gms | German Medical Science

Objectives: Sepsis-induced acute lung injury is a frequent complication in patients with extrapulmonary sepsis. The underlying mechanism of sepsis-induced acute lung injury is described to be a dysregulated immune response. However, little is known about sepsis-induced senescence pathway activation. Therefore, the aim of this study was to investigate the (1) degree of lung injury and (2) the detection of senescence marker in the systemic and pulmonary innate immune response in a 24-h mouse sepsis model.

Methods: The cecal ligation and puncture (CLP) sepsis mouse model study was conducted in accordance with the German legislation and ARRIVE guidelines. The mice were allocated randomly to two groups: sham (n=10) and CLP (n=10). All the animals received postoperative fluid therapy, antibiotics, and analgesics, the study being performed in compliance with the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) protocols. All the animals were monitored for 24-h.Plasma levels of IL-6, Syndecan-1, CC16, and CHIT1 were quantified using ELISA. Lung injury score, which included the estimation of leukocytes infiltration, fibrin deposition, interalveolar hemorrhage, and septal congestion, was assessed on hematoxylin-eosin lung tissue staining. The expression analysis of the ICAM-1, VCAM-1, PECAM-1, MMP-9, and CD47 was performed from lung tissue-isolated RNA.

Results and conclusion: In the CLP sepsis group, significantly higher plasma levels of pro-inflammatory cytokines, such as IL-6 were detected (P=0.01). Moreover, the animals with sepsis presented higher plasma values of Syndecan-1, implying an increased endothelial glycocalyx damage. The lung damage marker quantification in plasma revealed higher CC16 and CHIT-1 (P<0.001) values in CLP compared to the sham group. These data were further validated by the lung injury score assessment, where the CLP animals showed a significant increase (P=0.001) in morphological lung damage. Other characteristics of an ongoing pulmonary inflammatory process were determined by the expression analysis, which revealed an increase in ICAM-1 (P=0.028), VCAM-1, PECAM-1, CD47, and MMP-9 (P=0.001) expression in lung tissue in CLP group.

The presented study is based on a highly standardized preclinical sepsis model, which was conducted in accordance with the MQTiPSS protocols. Despite the antibiotic therapy, the sepsis animals showed systemically higher levels of pro-inflammatory cytokines. Moreover, the CLP group presented an increase in plasma lung damage markers, as well as an upregulation of adhesion molecules in lung tissue, which can amplify the pulmonary inflammation by immune cell recruitment. Furthermore, the expression profile of the lungs of the septic animals suggested an induction of the senescence pathways in sepsis-induced lung injury pathogenesis.