[Abstract]
Background: Pseudomonas aeruginosa (PA) is one of the most common Gram-negative bacteria causing hospital-acquired pulmonary infection, with high drug resistance and mortality. Therefore, it is urgent to introduce new non-antibiotic treatment strategies. Mesenchymal stem cells (MSCs), as important members of the stem cell family, were demonstrated to alleviate pathological damage in acute lung injury. However, the potential mechanism how MSC alleviate acute lung infection caused by PA remains unclear.
Objective: The purpose of this study was to investigate the effects of Adipose-derived mesenchymal stem cells (ASCs) on acute pulmonary infections and the possible mechanisms how ASCs reduce pulmonary inflammation induced by PA.
Methods: The therapeutic and mechanistic effects of ASCs on PA pulmonary infection were evaluated respectively in a murine model as well as in an in vitro model stimulated by PA and co-cultured with ASCs.
Results: 1. ASCs treatment significantly reduced the bacterial load, inflammation of lung tissue and histopathological damage by PA. 2. PA infection mainly activated Nod-like receptor containing a caspase activating and recruitment domain 4 (NLRC4) inflammasome in the lung of mice. ASCs attenuated acute lung infection in mice by inhibiting NLRC4 inflammasome activation. 3. NLRC4-/- mice showed a significant improvement in survival rate and lung bacterial load after PA infection. 4. ASCs mainly increased expression and secretion of STC-1 in response to PA-stimulated NLRC4 inflammasome activation.
Conclusions: PA infection attenuated macrophage phagocytosis through activation of NLRC4 inflammasome in macrophages, which eventually led to pulmonary inflammatory damage in mouse; ASCs reduced the activation of NLRC4 inflammasome in macrophages induced by PA infection, thereby increasing the phagocytic ability of macrophages, and ultimately improving lung tissue damage in mouse; ASCs may inhibit NLRC4 inflammasome through the secretion of STC-1.
【中文摘要】
背景：銅綠假單胞菌（PA）是引起醫院獲得性肺部感染最常見的革蘭氏陰性細菌之一，具有較高的耐藥性和死亡率。因此，迫切需要引入新的非抗生素治療策略。間充質幹細胞（MSCs）作為幹細胞家族的重要成員，可減輕急性肺部損傷。然而MSCs如何減輕PA所致急性肺部感染的潛在機制仍不清楚。
目的：本研究旨在探討脂肪來源的間充質幹細胞（ASCs）減輕PA所致急性肺部感染的作用及其可能的內在機制。
方法：分別通過動物模型以及由PA刺激並與ASCs共培養的體外模型評估ASCs對PA所致急性肺部感染的治療作用及機制。
結果：1. ASCs治療可顯著降低PA感染的肺組織細菌負荷及炎症水平，改善組織病理損傷。2. PA感染可激活小鼠肺組織巨噬細胞中的NLRC4炎症小體，ASCs通過抑制NLRC4炎症小體激活從而減輕小鼠急性肺損傷。3. NLRC4-/-小鼠在PA感染後的存活率和肺細菌負荷得到明顯改善。4. ASCs可能通過旁分泌STC-1抑制PA誘導的NLRC4炎症小體激活。
結論：PA通過激活巨噬細胞NLRC4炎症小體，降低巨噬細胞吞噬能力，從而導致小鼠肺組織炎症損傷。ASCs可抑制PA感染引起的巨噬細胞NLRC4炎症小體激活，改善巨噬細胞吞噬能力，從而減輕小鼠肺組織炎症損傷，這一機制可能與ASCs旁分泌STC-1有關聯。