Myeloperoxidase (MPO)-derived hypochlorous (HOCl) reacts with membrane plasmalogens to yield α-chlorofatty aldehydes such as 2-chlorofatty aldehyde (2-ClFALD) and its metabolite 2-chlorofatty acid (2-ClFA). Recent studies showed that 2-ClFALD and 2-ClFA serve as mediators of the inflammatory responses to sepsis by as yet unknown mechanisms. Since no scavenger for chlorinated lipids is available and based on the well-established role of the MPO/HOCl/chlorinated lipids axis in inflammatory responses, we hypothesized that treatment with MPO inhibitors (N-acetyl lysyltyrosylcysteine amide or 4-aminobenzoic acid hydrazide) would inhibit inflammation and proinflammatory mediator expression induced by cecal ligation and puncture (CLP). We employed intravital microscopy to quantify in vivo inflammatory responses in Sham and CLP rats with or without MPO inhibition. Small intestines, mesenteries, and lungs were collected to assess changes in MPO positive staining and lung injury, respectively, as well as free 2-ClFA and proinflammatory mediators levels. CLP caused neutrophil infiltration, 2-ClFA generation, acute lung injury, leukocyte-/platelet-endothelium interactions (LPECA), mast cell activation (MCA), plasminogen activator inhibitor-1 (PAI-1) production, and the expression of several cytokines, chemokines, and vascular endothelial growth factor, changes that were reduced by MPO inhibition. Pretreatment with a PAI-1 inhibitor or MC stabilizer prevented CLP-induced LECA and MCA, and abrogated exogenous 2-CLFALD-induced inflammatory responses. Thus, we provide evidence that MPO instigates these inflammatory changes in CLP and that chlorinated lipids may serve as a mechanistic link between the enzymatic activity of MPO and PAI-1- and mast cell-dependent adhesive interactions, providing a rationale for new therapeutic interventions in sepsis.

中文翻译：

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髓过氧化物酶在败血症的盲肠结扎和穿刺大鼠模型中引发促炎反应。

髓过氧化物酶 (MPO) 衍生的次氯酸 (HOCl) 与膜缩醛磷脂反应生成 α-氯代脂肪醛，例如 2-氯代脂肪酸 (2-ClFALD) 及其代谢物 2-氯代脂肪酸 (2-ClFA)。最近的研究表明，2-ClFALD 和 2-ClFA 通过尚不清楚的机制充当脓毒症炎症反应的介质。由于没有氯化脂质的清除剂，并且基于 MPO/HOCl/氯化脂质轴在炎症反应中的公认作用，我们假设用 MPO 抑制剂（N-乙酰基赖氨酰酪氨酰半胱氨酸酰胺或 4-氨基苯甲酰肼）治疗抑制由盲肠结扎和穿刺 (CLP) 诱导的炎症和促炎介质表达。我们采用活体显微镜来量化有或没有 MPO 抑制的假手术和 CLP 大鼠的体内炎症反应。收集小肠、肠系膜和肺以分别评估 MPO 阳性染色和肺损伤的变化，以及游离 2-ClFA 和促炎介质水平。CLP 引起中性粒细胞浸润、2-ClFA 生成、急性肺损伤、白细胞-/血小板-内皮相互作用 (LPECA)、肥大细胞活化 (MCA)、纤溶酶原激活剂抑制剂-1 (PAI-1) 的产生以及多种细胞因子的表达、趋化因子和血管内皮生长因子，这些变化因 MPO 抑制而减少。用 PAI-1 抑制剂或 MC 稳定剂预处理可防止 CLP 诱导的 LECA 和 MCA，并消除外源性 2-CLFALD 诱导的炎症反应。因此，