ARDS is a disease process that is characterized by diffuse inflammation in the lung parenchyma. The involvement of inflammatory mediators in ARDS has been the subject of intense investigation, and oxidant-mediated tissue injury is likely to be important in the pathogenesis of ARDS. In response to various inflammatory stimuli, lung endothelial cells, alveolar cells, and airway epithelial cells, as well as activated alveolar macrophages, produce both nitric oxide and superoxide, which may react to form peroxynitrite, which can nitrate and oxidize key amino acids in various lung proteins, such as surfactant protein A, and inhibit their functions. The nitration and oxidation of a variety of crucial proteins present in the alveolar space have been shown to be associated with diminished function in vitro and also have been identified ex vivo in proteins sampled from patients with acute lung injury (ALI)/ARDS. Various enzymes and low-molecular-weight scavengers that are present in the lung tissue and alveolar lining fluid decreased the concentration of these toxic species. The purpose of this brief chapter is to review the results from various studies demonstrating increased levels of reactive oxygen-nitrogen intermediates in the alveolar spaces of patients with ALI/ARDS.

Clinical studies have demonstrated that chronic alcohol abuse is an independent outcome variable in acute lung injury. The Emory Center for the Study of Acute Lung Injury is determining the mechanisms by which ethanol increases susceptibility to acute lung injury. We developed a rat model of chronic ethanol ingestion and demonstrated that ethanol predisposes rats to edematous lung injury elicited by endotoxemia or sepsis. Chronic ethanol ingestion in rats led to decreased levels of glutathione, an important antioxidant in the lung, and this defect was associated with alterations in epithelial cell permeability, decreased alveolar liquid clearance, decreased cell viability, and decreased surfactant production. Chronic ethanol ingestion also led to the activation of lung tissue remodeling as demonstrated by the increased expression of profibrotic growth factors, matrix components, and metalloproteases. In cultured fibroblasts, the induction of the matrix glycoprotein fibronectin by ethanol was mediated via nicotinic acetylcholine receptor-dependent signal transduction. We speculate that these alterations render the host susceptible to acute lung injury by diminishing the protective mechanisms of the lung and promoting exaggerated inflammatory and tissue repair responses elicited against injurious agents.

To review the animal models of COPD, and to compare these data to those found in humans.

Angiogenesis, defined as the growth of new capillaries from preexisting vessels, is a pervasive biological phenomenon that is at the core of many physiologic and pathologic processes. An opposing balance of angiogenic and angiostatic factors regulates angiogenesis. Examples of physiologic processes that depend on angiogenesis include embryogenesis, wound repair, and the ovarian/menstrual cycle. In contrast, chronic inflammation associated with chronic fibroproliferative disorders as well as growth and metastasis of solid tumors are associated with aberrant angiogenesis. CXC chemokines comprise a unique cytokine family that contains members that exhibit on a structural/functional basis either angiogenic or angiostatic biological activity. In this review, we will discuss the role of CXC chemokines and angiogenesis in pulmonary fibrosis.

Cell death by apoptosis has fundamental significance in both normal lung homeostasis and a variety of pathologic processes, and for this reason apoptosis in the lung is a rapidly growing area of investigation. Evidence from human lung biopsy specimens and from animal models of lung fibrosis points to important roles for apoptosis in both the pathogenesis and resolution of fibrotic lesions. As more evidence accumulates, the more apparent becomes the paucity of information on the regulation of this mode of cell death in the many different cell types of the lung parenchyma. This discussion will review the current state of knowledge regarding the roles of apoptosis in lung fibrosis and will focus on its role in pathogenesis.

Idiopathic pulmonary fibrosis (IPF) is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor (TGF)-beta, insulin-like growth factor (IGF)-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis (scleroderma). We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in fibrotic lung diseases and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with IPF.

