Gironella Meritxell, Folch-Puy Emma, LeGoffic Aude, Garcia Stéphane, Christa Laurence, Smith Andrew, Tebar Luis, Hunt Stephen P, Bayne Rosemary, Smith Andrew J H, Dagorn Jean-Charles, Closa Daniel, Iovanna Juan L
INSERM, U.624, Marseille, France.
Gut. 2007 Aug;56(8):1091-7. doi: 10.1136/gut.2006.116087. Epub 2007 Apr 4.
PAP/HIP was first reported as an additional pancreatic secretory protein expressed during the acute phase of pancreatitis. It was shown in vitro to be anti-apoptotic and anti-inflammatory. This study aims to look at whether PAP/HIP plays the same role in vivo.
A model of caerulein-induced pancreatitis was used to compare the outcome of pancreatitis in PAP/HIP(-/-) and wild-type mice.
PAP/HIP(-/-) mice showed the normal phenotype at birth and normal postnatal development. Caerulein-induced pancreatic necrosis was, however, less severe in PAP/HIP(-/-) mice than in wild-type mice, as judged by lower amylasemia and lipasemia levels and smaller areas of necrosis. On the contrary, pancreas from PAP/HIP(-/-) mice was more sensitive to apoptosis, in agreement with the anti-apoptotic effect of PAP/HIP in vitro. Surprisingly, pancreatic inflammation was more extensive in PAP/HIP(-/-) mice, as judged from histological parameters, increased myeloperoxidase activity and increased pro-inflammatory cytokine expression. This result, in apparent contradiction with the limited necrosis observed in these mice, is, however, in agreement with the anti-inflammatory function previously reported in vitro for PAP/HIP. This is supported by the observation that activation of the STAT3/SOCS3 pathway was strongly decreased in the pancreas of PAP/HIP(-/-) mice and by the reversion of the apoptotic and inflammatory phenotypes upon administration of recombinant PAP/HIP to PAP/HIP(-/-) mice.
The anti-apoptotic and anti-inflammatory functions described in vitro for PAP/HIP have physiological relevance in the pancreas in vivo during caerulein-induced pancreatitis.
PAP/HIP最初被报道为胰腺炎急性期表达的一种额外的胰腺分泌蛋白。体外实验表明它具有抗凋亡和抗炎作用。本研究旨在探讨PAP/HIP在体内是否发挥同样的作用。
采用雨蛙素诱导的胰腺炎模型，比较PAP/HIP基因敲除小鼠和野生型小鼠胰腺炎的结局。
PAP/HIP基因敲除小鼠出生时表现出正常的表型，出生后发育也正常。然而，与野生型小鼠相比，雨蛙素诱导的胰腺坏死在PAP/HIP基因敲除小鼠中较轻，这可通过较低的淀粉酶血症和脂肪酶血症水平以及较小的坏死面积来判断。相反，PAP/HIP基因敲除小鼠的胰腺对凋亡更敏感，这与PAP/HIP在体外的抗凋亡作用一致。令人惊讶的是，从组织学参数、髓过氧化物酶活性增加和促炎细胞因子表达增加判断，PAP/HIP基因敲除小鼠的胰腺炎症更广泛。这一结果与在这些小鼠中观察到的有限坏死明显矛盾，但与之前报道的PAP/HIP在体外的抗炎功能一致。PAP/HIP基因敲除小鼠胰腺中STAT3/SOCS3通路的激活强烈降低以及给PAP/HIP基因敲除小鼠注射重组PAP/HIP后凋亡和炎症表型的逆转支持了这一点。
体外描述的PAP/HIP的抗凋亡和抗炎功能在雨蛙素诱导的胰腺炎体内胰腺中具有生理相关性。
