Rationale Acute respiratory distress syndrome (ARDS) is a lethal complication of severe bacterial pneumonia due to the inability to dampen overexuberant immune responses without compromising pathogen clearance. Both of these processes involve tissue-resident and bone marrow (BM)–recruited macrophage (MΦ) populations which can be polarised to have divergent functions. Surprisingly, despite the known immunomodulatory properties of mesenchymal stem cells (MSCs), simultaneous interactions with tissue-resident and recruited BMMΦ populations are largely unexplored. Objectives We assessed the therapeutic use of human placental MSCs (PMSCs) in severe bacterial pneumonia with elucidation of the roles of resident alveolar MΦs (AMΦs) and BMMΦs. Methods We developed a lethal, murine pneumonia model using intratracheal infection of a clinically relevant Klebsiella pneumoniae (KP) strain with subsequent intravenous human PMSC treatment. Pulmonary AMΦ and recruited BMMΦ analyses, histological evaluation, bacterial clearance and mice survival were assessed. To elucidate the role of resident AMΦs in improving outcome, we performed AMΦ depletion in the KP - pneumonia model with intratracheal clodronate pretreatment. Measurements and main results Human PMSC treatment decreased tissue injury and improved survival of severe KP - pneumonia mice by decreasing the presence and function of recruited M1 BMMΦ while preserving M2 AMΦs and enhancing their antibacterial functions. Interestingly, PMSC therapy failed to rescue AMΦ-depleted mice with KP pneumonia, and PMSC-secreted IL-1β was identified as critical in increasing AMΦ antibacterial activities to significantly improve pathogen clearance—especially bacteraemia—and survival. Conclusions Human PMSC treatment preferentially rescued resident M2 AMΦs over recruited M1 BMMΦs with overall M2 polarisation to improve KP-related ARDS survival. Data are available upon reasonable request.

中文翻译：

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在克雷伯氏菌介导的急性呼吸窘迫综合征中，胎盘间充质干细胞通过 IL-1β 促进 M2 肺泡超过 M1 骨髓巨噬细胞

基本原理 急性呼吸窘迫综合征 (ARDS) 是严重细菌性肺炎的致命并发症，因为它无法在不影响病原体清除的情况下抑制过度旺盛的免疫反应。这两个过程都涉及组织驻留和骨髓 (BM) 募集的巨噬细胞 (MΦ) 群体，它们可以被极化以具有不同的功能。令人惊讶的是，尽管间充质干细胞 (MSC) 具有已知的免疫调节特性，但与组织驻留和募集的 BMMΦ 群体的同时相互作用在很大程度上尚未得到探索。目的 我们评估了人胎盘间充质干细胞 (PMSCs) 在严重细菌性肺炎中的治疗用途，并阐明了常驻肺泡 MΦs (AMΦs) 和 BMMΦs 的作用。方法 我们开发了一种致命的、使用气管内感染临床相关的肺炎克雷伯菌 (KP) 菌株并随后进行静脉内人 PMSC 治疗的小鼠肺炎模型。评估了肺 AMΦ 和募集的 BMMΦ 分析、组织学评估、细菌清除率和小鼠存活率。为了阐明常驻 AMΦ 在改善结果中的作用，我们在 KP - 肺炎模型中进行了 AMΦ 耗竭，并进行了气管内氯膦酸盐预处理。测量和主要结果 人类 PMSC 治疗通过减少募集的 M1 BMMΦ 的存在和功能，同时保留 M2 AMΦ 并增强其抗菌功能，减少组织损伤并提高严重 KP - 肺炎小鼠的存活率。有趣的是，PMSC 疗法未能挽救患有 KP 肺炎的 AMΦ 耗尽小鼠，PMSC 分泌的 IL-1β 被确定为增加 AMΦ 抗菌活性以显着改善病原体清除率（尤其是菌血症）和存活率的关键。结论 人类 PMSC 治疗优先拯救驻留的 M2 AMΦs，而不是招募的具有整体 M2 极化的 M1 BMMΦs，以改善 KP 相关的 ARDS 存活率。可根据合理要求提供数据。