Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome.
Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome.
复制标题
组织蛋白酶 S 会导致急性呼吸窘迫综合征中的肺部炎症。
DOI：
10.1164/rccm.202107-1631oc
复制
发表时间：
2022
影响因子：
24.7
通讯作者：
McKelvey MC
中科院分区：
文献类型：
--
作者：
McKelvey MC
基本原理：虽然半胱氨酸蛋白酶组织蛋白酶S已被牵连在几个炎性肺病的发病机制，其作用还没有被检查在急性呼吸窘迫综合征的情况下，仍然缺乏具体和有效的药理学treatment.Objectives的条件：描述组织蛋白酶S在急性肺部炎症的状态和检查组织蛋白酶S在疾病pathogenesis.Methods的作用：人和小鼠模型BAL液样本中的组织蛋白酶S及其内源性抑制剂的存在和活性进行了分析。将重组组织蛋白酶S直接滴注到小鼠的肺中。在两种急性肺损伤模型中检查了组织蛋白酶S敲除和药理学抑制的作用。蛋白酶激活受体-1拮抗作用被用来测试组织蛋白酶S介导的inflammation. Measures和主要结果：肺组织蛋白酶S浓度和活性升高，在急性呼吸窘迫综合征，表型可能加剧了内源性抗蛋白酶胱抑素SN的损失。直接将组织蛋白酶S滴入肺中可诱导急性呼吸窘迫综合征的关键病理，包括嗜中性粒细胞增多和肺泡渗漏。相反，在急性肺损伤的鼠模型中，基因敲除和组织蛋白酶S的预防性或治疗性抑制减少了中性粒细胞募集和蛋白质渗漏。组织蛋白酶S可能部分介导其致病作用，通过蛋白酶激活受体-1，因为拮抗这种受体废除组织蛋白酶S诱导的气道inflammation.Conclusions：组织蛋白酶S有助于急性肺损伤，并可能代表一个新的治疗急性呼吸窘迫综合征的靶点。
Rationale:Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments.Objectives:To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis.Methods:Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors. Recombinant cathepsin S was instilled directly into the lungs of mice. The effects of cathepsin S knockout and pharmacological inhibition were examined in two models of acute lung injury. Protease-activated receptor-1 antagonism was used to test a possible mechanism for cathepsin S–mediated inflammation.Measurements and Main Results:Pulmonary cathepsin S concentrations and activity were elevated in acute respiratory distress syndrome, a phenotype possibly exacerbated by the loss of the endogenous antiprotease cystatin SN. Direct cathepsin S instillation into the lungs induced key pathologies of acute respiratory distress syndrome, including neutrophilia and alveolar leakage. Conversely, in murine models of acute lung injury, genetic knockdown and prophylactic or therapeutic inhibition of cathepsin S reduced neutrophil recruitment and protein leakage. Cathepsin S may partly mediate its pathogenic effects via protease-activated receptor-1, because antagonism of this receptor abrogated cathepsin S–induced airway inflammation.Conclusions:Cathepsin S contributes to acute lung injury and may represent a novel therapeutic target for acute respiratory distress syndrome.