Novel Synthetic, Host-defense Peptide Protects Against Organ Injury/Dysfunction in a Rat Model of Severe Hemorrhagic Shock
Novel Synthetic, Host-defense Peptide Protects Against Organ Injury/Dysfunction in a Rat Model of Severe Hemorrhagic Shock
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DOI：
10.1097/sla.0000000000002186
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发表时间：
2018-08-01
影响因子：
9
通讯作者：
Thiemermann，Christoph
中科院分区：
文献类型：
--
作者：
Yamada，Noriaki;Martin，Lukas B.;Thiemermann，Christoph
目的：评价创伤和失血性休克（HS）患者体内宿主防御/抗菌肽LL-37的水平以及合成的宿主防御肽Pep 19 -4LF对HS相关的多器官功能衰竭（MOF）的影响。背景：HS是严重创伤患者常见的死亡原因。方法：（1）对47例创伤/HS患者进行LL-37测定。(2)雄性Wistar大鼠进行HS（90分钟，目标平均动脉压：27-32 mm Hg）或假手术。复苏后分别给予Pep 19 -4LF [66（n= 8）或333 μg/kg· h（n= 8）]或溶媒（n= 12）治疗4 h。用Pep 19 -4LF（高剂量）处理的HS大鼠在4小时复苏期结束时具有更高的平均动脉压（79±4 vs 54±5 mm Hg），并且与用媒介物处理的HS大鼠相比具有更少的肾功能不全、肝损伤和肺部炎症。Pep 19 - 4 LF增强（肾/肝）（1）蛋白激酶B和（2）内皮型一氧化氮合酶的磷酸化。Pep 19 - 4 LF可减弱HS诱导的（1）p65从胞浆到细胞核的移位，（2）Ser 176/180上IκB激酶的磷酸化，（3）Ser 32/36上IκBα的磷酸化，从而抑制核因子κ B和促炎细胞因子的形成。Pep 19 -4LF阻止释放肿瘤坏死因子α硫酸乙酰肝素引起的人单核细胞通过结合到这种损伤相关的分子pattern.Conclusions：创伤相关的HS结果释放LL-37。合成的宿主防御/抗微生物肽Pep 19 -4LF减轻与HS相关的器官损伤/功能障碍。
Objective:To evaluate (1) levels of the host-defense/antimicrobial peptide LL-37 in patients with trauma and hemorrhagic shock (HS) and (2) the effects of a synthetic host-defense peptide; Pep19-4LF on multiple organ failure (MOF) associated with HS.Background:HS is a common cause of death in severely injured patients. There is no specific therapy that reduces HS-associated MOF.Methods:(1) LL-37 was measured in 47 trauma/HS patients admitted to an urban major trauma center.(2) Male Wistar rats were submitted to HS (90 min, target mean arterial pressure: 27–32 mm Hg) or sham operation. Rats were treated with Pep19-4LF [66 (n= 8) or 333 μg/kg· h (n= 8)] or vehicle (n= 12) for 4 hours following resuscitation.Results:Plasma LL-37 was 12-fold higher in patients with trauma/HS compared to healthy volunteers. HS rats treated with Pep19-4LF (high dose) had a higher mean arterial pressure at the end of the 4-hour resuscitation period (79±4 vs 54±5 mm Hg) and less renal dysfunction, liver injury, and lung inflammation than HS rats treated with vehicle. Pep19-4LF enhanced (kidney/liver) the phosphorylation of (1) protein kinase B and (2) endothelial nitric oxide synthase. Pep19-4LF attenuated the HS-induced (1) translocation of p65 from cytosol to nucleus,(2) phosphorylation of IκB kinase on Ser 176/180, and (3) phosphorylation of IκBα on Ser 32/36 resulting in inhibition of nuclear factor kappa B and formation of proinflammatory cytokines. Pep19-4LF prevented the release of tumor necrosis factor alpha caused by heparan sulfate in human mononuclear cells by binding to this damage-associated molecular pattern.Conclusions:Trauma-associated HS results in release of LL-37. The synthetic host-defense/antimicrobial peptide Pep19-4LF attenuates the organ injury/dysfunction associated with HS.