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"Cystic Fibrosis is a disease caused by genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel resulting in dysfunctional chloride ion transport. Clinical manifestations of the disease include pancreatic fibrosis, malnutrition, and most importantly, failure of the mucociliary clearance. Drug intervention have significantly improved the quality and prognosis for CF patients. However, disease severity remains quite variable from patient-to-patient. For instance, exposures to air pollutants, such as cigarette smoke, can significantly affect the outcome of CF patients. Although epidemiological and clinical studies have shown adverse effects of second-hand smoke exposure on CFTR function, the molecular mechanism by which smoke exposure alters CFTR activity remains obscure. In this study, we investigate passive smoke effects on WT-CFTR and corrected F508del-CFTR. Consistent with previous reports, exposure to 30% CSE for 1 h suppressed the subsequent stimulation of short circuit current (Isc) by forskolin, resulting in a decrease in CFTR function. Notably, corrected F508del-CFTR was found to be more sensitive to smoke than WT-CFTR. In addition to inhibiting the forskolin response, CSE exposure also caused a large, transient increase in basal Isc which was absent when cells were pretreated with CFTRinh-172 and when CFBE cells expressing F508del CFTR were exposed to CSE. This transient stimulation was blocked by H89 (a PKA inhibitor) and NS398 (a cAMP inhibitor), suggesting that this activation was cAMP-dependent protein kinase activation. Hydrogen peroxide has been shown previously to stimulate CFTR function, primarily through the autocrine signaling pathway prostaglandin E2 binding primarily to the prostaglandin type E4 receptor to initiate the activation of CFTR. Since cigarette smoke contains oxidants, we first explored the role of reactive oxygen species by pre-treating cells with N-acetylcysteine (NAC). The stimulation by CSE was strongly attenuated after 10mM NAC, consistent with the involvement of reactive oxygen species. Next, we assessed the role of prostaglandin E2 by pre-treating cells with potent antagonist of the EP4 receptor, GW-627368. The tobacco smoke-induced increase in CFTR-mediated chloride secretion was significantly reduced in the presence of the EP4 receptor antagonist. The acute secretory response to CSE may be a host defense mechanism that clears noxious stimuli from the epithelial surface, which is seemingly lost in CF patients with the DelF508-CFTR mutation."--