Leonard W. Velsor

Role for cystic fibrosis transmembrane conductance regulator protein in a glutathione response to bronchopulmonary pseudomonas infection.

ABSTRACT The lung maintains an elevated level of glutathione (GSH) in epithelial lining fluid (ELF) compared to serum. The mechanism(s) by which the lung maintains high levels of ELF GSH and factors that modulate them are largely unexplored. We hypothesized that lung cystic fibrosis transmembrane conductance regulator protein (CFTR) modulates GSH efflux in response to extracellular stress, which occurs with lung infections. Mice were challenged intratracheally with Pseudomonas aeruginosa, and on the third day of infection bronchoalveolar lavage fluid was obtained and analyzed for cytokines and antioxidants. Lung tissue antioxidants and enzyme activities were also assessed. P. aeruginosa lung infection increased levels of inflammatory cytokines and neutrophils in the ELF. This corresponded with a marked threefold increase in GSH and a twofold increase in urate levels in the ELF of P. aeruginosa-infected wild-type mice. A twofold increase in urate levels was also observed among lung tissue antioxidants of P. aeruginosa-infected wild-type mice. There were no changes in markers of lung oxidative stress associated with the P. aeruginosa lung infection. In contrast with wild-type mice, the CFTR knockout mice lacked a significant increase in ELF GSH when challenged with P. aeruginosa, and this correlated with a decrease in the ratio of reduced to oxidized GSH in the ELF, a marker of oxidative stress. These data would suggest that the lung adapts to infectious agents with elevated ELF GSH and urate. Individuals with lung diseases associated with altered antioxidant transport, such as cystic fibrosis, might lack the ability to adapt to the infection and present with a more severe inflammatory response.

Pulmonary edema fluid antioxidants are depressed in acute lung injury.

ObjectiveTo test the hypothesis that low concentrations of distal airspace water-soluble antioxidants are associated with acute lung injury. DesignProspective, cohort study. SettingMedical intensive care unit of two tertiary care hospitals. SubjectsSubjects were 29 patients with acute lung injury and 23 normal, healthy, volunteers. InterventionsNone. Measurements and Main ResultsPulmonary edema fluid from subjects with acute lung injury was aspirated immediately after intubation. Compared with the bronchoalveolar lavage from normal subjects (corrected for dilution using urea concentrations), undiluted edema fluid from acute lung injury subjects had significantly lower concentrations of the antioxidants urate (757 ± 232 &mgr;M vs. 328 ± 75 &mgr;M), glutathione (138 ± 25 &mgr;M vs. 7 ± 4 &mgr;M), and ascorbate (85 ± 21 &mgr;M vs. 27 ± 10 &mgr;M). ConclusionsAcute lung injury is associated with decreased concentrations of water-soluble antioxidants in the distal airspaces. In acute lung injury, the distal airspace antioxidants ascorbate, urate, and glutathione may play a role in attenuating lung injury.