Griesbacher T, Rainer I, Tiran B, Peskar B A
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
Br J Pharmacol. 2008 Nov;155(6):865-74. doi: 10.1038/bjp.2008.321. Epub 2008 Aug 11.
Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention of oedema formation by bradykinin B(2) receptor antagonists induces a progression to a haemorrhagic course in this model. We have investigated whether increased kallikrein activity in the pancreas is responsible for vascular damage and whether this could be prevented by selective kallikrein inhibitors.
Caerulein was infused i.v. and vascular damage was assessed by histological evaluation and determination of haemoglobin accumulation in the tissue. In addition, oedema formation, tissue and plasma kallikrein (PK) activities and the endogenous kallikrein inhibitors alpha(1)-antitrypsin (alpha(1)-AT) and alpha(2)-macroglobulin (alpha(2)-M) were measured.
Haemorrhagic lesions induced by icatibant in caerulein-induced pancreatitis were associated with a reduction in alpha(1)-AT and alpha(2)-M in the pancreas and a concomitant augmentation of tissue kallikrein (TK) activity. The TK inhibitor VA999024 (previously FE999024), or its combination with the PK inhibitor VA999026 (previously FE999026), inhibited oedema formation to the same extent but did not induce vascular damage. Furthermore, VA999024 inhibited TK activity. When icatibant was combined with VA999024 and VA999026, progression from oedematous to haemorrhagic pancreatitis was abolished.
Reduced oedema formation by B(2) antagonists prevented influx of endogenous kallikrein inhibitors and led to an excessive activity of kallikrein in the pancreas leading to vascular damage. This can be prevented by a combined inhibition of both tissue-type and plasma-type kallikrein. Kallikrein inhibitors thus should be further evaluated for their therapeutic potential in preventing haemorrhagic lesions in acute pancreatitis.
用蛙皮素进行外分泌过度刺激是水肿性急性胰腺炎的一种成熟模型。在该模型中，缓激肽B(2)受体拮抗剂预防水肿形成会导致病情进展为出血性病程。我们研究了胰腺中激肽释放酶活性增加是否是血管损伤的原因，以及选择性激肽释放酶抑制剂是否可以预防这种情况。
静脉注射蛙皮素，通过组织学评估和测定组织中血红蛋白积累来评估血管损伤。此外，还测量了水肿形成、组织和血浆激肽释放酶（PK）活性以及内源性激肽释放酶抑制剂α(1)-抗胰蛋白酶（α(1)-AT）和α(2)-巨球蛋白（α(2)-M）。
在蛙皮素诱导的胰腺炎中，依替巴肽诱导的出血性病变与胰腺中α(1)-AT和α(2)-M的减少以及组织激肽释放酶（TK）活性的相应增加有关。TK抑制剂VA999024（以前的FE999024）或其与PK抑制剂VA999026（以前的FE999026）的组合，在相同程度上抑制了水肿形成，但未诱导血管损伤。此外，VA999024抑制了TK活性。当依替巴肽与VA999024和VA999026联合使用时，从水肿性胰腺炎到出血性胰腺炎的进展被消除。
B(2)拮抗剂减少水肿形成可防止内源性激肽释放酶抑制剂的流入，并导致胰腺中激肽释放酶活性过高，从而导致血管损伤。这可以通过联合抑制组织型和血浆型激肽释放酶来预防。因此，激肽释放酶抑制剂在预防急性胰腺炎出血性病变方面的治疗潜力应进一步评估。
