Mösenlechner Martin, Schlösser Daniela, Braumüller Sonja, Dörfer Lena, Mannes Marco, Kawach Rawan, Strauss Gudrun, Schmidt Christoph Q, Lupu Ludmila, Huber-Lang Markus S
Institute of Clinical and Experimental Trauma-Immunology, University Medical Center Ulm, Ulm, Germany.
Boehringer Ingelheim, Biberach an der Riß, Germany.
Shock. 2025 Mar 1;63(3):448-455. doi: 10.1097/SHK.0000000000002512. Epub 2024 Dec 4.
Background: Sepsis continues to pose a significant threat to human life and represents a substantial financial burden. In addition to replicative stress resulting from telomeric loss, recent studies have identified multiple factors contributing to cell cycle arrest. Furthermore, our understanding of pathways associated with cellular senescence, such as CD47-mediated suppression of efferocytosis, has expanded. However, beyond in vitro experiments, the impact of cell stress during complex systemic illnesses, including sepsis, remains poorly understood. Consequently, we conducted an investigation into molecular alterations related to senescence-associated pulmonary mechanisms during experimental nonpulmonary sepsis. Methods: Male C57BL/6JRj mice were anesthetized and subjected to either control conditions (sham) or cecal ligation and puncture (CLP) to induce sepsis. Twenty-four hours or 7 d after CLP, animals were killed, and blood, bronchoalveolar fluids, and lungs were harvested and analyzed for morphological and biochemical changes. Results: Histological damage in pulmonary tissue, as well as increases in plasma levels of surfactant protein D, indicated development of alveolar-focused acute lung injury after CLP. Additionally, we observed a significant upregulation of the CD47-QPCTL-SHP-1 axis in lungs of septic mice. Whereas the expression of p16, a marker primarily indicating manifested forms of senescence, was decreased after CLP, the early marker of cellular senescence, p21, was increased in the lungs during sepsis. Later, at 7 d after CLP, pulmonary expression of CD47 and QPCTL-1 was decreased, whereas SHP-1 was significantly enhanced. Conclusion: Our findings suggest an activation of senescent-associated pathways during experimental sepsis. However, expanding the experiments to other organ systems and in vivo long-term models are necessary to further evaluate the sustained mechanisms and immunopathophysiological consequences of cellular senescence triggered by septic organ injury.
脓毒症继续对人类生命构成重大威胁，并带来巨大的经济负担。除了端粒丢失导致的复制应激外，最近的研究还发现了多种导致细胞周期停滞的因素。此外，我们对与细胞衰老相关的通路的理解也有所扩展，比如CD47介导的吞噬作用抑制。然而，除了体外实验，在包括脓毒症在内的复杂全身性疾病中，细胞应激的影响仍知之甚少。因此，我们对实验性非肺部脓毒症期间与衰老相关的肺部机制的分子改变进行了研究。方法：将雄性C57BL/6JRj小鼠麻醉，使其处于对照条件（假手术）或进行盲肠结扎和穿刺（CLP）以诱导脓毒症。CLP后24小时或7天，处死动物，采集血液、支气管肺泡灌洗液和肺组织，分析其形态学和生化变化。结果：肺组织的组织学损伤以及血浆中表面活性蛋白D水平的升高表明，CLP后出现了以肺泡为中心的急性肺损伤。此外，我们观察到脓毒症小鼠肺中CD47-QPCTL-SHP-1轴显著上调。虽然主要指示衰老表现形式的标志物p16的表达在CLP后降低，但细胞衰老的早期标志物p21在脓毒症期间肺中升高。随后，在CLP后7天，肺中CD47和QPCTL-1的表达降低，而SHP-1显著增强。结论：我们的研究结果表明，在实验性脓毒症期间衰老相关通路被激活。然而，有必要将实验扩展到其他器官系统和体内长期模型，以进一步评估脓毒症器官损伤引发的细胞衰老的持续机制和免疫病理生理后果。
