Intestinal Failure (New York, N.Y.) · 2025
Alpha1-antitrypsin protects the intestine from ischemia-reperfusion injury in a rat intestinal clamping model.
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Dubois Antoine, Clarysse Mathias, Farré Ricard, Wylin Tine, Heetfeld Veerle, Canovai Emilio, Vanuytsel Tim, Hertogh Gert De, Pirenne Jacques, Ceulemans Laurens J
Аннотация
BACKGROUND: Ischemia-reperfusion injury (IRI) remains a significant hurdle when blood flow is restored to ischemic tissue. Alpha1-antitrypsin (AAT), a serine protease inhibitor, has demonstrated strong anti-inflammatory properties, including inhibition of neutrophil recruitment and activation. In this study we aim to investigate its potential to mitigate intestinal IRI (IIRI).
MATERIAL AND METHODS: The experimental protocol included two phases, performed in male Sprague-Dawley rats (250-350 g). Intravenous treatment was administered 10 min before ischemia induced by 60 min of superior mesenteric artery clamping. In the first phase, groups (N = 7/group) were: sham (PBS), AAT/60 (AAT60mg/kg+IRI), and AAT/100 (AAT100mg/kg+IRI), with 7-day survival as primary endpoint. Selecting AAT dose based on Phase 1 results, Phase 2 included three groups (N = 6/group): sham (PBS), control (PBS+IRI), and AAT (AAT+IRI). Reperfusion lasted 60 min, followed by animals sacrifice for sampling. Endpoints were transepithelial electrical resistance (TEER, villus length-adjusted), histological injury (Park-Chiu score), neutrophil infiltration (MPO immunohistochemistry), ileal cytokine levels (IL-6,IL-10,IL-1β,TNFα), and arterial blood analysis (blood gas, endotoxin, IL-6).
RESULTS: In phase 1, AAT/60 vs control 7-day survival was 100 % vs 14 % (p = 0.001)(AAT/100: 86 %), selecting AAT/60 for Phase 2. For AAT/60 vs control, mean(SD) TEER values were 18.87(8.36) vs 12.00(3.43)Ω·cm² (p = 0.991). Park-Chiu scores were 2(1) vs 4(1)(p = 0.029), with neutrophil infiltration of 0.61(0.14)% vs 1.28(0.64)% (p = 0.028). Lactate acidosis was reduced (lactate: 2.02(0.72) vs 4.00(0.70)mmol/L, p < 0.001; pH: 7.36(0.04) vs 7.28(0.02), p = 0.004), whereas arterial endotoxin levels, arterial IL-6 levels, and ileal cytokine expression were similar.
CONCLUSION: By modulating neutrophil activity, AAT appears to reduce IIRI local/systemic effects, leading to improved 7-day survival.
MATERIAL AND METHODS: The experimental protocol included two phases, performed in male Sprague-Dawley rats (250-350 g). Intravenous treatment was administered 10 min before ischemia induced by 60 min of superior mesenteric artery clamping. In the first phase, groups (N = 7/group) were: sham (PBS), AAT/60 (AAT60mg/kg+IRI), and AAT/100 (AAT100mg/kg+IRI), with 7-day survival as primary endpoint. Selecting AAT dose based on Phase 1 results, Phase 2 included three groups (N = 6/group): sham (PBS), control (PBS+IRI), and AAT (AAT+IRI). Reperfusion lasted 60 min, followed by animals sacrifice for sampling. Endpoints were transepithelial electrical resistance (TEER, villus length-adjusted), histological injury (Park-Chiu score), neutrophil infiltration (MPO immunohistochemistry), ileal cytokine levels (IL-6,IL-10,IL-1β,TNFα), and arterial blood analysis (blood gas, endotoxin, IL-6).
RESULTS: In phase 1, AAT/60 vs control 7-day survival was 100 % vs 14 % (p = 0.001)(AAT/100: 86 %), selecting AAT/60 for Phase 2. For AAT/60 vs control, mean(SD) TEER values were 18.87(8.36) vs 12.00(3.43)Ω·cm² (p = 0.991). Park-Chiu scores were 2(1) vs 4(1)(p = 0.029), with neutrophil infiltration of 0.61(0.14)% vs 1.28(0.64)% (p = 0.028). Lactate acidosis was reduced (lactate: 2.02(0.72) vs 4.00(0.70)mmol/L, p < 0.001; pH: 7.36(0.04) vs 7.28(0.02), p = 0.004), whereas arterial endotoxin levels, arterial IL-6 levels, and ileal cytokine expression were similar.
CONCLUSION: By modulating neutrophil activity, AAT appears to reduce IIRI local/systemic effects, leading to improved 7-day survival.