Abstract

Rational: Lung fibroblast senescence is involved in the pathophysiology of COPD. However, the composition and the roles of the secretome of senescent COPD fibroblasts are incompletely characterized. Interestingly, secreted PLA2 (sPLA2), secreted by senescent cells, can induce senescence and inflammation. The aim of this study was to analyze the role of sPLA2 in pulmonary fibroblast senescence.

Methods: Fibroblasts were isolated from patients with COPD and control subjects. Patients in the different groups were similar in age and smoking history. Non-senescent fibroblasts were exposed to different doses of sPLA2, and senescence markers and inflammatory profile was analyzed. sPLA2 levels were quantified in serum of COPD and controls.  

Results: In comparison with non-smokers and smoker controls, senescent lung COPD fibroblasts exhibited a higher mRNA and protein expression of the sPLA2 isoform XIIA and of syndecan 4 (one of its receptors). sPLA2 XIIA induced in turn senescence of non-senescent pulmonary fibroblasts via a pathway involving consecutively syndecan 4, activation of MAPK and p-serine 727 STAT-3, increased mitochondrial ROS production, and activation of AMPK/p53. This pathway was associated with a specific inflammatory secretome (IL-10, IL-12 and TNFa), suggesting occurrence of a mitochondrial damage-induced senescence (MIDAS).  COPD fibroblasts were more susceptible to this sPLA2 XIIA effect than controls. sPLA2 XIIA levels were significantly higher in serum from COPD patients as compared to controls.

Conclusion: sPLA2 XIIA is involved in senescence, in COPD and could be a potential target to dampen this process.