title: Nonischemic lung injury by mediators from unilateral ischemic reperfused lung: ameliorating effect of tumor necrosis factor-alpha-converting enzyme inhibitor.
abstract: We hypothesized that the ischemic reperfused (I/R) lung expresses and liberates tumor necrosis factor-alpha (TNF-alpha) to injure the nonischemic lung, and that a TNF-alpha-converting enzyme inhibitor (TACEI) prevents injury of the nonischemic lung by blocking TNF-alpha liberation from the I/R lung. In isolated ventilated rat lungs in which differential perfusion to the right (RL) or left (LL) lung was feasible, LLs were selectively made ischemic (60 min) while maintaining perfusion to RLs, then reperfused (30 min) in a nonrecirculating manner with buffer solution (non-R; n = 18) or in a recirculating manner with buffer containing TACEI (TACEI[+]; n = 18) or without TACEI (TACEI[-]; n = 18). Ischemia reperfusion induced TNF-alpha messenger RNA expression in the ischemic LLs; the expression was highest in TACEI(+) group (P < 0.01). The expression of TNF-alpha, which was detected as immunofluorescence signals on CD34-positive endothelial cells, was observed in ischemic LLs; the highest expression being that in the TACEI(+) group. Wet/dry ratio and protein content in bronchoalveolar lavage fluid were higher in LLs than in RLs, and among the RLs, these 2 parameters were significantly increased in the TACEI(-) group (P < 0.01) in which the RLs were exposed to the TNF-alpha-rich perfusate. On the other hand, protein content in bronchoalveolar lavage fluid of the TACEI(+) group in which RLs were exposed to recirculating perfusate containing little TNF-alpha was decreased to a level close to but still higher than that in the non-R group (P < 0.05). The unilateral I/R lung affected the permeability of the nonischemic lung by liberating mainly TNF-alpha and induced TNF-alpha, interleukin (IL)-1beta, IL-6, and IL-10 messenger RNA expression in the nonischemic lung. These findings support the idea of organ-organ interaction in which an injured organ affects a remote organ by liberating humoral mediators.
authors.affiliation: Department of Critical Care Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Gabriela S
authors.initials: GS
authors.lastname: Georgieva
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kurata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikeda
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.forename: Chieko
authors.initials: C
authors.lastname: Mitaka
authors.forename: Takasuke
authors.initials: T
authors.lastname: Imai
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein