TY - JOUR T1 - Phospholipase A2-Receptor 1 Promotes Lung-Cell Senescence and Emphysema in Obstructive Lung Disease JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00752-2020 SP - 2000752 AU - Delphine Beaulieu AU - Aya Attwe AU - Marielle Breau AU - Larissa Lipskaia AU - Elisabeth Marcos AU - Emmanuelle Born AU - Jin Huang AU - Shariq Abid AU - Geneviève Derumeaux AU - Amal Houssaini AU - Bernard Maitre AU - Marine Lefevre AU - Nora Vienney AU - Philippe Bertolino AU - Sara Jaber AU - Hiba Noureddine AU - Delphine Goehrig AU - David Vindrieux AU - David Bernard AU - Serge Adnot Y1 - 2021/01/01 UR - http://erj.ersjournals.com/content/early/2021/01/08/13993003.00752-2020.abstract N2 - Rationale 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 via JAK/STAT signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis.Methods Assessment of cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to PLA2R1 knock-down, PLA2R1 gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether PLA2R1 upregulation caused lung lesions, we developed transgenic mice overexpressing PLA2R1 (PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the PLA2R1 gene (LV-PLA2R1 mice).Measurements and Results We found that PLA2R1 was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. PLA2R1 knockdown extended the population doubling capacity of these cells and inhibited their proinflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. 5 month-old PLA2R1-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-PLA2R1-treated mice developed lung emphysema within 4 weeks, and this was markedly attenuated by concomitant ruxolitinib treatment.Conclusion 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Beaulieu has nothing to disclose.Conflict of interest: Dr. Attwe has nothing to disclose.Conflict of interest: Dr. Breau has nothing to disclose.Conflict of interest: Dr. Lipskaia has nothing to disclose.Conflict of interest: Dr. Marcos has nothing to disclose.Conflict of interest: Dr. Born has nothing to disclose.Conflict of interest: Dr. Huang has nothing to disclose.Conflict of interest: Dr. Abid has nothing to disclose.Conflict of interest: Dr. Derumeaux has nothing to disclose.Conflict of interest: Dr. Houssaini has nothing to disclose.Conflict of interest: Dr. Maitre has nothing to disclose.Conflict of interest: Dr. Lefevre has nothing to disclose.Conflict of interest: Dr. Vienney has nothing to disclose.Conflict of interest: Dr. Bertolino has nothing to disclose.Conflict of interest: Dr. Jaber has nothing to disclose.Conflict of interest: Dr. Noureddine has nothing to disclose.Conflict of interest: Dr. Goehrig has nothing to disclose.Conflict of interest: Dr. Vindrieux has nothing to disclose.Conflict of interest: Dr. Bernard has nothing to disclose.Conflict of interest: Dr. Adnot has nothing to disclose. ER -