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

• Published in: American journal of respiratory and critical care medicine 1998-02, Vol.157 (2), p.629-637
• Main Authors: MATUSCHAK, G. M, MUNOZ, C. F, JOHANNS, C. A, RAHMAN, R, LECHNER, A. J
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Emergency and intensive care: infection, septic shock; Intensive care medicine; Medical sciences
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.157.2.9707120

Decreases in the alveolar O sub(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 super(9) 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- alpha , IL-1 alpha , IL-1 beta , and PGE sub(2) while monitoring pulmonary artery pressure (Ppa). Changes in the filtration coefficient (K sub(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 sub(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 sub(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 sub(2) radicals. These findings identify the alveolar Po sub(2) as a potent immunomodulatory signal whose reductions early after gram-negative sepsis may enhance lung inflammation in ARDS.