Upregulation of postbacteremic TNF-α and IL-1α gene expression by alveolar hypoxia/reoxygenation in perfused rat lungs

Decreases in the alveolar O-2 tension commonly follow gram-negative bacteremic shock that progresses to the acute respiratory distress syndrome (ARDS). To examine the effects of alveolar hypoxia and reoxygenation (H/R) on postbacteremic pulmonary cytokine expression, lungs from Sprague-Dawley rats (n = 43) were perfused over 180 min after hematogenous infection with 10(9) live Escherichia coli serotype 055:B5 (EC) or infusion of 0.9% NaCl (NS). Compared with normoxic EC and NS controls, EC + H/R and NS + H/R lungs received 90 min of constant-flow hypoxia followed by 60 min of reoxygenation. Perfusates were cultured and analyzed for TNF-alpha, IL-1 alpha, IL-1 beta, and PGE(2) while monitoring pulmonary artery pressure (Ppa). Changes in the filtration coefficient (K-f) were evaluated at 180 min when cytokine mRNA levels were assessed in lung homogenates. Transcripts of the anti-inflammatory cytokine TGF-beta 1 and of inducible cyclooxygenase (COX-2) were similarly analyzed. For equivalent EC clearance, Ppa, and K-f as in normoxic EC, postbacteremic H/R increased TNF-alpha gene expression and doubled the export of TNF-alpha from the lungs, an effect not blocked by allopurinol. IL-1 alpha transcripts were also increased in EC + H/R versus EC lungs, in contrast to the lack of change in IL-1 beta, TGF-beta, or COX-2 mRNA levels, or in cell-associated or circulating IL-1 beta and PGE(2). Thus, gram-negative bacteremic lung infection and secondary alveolar H/R upregulate the expression of specific inflammatory cytokines compared with pulmonary infection under normoxic conditions, independently of xanthine oxidase-induced O-2 radicals. These findings identify the alveolar Po-2 as a potent immunomodulatory signal whose reductions early after gram-negative sepsis may enhance lung inflammation in ARDS.