Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease.

BACKGROUND

Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2 receptor 1 (PLA2R1) as a positive regulator of cell senescence acting Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis.

METHODS

We assessed cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to knockdown, gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether upregulation caused lung lesions, we developed transgenic mice overexpressing (-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the gene (LV- mice).

RESULTS

We found that was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. knockdown extended the population doubling capacity of these cells and inhibited their pro-inflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. Five-month-old -TG mice exhibited lung cell senescence, and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV--treated mice developed lung emphysema within 4 weeks and this was markedly attenuated by concomitant ruxolitinib treatment.

CONCLUSIONS

Our data support a major role for PLA2R1 activation in driving lung cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.