Am. J. Respir. Crit. Care Med., Volume 157, Number 2, February 1998, 629-637

Upregulation of Postbacteremic TNF- and IL-1 Gene Expression by Alveolar Hypoxia/Reoxygenation in Perfused Rat Lungs

GEORGE M. MATUSCHAK, CESAR F. MUNOZ, CHERYL A. JOHANNS, RASHID RAHMAN, and ANDREW J. LECHNER

Division of Pulmonology, Department of Internal Medicine, Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine; and Department of Critical Care Medicine, Saint John's Mercy Medical Center, Saint Louis, Missouri

Decreases in the alveolar O₂ 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 10⁹ live Escherichia coli serotype O55: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-, IL-1, IL-1, and PGE₂ 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-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- gene expression and doubled the export of TNF- from the lungs, an effect not blocked by allopurinol. IL-1 transcripts were also increased in EC + H/R versus EC lungs, in contrast to the lack of change in IL-1, TGF-, or COX-2 mRNA levels, or in cell-associated or circulating IL-1 and PGE₂. 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 O₂ radicals. These findings identify the alveolar PO₂ as a potent immunomodulatory signal whose reductions early after gram-negative sepsis may enhance lung inflammation in ARDS.

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