The pathogenesis of pulmonary fibrosis remains incompletely understood. Studies of associated inflammation have led to the discovery of a number of cytokines and chemokines that are found to be important either directly or indirectly for the fibrotic process. However, the importance of inflammation in pulmonary fibrosis is unclear, and at the time of diagnosis the inflammatory component is variable and usually not responsive to anti-inflammatory therapeutic agents. Patients usually exhibit evidence of active fibrosis with increased numbers of activated fibroblasts, many of which have the phenotypic characteristics of myofibroblasts. At these sites, increased amounts of extracellular matrix deposition are evident with effacement of the normal alveolar architecture. Animal model studies show the myofibroblast to be the primary source of type I collagen gene expression in active fibrotic sites. In vitro studies show differentiation of these cells from fibroblasts under the influence of certain cytokines but indicate their susceptibility to nitric oxide-mediated apoptosis. In addition to promoting myofibroblast differentiation, transforming growth factor-beta1 provides protection against apoptosis. Thus, this well-known fibrogenic cytokine is important both for the emergence of the myofibroblast and its survival against apoptotic stimuli. This is consistent with the critical importance of this cytokine in diverse models of fibrosis in various tissues. In view of these properties, the persistence or prolonged survival of the myofibroblast may be key to understanding why certain forms of lung injury may result in progressive disease, terminating in end-stage disease.

Primary pulmonary hypertension (PPH) is a serious pulmonary vascular disease occurring mostly in adult women. Although its occurrence in families was reported within a few years after the original clinical report, PPH was formerly believed rarely to have a genetic basis. Recent progress has not only clarified a basic molecular mechanism for PPH in families, but has also identified mutations of the same gene in many sporadic PPH patients, suggesting that its basis is commonly genetic. Extensive investigations in many centers are now in progress to provide a complete dissection of all the pathogenetic mechanisms of PPH.

Damage to the airway epithelium is one prominent feature of chronic asthma. Mucosal damage includes gap openings, partial denudation, and loss of ciliated cells. Apoptosis of the airway epithelium is increasingly recognized as a potential mechanism by which damage may occur. Corticosteroids (CSs) induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, CS therapy does not necessarily reverse epithelial damage. We examined whether CS therapy actually could induce airway epithelial apoptosis using culture models of primary airway epithelial cells and cell lines. The administration of CSs in low-micromolar concentrations induces apoptosis that involves the disruption of mitochondrial polarity, the activation of caspases, and the involvement of Bcl-2. Clear differences exist between CS-induced apoptosis in the cultured epithelium vs cultured hematopoietic cells in regard to time course and resistance to apoptosis. Our data suggest that the use of CSs, in concentrations that could be attained in vivo with the inhalation of potent preparations or with systemic administration, may be one factor in the airways remodeling and epithelial damage that is seen in many patients with chronic, persistent asthma.

The adhesion of cells to the extracellular matrix (ECM) protein, fibronectin, is important in the regulation and coordination of such complex processes as cell growth, migration, differentiation, and ECM organization. The deposition of fibronectin into the ECM is a cell-dependent process that is normally tightly regulated to ensure controlled matrix deposition. Increased deposition of fibronectin and collagen into the subepithelial space of the airways is observed in all forms of asthma and occurs early in the progression of the disease. Experimental evidence suggests a model in which fibronectin matrix accumulation contributes to the progression of asthma by altering both the structural properties of the airways and the functional properties of cells of the airway wall.

Asthma and COPD are the most prevalent of lung diseases and contribute an enormous burden of morbidity in North America and globally. In both conditions, inflammation leads to airway remodeling, which contributes to airway narrowing. To date, airway remodeling has only been assessed using histological examination of airways. However, it may now be possible to assess and quantify the extent of airway remodeling in vivo using high-resolution CT (HRCT). The aim of this article is to review the use of HRCT in the investigation of airway remodeling. A number of investigators have reported techniques to make measurements of airway dimensions using CT and an increasing number of quantitative methods are being developed. Using these techniques, airway dimensions have been examined in patients with asthma and COPD. In patients with asthma, the airway wall area was increased without a decrease in luminal area, whereas in patients with COPD, the airway luminal area was decreased and airway wall area was increased. The different pattern of remodeling may reflect fundamental differences in the inflammatory processes in asthma and COPD and could influence the reversibility of the narrowing. It has also been shown that, by quantifying both the extent of emphysema and of airway remodeling, CT is useful in differentiating COPD patients who have primarily parenchymal disease from those who have primarily airway pathology. With additional advances in technology, it is likely that quantitative assessment of airway wall dimensions will ultimately provide a valuable tool for the study of airway disease.

This essay summarizes 16 reports, published since 1956, that describe the effects of hyperoxia on exercise endurance in persons with COPD who have severe airflow obstruction (ie, FEV(1) < 1.0 L or < 39% of predicted) and mild hypoxemia at rest (ie, PaO(2) > 62 mm Hg or arterial oxygen saturation [SaO(2)] measured by pulse oximetry of > 91%). The term hyperoxia is used because, in a proportion of study participants, oxygen administration increased exercise endurance in a dose-dependent fashion, up to a fraction of inspired oxygen of 0.5 or a flow of 100% O(2) of 6 L/min. The process appears to be dependent on an increase in PaO(2) rather than on the restoration of SaO(2) to normal levels. The results of pulmonary function tests were not predictive of response. Increased exercise performance was associated with a decrease in dyspnea, respiratory frequency, and minute ventilation. The slowing of respiratory frequency and the decrease in pulmonary air trapping likely accounted for the decrease in dyspnea. Slowing of the respiratory rate, which occurred at the expense of the retention of CO(2), is most likely due to a hyperoxia-induced decrease in chemoreceptor ventilatory drive from the aortic and carotid bodies. Research is called for to determine the following: (1) the prevalence of COPD patients who have severe airflow limitation accompanied by mild hypoxemia; (2) the proportion of these patients who show improvements in exercise performance during a test of hyperoxic exercise; and (3) whether enhanced exercise performance during a brief test translates into a meaningful increase in the ability to perform the activities of daily living.

Alpha1-antitrypsin (AAT) deficiency is a genetic disease that is widely known in Europe as a disease of white individuals, who, along with their descendants in other parts of the world, are at the highest risk for liver and/or lung disease. There is a limited database of individuals affected by this disease worldwide. It has been estimated, for example, that there are 70,000 to 100,00 individuals affected in the United States, with comparable numbers in Europe.

Stress from many sources, including pain, fever, and hypotension, activates the hypothalamic-pituitary-adrenal (HPA) axis with the sustained secretion of corticotropin and cortisol. Increased glucocorticoid action is an essential component of the stress response, and even minor degrees of adrenal insufficiency can be fatal in the stressed host. HPA dysfunction is a common and underdiagnosed disorder in the critically ill. We review the risk factors, pathophysiology, diagnostic approach, and management of HPA dysfunction in the critically ill.

Lung diffusing capacity (DL) for carbon monoxide (DLCO), nitric oxide (DLNO) or oxygen (DLO2) increases from rest to peak exercise without reaching an upper limit; this recruitment results from interactions among alveolar volume (VA), and cardiac output (q), as well as changing physical properties and spatial distribution of capillary erythrocytes, and is critical for maintaining a normal arterial oxygen saturation. DLCO and DLNO can be used to interpret the effectiveness of diffusive oxygen transport and track structural alterations of the alveolar-capillary barrier, providing sensitive noninvasive indicators of microvascular integrity in health and disease. Clinical interpretation of DL should take into account Q in addition to VA and hemoglobin concentration.

This review discusses real-time pulmonary ultrasonography (US) for the practicing pulmonologist. US supplements chest radiography and chest CT scanning. Major advantages include bedside availability, absence of radiation, and guided aspiration of fluid-filled areas and solid tumors. Pulmonary vessels and vascular supply of consolidations may be visualized without contrast. US may help to diagnose conditions such as pneumothorax, hemothorax, pleural or pericardial effusion, pneumonia, and pulmonary embolism in the critically ill patient who is in need of bedside diagnostic testing. The technique of US, which is cost-effective compared to CT scanning and MRI, may be learned relatively easily by the pulmonologist.

To examine the reports on cardiac Munchausen syndrome for clinical characteristics.

To systematically review the evidence of randomized trials evaluating the effects of residential air filtration systems on patients with asthma.