniform consensus on the clinical definition of ARDS and begin to classify patients according to specific clinical or physiologic observations, chest radiographic observation will acquire greater diagnostic and prognostic significance in these critically ill patients.     

Pulmonary edema fluid from patients with acute lung injury augments in vitro alveolar epithelial repair by an IL-1beta-dependent mechanism

Efficient alveolar epithelial repair is crucial for the restoration of the injured alveolar epithelial barrier in patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). We hypothesized that pulmonary edema fluid from patients with ALI /ARDS would inhibit alveolar epithelial repair as measured in an in vitro epithelial wound-repair model using the human alveolar epithelial-like cell line A549. In contrast to our initial hypothesis, pulmonary edema fluid from patients with ALI/ARDS increased alveolar epithelial repair by 33 +/- 3% compared with pooled plasma from healthy donors (p < 0.01). By contrast, the plasma and the pulmonary edema fluid from patients with hydrostatic pulmonary edema, and the plasma from patients with ALI/ARDS had similar effects on epithelial repair as pooled plasma from healthy donors. Inhibition of interleukin-1beta (IL-1beta) activity by IL-1 receptor antagonist reduced alveolar epithelial repair induced by ALI/ARDS edema fluid by 46 +/- 4% (p < 0.001), indicating that IL-1beta contributed significantly to the increased epithelial repair. In summary, pulmonary edema fluid collected early in the course of ALI/ARDS increased alveolar epithelial repair in vitro by an IL-1beta-dependent mechanism. These data demonstrate a novel role for IL-1beta in patients with ALI/ARDS, indicating that IL-1beta may promote repair of the injured alveolar epithelium.     

Progress toward improving animal models for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) remains a disease with an unknown cause and a poor prognosis. Among attempts to define disease pathogenesis, animal models of experimental lung fibrosis have a prominent role. Commonly used models include exposure to bleomycin, silica, fluorescein isothiocyanate; irradiation; or expression of specific genes through a viral vector or transgenic system. These all have been instrumental in the study of lung fibrosis, but all have limitations and fall short of recapitulating a pattern of usual interstitial pneumonia, the pathologic correlate to IPF. A model of repetitive bleomycin lung injury has recently been reported that results in marked lung fibrosis, prominent alveolar epithelial cell hyperplasia, a pattern of temporal heterogeneity and persistence of aberrant remodeling well after stimulus removal, representing a significant addition to the collection of animal lung fibrosis models. Taken together, animal models remain a key component in research strategies to better define IPF pathogenesis.     

One hundred percent oxygen lung injury in adult baboons

Healthy adult baboons exposed to 100% oxygen for 5 to 7 days maintained on continuous mechanical ventilation develop severe bilateral noncardiogenic pulmonary edema that resembles in many aspects the human adult respiratory distress syndrome (ARDS). In the present study, we evaluated the effects of hyperoxia for 5 to 6 days in 8 baboons to compare changes in abnormalities in bronchoalveolar lavage fluid (BALF) biochemical markers, hemodynamic measurements, and pulmonary function tests in order to find early predictors of lung injury. All animals had bilateral alveolar infiltrates, severe hypoxemia, and progressive deterioration of pulmonary function tests. Diffuse alveolar damage and mild-moderate pneumonias were found and were associated with low-grade bacterial infection. Total lung capacity, diffusing capacity for carbon monoxide, pulmonary static compliance, and oxygenation were significantly impaired after Day 5; BALF proteins, elastase, and total polymorphonuclear leukocytes increased significantly at least 24 h before (Day 4) any abnormalities in chest radiographs, pulmonary function tests, and hemodynamic measurements were detected. We conclude that exposure to 100% oxygen in this model causes marked gas exchange, hemodynamic, biochemical, cytologic, radiographic, and pathologic changes similar to those noted in patients with ARDS. Bronchoalveolar lavage abnormalities precede hemodynamic and gas exchange abnormalities.