Cystic fibrosis and normal human airway epithelial cell response to influenza a viral infection.

Viral infections produce severe respiratory morbidity in children with cystic fibrosis (CF). CF cells are more susceptible to virus in part because of impaired airway epithelial activation of signal transducer and activator of transcription 1 (Stat1). As Stat1 is a fundamental regulator of antiviral defenses, we hypothesized that there may be multiple alterations in the antiviral defense of CF epithelium compared with normal (NL). To obtain a comprehensive view of mucosal host responses to influenza and characterize the difference between CF and NL responses to influenza, gene expression profiles of primary human airway epithelial cells (HAEC) were evaluated using an interferon (IFN)-stimulated genes/AU/double-stranded RNA (dsRNA) microarray or quantitative real-time polymerase chain reaction (PCR) following influenza A infection. Gene expression was significantly modified by influenza in NL (228 genes) and CF (101 genes), with a similar pattern of gene response but with overall less numbers of responsive genes in CF (p < 0.05). Moreover, CF cells had less IFN-related antiviral gene induction at 24 h but greater inflammatory cytokine gene induction at 1 h after infection. Taken together, the lesser antiviral and greater early inflammatory response likely contribute to the severe respiratory illness of CF patients with viral infections.

Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I-III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high-level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.

Impaired innate host defense causes susceptibility to respiratory virus infections in cystic fibrosis.

Viral infection is the primary cause of respiratory morbidity in cystic fibrosis (CF) infants. Here, we identify that host factors allow increased virus replication and cytokine production, providing a mechanism for understanding the severity of virus disease in CF. Increased virus is due to lack of nitric oxide synthase 2 (NOS2) and 2', 5' oligoadenylate synthetase (OAS) 1 induction in response to virus or IFNgamma. This can be attributed to impairment of activation of signal transducer and activator of transcription (STAT)1, a fundamental component to antiviral defense. NO donor or NOS2 overexpression provides protection from virus infection in CF, suggesting that NO is sufficient for antiviral host defense in the human airway and is one strategy for antiviral therapy in CF children.