ASL volume and innate defense in CF and COPD Airways

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Mucus plugs form in the airway lumens of CF and COPD patients, raising the likelihood that ion transport[unreadable] and mucin secretion have become uncoupled. We have previously shown that the height (volume) of normal[unreadable] (NL) airway surface liquid (ASL) is regulated, and that dysregulation of CF airway ion transport due to a lack[unreadable] of CFTR causes ASL volume depletion and cessation of mucus transport. This defect is predicted to[unreadable] impair the mucus component of the innate host defense, leading to increased frequency of respiratory[unreadable] infections. The underlying mechanisms of ASL regulation and the relevance to CF and COPD are unknown.[unreadable] Our long term goal is to understand how ASL volume is autoregulated in normal as compared to diseased[unreadable] (CF and COPD) airways under physiological conditions, and in response to acute challenges such as[unreadable] cigarette smoke, inflammation and respiratory viral infections. We have previously observed that extracellular[unreadable] purine nucleoside (adenosine)-dependent pathways for ASL volume autoregulation are present in normal but[unreadable] not CF airways. However, when cultured with a novel system that mimics the shear stresses associated with[unreadable] normal tidal breathing in vivo, CF cultures exhibit ASL volume homeostasis and maintain mucus transport[unreadable] mediated by shear stress-dependent extracellular purine nucleotide (ATP) release. Superimposed on the[unreadable] acute regulation of ASL volume by ATP and ADO are chronic effects of cytokines/inflammatory mediators[unreadable] through regulation of ion channel density and signaling pathways. CF airways are uniquely vulnerable to viral[unreadable] (RSV) infections deplete ASL volume via upregulation of extracellular ATPases causing reduction of ASL[unreadable] ATP levels. Cigarette smoke exposure also inhibits CFTR and ADO-regulated ASL volume regulation. Based[unreadable] on these observations, we propose that an initiating event in the development of COPD and CF is a failure of[unreadable] ion transport to regulate ASL volume, resulting in the accumulation of poorly cleared mucus plaques/plugs[unreadable] on airway surfaces. These plaques/plugs then act as the primary site of pathogen infections, impair[unreadable] macrophage/neutrophil influx and ultimately lead to the airway remodeling that is characteristic of CF airway[unreadable] disease and COPD. Elucidation of the basic mechanisms that account for the major inherited (CF) and[unreadable] acquired (COPD) forms of chronic inflammatory airways disease is vital for the public health of the US[unreadable] population. Such knowledge will likely lead to the development of novel, uniquely effective therapies for[unreadable] these diseases.