American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · May 2009
ReviewRecent advances in genetic predisposition to clinical acute lung injury.
It has been well established that acute lung injury (ALI), and the more severe presentation of acute respiratory distress syndrome (ARDS), constitute complex traits characterized by a multigenic and multifactorial etiology. Identification and validation of genetic variants contributing to disease susceptibility and severity has been hampered by the profound heterogeneity of the clinical phenotype and the role of environmental factors, which includes treatment, on outcome. ⋯ Identification of novel candidate genes for which genetic association studies have confirmed a role in disease has been greatly aided by the powerful tool of high-throughput expression profiling. This article will review these studies to date, summarizing candidate genes associated with ALI and ARDS, acknowledging those that have been replicated in independent populations, with a special focus on the specific pathways for which candidate genes identified so far can be clustered.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Aug 2008
ReviewThe porcine lung as a potential model for cystic fibrosis.
Airway disease currently causes most of the morbidity and mortality in patients with cystic fibrosis (CF). However, understanding the pathogenesis of CF lung disease and developing novel therapeutic strategies have been hampered by the limitations of current models. ⋯ Thus pigs with a targeted CFTR gene might provide a good model for CF. Here, we review aspects of porcine airways and lung that are relevant to CF.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Apr 2008
ReviewMechanisms of cigarette smoke-induced COPD: insights from animal models.
Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. ⋯ Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Dec 2006
ReviewExtravascular lung water measurements and hemodynamic monitoring in the critically ill: bedside alternatives to the pulmonary artery catheter.
The recently completed Fluid and Catheter Treatment Trial conducted by the National Institutes of Health ARDSNetwork casts doubt on the value of routine pulmonary artery catheterization for hemodynamic management of the critically ill. Several alternatives are available, and, in this review, we evaluate the theoretical, validation, and empirical databases for two of these: transpulmonary thermodilution measurements (yielding estimates of cardiac output, intrathoracic blood volume, and extravascular lung water) that do not require a pulmonary artery catheter, and hemodynamic measurements (including estimates of cardiac output and ejection time, a variable sensitive to intravascular volume) obtained by esophageal Doppler analysis of blood flow through the descending aorta. We conclude that both deserve serious consideration as a means of acquiring useful hemodynamic data for managing shock and fluid resuscitation in the critically ill, especially in those with acute lung injury and pulmonary edema, but that additional study, including carefully performed, prospective clinical trials demonstrating outcome benefit, is needed.
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The mechanisms of pulmonary edema resolution are different from those regulating edema formation. Absorption of excess alveolar fluid is an active process that involves vectorial transport of Na+ out of alveolar air spaces with water following the Na+ osmotic gradient. ⋯ During lung injury, mechanisms regulating alveolar fluid reabsorption are inhibited by yet unclear pathways and can be upregulated by pharmacological means. Better understanding of the mechanisms that regulate edema clearance may lead to therapeutic interventions to improve the ability of lungs to clear fluid, which is of clinical significance.