Wenceslau Camilla Ferreira, McCarthy Cameron G, Szasz Theodora, Goulopoulou Styliani, Webb R Clinton
Department of Physiology, Georgia Regents University, Augusta, Georgia
Department of Physiology, Georgia Regents University, Augusta, Georgia.
Am J Physiol Heart Circ Physiol. 2015 Apr 1;308(7):H768-77. doi: 10.1152/ajpheart.00779.2014. Epub 2015 Jan 30.
Fifty percent of trauma patients who present sepsis-like syndrome do not have bacterial infections. This condition is known as systemic inflammatory response syndrome (SIRS). A unifying factor of SIRS and sepsis is cardiovascular collapse. Trauma and severe blood loss cause the release of endogenous molecules known as damage-associated molecular patterns. Mitochondrial N-formyl peptides (F-MIT) are damage-associated molecular patterns that share similarities with bacterial N-formylated peptides and are potent immune system activators. The goal of this study was to investigate whether F-MIT trigger SIRS, including hypotension and vascular collapse via formyl peptide receptor (FPR) activation. We evaluated cardiovascular parameters in Wistar rats treated with FPR or histamine receptor antagonists and inhibitors of the nitric oxide pathway before and after F-MIT infusion. F-MIT, but not nonformylated peptides or mitochondrial DNA, induced severe hypotension via FPR activation and nitric oxide and histamine release. Moreover, F-MIT infusion induced hyperthermia, blood clotting, and increased vascular permeability. To evaluate the role of leukocytes in F-MIT-induced hypotension, neutrophil, basophil, or mast cells were depleted. Depletion of basophils, but not neutrophils or mast cells, abolished F-MIT-induced hypotension. Rats that underwent hemorrhagic shock increased plasma levels of mitochondrial formylated proteins associated with lung damage and antagonism of FPR ameliorated hemorrhagic shock-induced lung injury. Finally, F-MIT induced vasodilatation in isolated resistance arteries via FPR activation; however, F-MIT impaired endothelium-dependent relaxation in the presence of blood. These data suggest that F-MIT may be the link among trauma, SIRS, and cardiovascular collapse.
出现类似脓毒症综合征的创伤患者中有50%并无细菌感染。这种情况被称为全身炎症反应综合征（SIRS）。SIRS和脓毒症的一个共同因素是心血管衰竭。创伤和严重失血会导致称为损伤相关分子模式的内源性分子释放。线粒体N-甲酰肽（F-MIT）是与细菌N-甲酰化肽有相似之处的损伤相关分子模式，是强大的免疫系统激活剂。本研究的目的是调查F-MIT是否通过甲酰肽受体（FPR）激活引发SIRS，包括低血压和血管衰竭。我们在输注F-MIT前后，评估了用FPR或组胺受体拮抗剂以及一氧化氮途径抑制剂处理的Wistar大鼠的心血管参数。F-MIT而非非甲酰化肽或线粒体DNA通过FPR激活以及一氧化氮和组胺释放诱导严重低血压。此外，输注F-MIT会引起体温过高、血液凝固，并增加血管通透性。为了评估白细胞在F-MIT诱导的低血压中的作用，使中性粒细胞、嗜碱性粒细胞或肥大细胞减少。嗜碱性粒细胞减少而非中性粒细胞或肥大细胞减少消除了F-MIT诱导的低血压。经历失血性休克的大鼠血浆中与肺损伤相关的线粒体甲酰化蛋白水平升高，FPR拮抗作用改善了失血性休克诱导的肺损伤。最后，F-MIT通过FPR激活在离体阻力动脉中诱导血管舒张；然而，在有血液存在的情况下，F-MIT损害内皮依赖性舒张。这些数据表明，F-MIT可能是创伤、SIRS和心血管衰竭之间的联系。
