Gut Ischemia-Reperfusion Primes the Neutrophil, the Lung, and the Host.
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The gut and the neutrophil have been emphasized to play mechanistic roles in the development of adult respiratory distress syndrome and multiple organ failure (MOF). While a massive single insult (one-hit model) can precipitate early MOF, the more classic presentation is multiple sequential insults (two-hit model) in which the inflammatory system is primed to respond to a secondary activating stimulus. We hypothesized that gut ischemia/reperfusion (I/R) primes the systemic inflammatory cascade and a subsequent activating stimulus results in distant organ injury. Adult male Sprague-Dawley rats underwent 45min of superior mesenteric artery occlusion and ensuing reperfusion (gut I/R) as the first insult. A second insult, low dose endotoxin (2.5mg/kg), was given at 6hr reperfusion and the effects on pulmonary capillary permeability (assessed by 125I-albumin leak) and mortality were determined. Forty-five min of laparotomy (LAP) was the control for gut ischemia while saline injection 6hr later was the control for endotoxin. The animals were allocated into 4 groups: i) LAP+Saline, ii) I/R+Saline, iii) LAP+Endotoxin, and iv) I/R+Endotoxin. Only the combined insult, I/R+Endotoxin, increased 125I-albumin lung leakage at 18hr reperfusion and the mortality rate of this group was 39% which was significantly higher than those of LAP+Saline (0%), I/R+Saline (0%) and LAP+Endotoxin (4%). In the next study, the effects of the priming event (gut I/R; 45min/6hr) on the lung and neutrophils were investigated. Neutrophil depleted animals were obtained by pretreatment with vinblastine (0.75mg/kg, iv, 3 days prior). Lung leakage was again measured by the 125I-albumin leak while pulmonary neutrophil sequestration was quantitated by myeloperoxidase assay. Circulating neutrophil priming was reflected by the difference in superoxide production with and without the activating stimulus, N-formyl-methionyl-leucyl-phenylalanine. We observed that, a) 45min of gut ischemia provoked transient mild lung leakage at 6hr reperfusion which had normalized by 18hr, b) this transient lung leakage was abrogated by neutrophil depletion, c) both gut I/R and sham-laparotomy increased lung neutrophil accumulation, and d) only gut I/R markedly primed circulating neutrophils. These findings indicate that a relatively brief period of gut I/R primes the neutrophil, the lung and the host such that low dose endotoxin exposure activates inflammatory mechanisms, resulting in advanced pulmonary failure and mortality.
- 一般社団法人 日本救急医学会の論文
一般社団法人 日本救急医学会 | 論文
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