Proceedings of the American Thoracic Society
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Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are a frequent cause of intensive care unit admission, affecting over 200,000 patients in the United States each year. Mechanical ventilation is a life-saving intervention in the setting of ARDS and ALI, but clinical trials have demonstrated that mechanical ventilation with excessive tidal volumes plays a role in promoting and perpetuating lung injury and leads to excess mortality. This process has been labeled ventilator-induced lung injury (VILI), but the molecular mechanisms driving this process and its interactions with predisposing risk factors such as sepsis and chemical injury remain incompletely understood. ⋯ Several recent studies have used this approach to study VILI in isolation and associated with endotoxin instillation or saline lavage. These studies and others examining gene expression profiles in epithelial cells subjected to cyclic stretch have provided novel insights on the molecular mechanisms underlying VILI. This review will summarize these findings and discuss implications for future studies.
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Chronic obstructive pulmonary disease with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, because only a proportion ( approximately 15%) of smokers develop chronic obstructive pulmonary disease with emphysema, clearly genetic susceptibility must play a significant part in determining both the age of onset and the rapidity of decline in lung function. In mice, interference with key genes, either by null mutation, hypomorphism, or gain or loss of function, results in phenotypes comprising either neonatal lethal respiratory distress if the structural effect is severe, or reduced alveolarization and/or early-onset emphysema if the effect is milder. ⋯ Interestingly, polymorphisms in the fibrillin, transforming growth factor-beta type II receptor, and matrix metalloproteinase-9 genes have been described in humans with emphysema. Thus, dysplastic or degraded matrix cannot provide the structural niche for alveolar stem/progenitor cells to assume the correct phenotype and/or repair the alveolar cell lineage niche. The hope is that providing the correct exogenous signals can coax them into doing so.
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Cardiopulmonary function in patients with chronic thromboembolic pulmonary hypertension can almost be normalized by pulmonary endarterectomy. The procedure involves the removal of organized and incorporated fibrous obstructive tissue from the pulmonary arteries during circulatory arrest under deep hypothermia. Mortality rates reported for patients who have undergone pulmonary endarterectomy range from 4 to 24%. ⋯ Important complications are persistent pulmonary arterial hypertension due to inadequate endarterectomy or significant secondary vasculopathy, and reperfusion edema in the endarterectomized parts of the lung. Adequate postoperative care is therefore essential. Preoperative hemodynamic severity and the site of anatomic obstruction are believed to be key predictors of postoperative outcome.
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Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of "classical" asthma. However, the relationship between chronic obstructive pulmonary disease (COPD) and asthma is controversial and the variety of mechanisms that can mediate the alveolar destruction in emphysema have not been adequately defined. To address these issues, we used overexpression transgenic approaches to define the effects of Th1/Tc1 and Th2/Tc2 cytokines in the mature murine lung and compared findings in these transgenic systems to the effects of similar interventions after cigarette smoke (CS) exposure. ⋯ Interestingly, abnormalities in vascular endothelial growth factor (VEGF) were also appreciated with VEGF(165) excess producing an asthmalike pulmonary response and IFN-gamma abrogating this response while inducing emphysematous alveolar destruction. These findings provide molecular support for both points of view in the British/Dutch hypothesis controversy regarding the relationship between asthma and COPD. They also highlight the complexity of the pathways that can induce alveolar destruction and suggest that there is a continuum, based on VEGF, between asthma and COPD.