{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T20:41:05Z","timestamp":1784234465513,"version":"3.55.0"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Efficient phagocytosis of pathogens by the innate immune system during infectious injury is vital for restoring tissue integrity. Impaired phagocytosis, such as in the case of infection with<jats:italic>Pseudomonas aeruginosa<\/jats:italic>, a broad-spectrum antibiotic-resistant Gram-negative bacterium, can lead to a life threatening lung disorder, acute lung injury (ALI). Evidence indicates that loss of protease-activated receptor 2 (PAR2) impaired<jats:italic>Pseudomonas aeruginosa<\/jats:italic>clearance leading to non-resolvable ALI, but the mechanism remains unclear. Here, we focused on the alveolar macrophages (AMs), the predominant population of lung-resident macrophages involved in sensing bacteria, to understand their role in PAR2-mediated phagocytosis of<jats:italic>Pseudomonas aeruginosa<\/jats:italic>. We found that upon binding<jats:italic>Pseudomonas aeruginosa<\/jats:italic>, PAR2-expressing but not PAR2-null AMs had increased cAMP levels, which activated Rac1 through protein kinase A. Activated Rac1 increased actin-rich protrusions to augment the phagocytosis of<jats:italic>Pseudomonas aeruginosa<\/jats:italic>. Administration of liposomes containing constitutively active Rac1 into PAR2-null mice lungs rescued phagocytosis and enhanced the survival of PAR2-null mice from pneumonia. These studies showed that PAR2 drives the cAMP-Rac1 signaling cascade that activates<jats:italic>Pseudomonas aeruginosa<\/jats:italic>phagocytosis in AMs, thereby preventing death from bacterial pneumonia.<\/jats:p>","DOI":"10.3389\/fphar.2022.874197","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T06:04:31Z","timestamp":1663653871000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Protease-activated receptor 2 promotes clearance of Pseudomonas aeruginosa infection by inducing cAMP-Rac1 signaling in alveolar macrophages"],"prefix":"10.3389","volume":"13","author":[{"given":"Sheikh","family":"Rayees","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagdish Chandra","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhagwati","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vigneshwaran","family":"Vellingiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somenath","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolly","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"104736","DOI":"10.1016\/j.phrs.2020.104736","article-title":"Acute lung injury: The therapeutic role of Rho kinase inhibitors","volume":"155","author":"Abedi","year":"2020","journal-title":"Pharmacol. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1111\/j.1574-6968.1999.tb13748.x","article-title":"Adherence and internalization of Streptococcus uberis to bovine mammary epithelial cells are mediated by host cell proteoglycans","volume":"177","author":"Almeida","year":"1999","journal-title":"FEMS Microbiol. Lett."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e12175","DOI":"10.14814\/phy2.12175","article-title":"cAMP controls the restoration of endothelial barrier function after thrombin-induced hyperpermeability via Rac1 activation","volume":"2","author":"Aslam","year":"2014","journal-title":"Physiol. Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"8531","DOI":"10.1073\/pnas.1215902110","article-title":"Reciprocal regulation of PKA and Rac signaling","volume":"110","author":"Bachmann","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.3389\/fimmu.2018.01675","article-title":"Pseudomonas aeruginosa LasB subverts alveolar macrophage activity by interfering with bacterial killing through downregulation of innate immune defense, reactive oxygen species generation, and complement activation","volume":"9","author":"Bastaert","year":"2018","journal-title":"Front. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.mvr.2009.11.007","article-title":"Rac GTPase is a hub for protein kinase A and Epac signaling in endothelial barrier protection by cAMP","volume":"79","author":"Birukova","year":"2010","journal-title":"Microvasc. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.immuni.2013.08.026","article-title":"Autophagy regulates phagocytosis by modulating the expression of scavenger receptors","volume":"39","author":"Bonilla","year":"2013","journal-title":"Immunity"},{"key":"B47","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/s0076-6879(00)22004-1","article-title":"Detection of apoptosis by annexin V labeling","volume":"322","author":"Bossy-Wetzel","year":"2000","journal-title":"Methods Enzymol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"326","DOI":"10.3389\/fmicb.2020.00326","article-title":"Escaping the phagocytic oxidative burst: The role of SODB in the survival of Pseudomonas aeruginosa within macrophages","volume":"11","author":"Cavinato","year":"2020","journal-title":"Front. Microbiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1128\/MCB.00898-07","article-title":"Protein kinase A-dependent phosphorylation modulates beta1Pix guanine nucleotide exchange factor activity through 14-3-3beta binding","volume":"28","author":"Chahdi","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1478-811X-8-31","article-title":"PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration","volume":"8","author":"Chaitanya","year":"2010","journal-title":"Cell Commun. Signal."},{"key":"B12","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1111\/j.1745-7270.2008.00438.x","article-title":"Epac and PKA: a tale of two intracellular cAMP receptors","volume":"40","author":"Cheng","year":"2008","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1073\/pnas.1108464109","article-title":"Toll-like receptor 5 (TLR5), IL-1\u03b2 secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing.","volume":"109","author":"Descamps","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e91214","DOI":"10.1172\/jci.insight.91214","article-title":"Tissue-resident macrophages can contain replication-competent virus in antiretroviral-naive, SIV-infected Asian macaques","volume":"2","author":"Dinapoli","year":"2017","journal-title":"JCI Insight"},{"key":"B16","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.ccm.2004.10.014","article-title":"Acute lung injury and bacterial infection","volume":"26","author":"Dreyfuss","year":"2005","journal-title":"Clin. Chest Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1165\/rcmb.4908","article-title":"Proteinase-activated receptor-2 and human lung epithelial cells: disarming by neutrophil serine proteinases","volume":"28","author":"Dulon","year":"2003","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1165\/rcmb.2004-0274OC","article-title":"Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells","volume":"32","author":"Dulon","year":"2005","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"10266","DOI":"10.1074\/jbc.RA119.006974","article-title":"Collagenolytic matrix metalloproteinases antagonize proteinase-activated receptor-2 activation, providing insights into extracellular matrix turnover","volume":"294","author":"Falconer","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1146\/annurev-pathol-011811-132445","article-title":"The cell biology of phagocytosis","volume":"7","author":"Flannagan","year":"2012","journal-title":"Annu. Rev. Pathol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"R1279","DOI":"10.1016\/j.cub.2016.10.059","article-title":"Phagocytosis: How macrophages tune their non-professional counterparts","volume":"26","author":"Freeman","year":"2016","journal-title":"Curr. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1038\/nature20141","article-title":"Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation","volume":"539","author":"Han","year":"2016","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2448","DOI":"10.4049\/jimmunol.178.4.2448","article-title":"Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice","volume":"178","author":"Hashimoto","year":"2007","journal-title":"J. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1038\/s41467-017-00928-3","article-title":"Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice","volume":"8","author":"He","year":"2017","journal-title":"Nat. Commun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13578-019-0292-0","article-title":"Caspase-11, a specific sensor for intracellular lipopolysaccharide recognition, mediates the non-canonical inflammatory pathway of pyroptosis","volume":"9","author":"Huang","year":"2019","journal-title":"Cell Biosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"4096","DOI":"10.1016\/j.celrep.2020.02.112","article-title":"SPHK2-Generated S1P in CD11b(+) macrophages blocks STING to suppress the inflammatory function of alveolar macrophages","volume":"30","author":"Joshi","year":"2020","journal-title":"Cell Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1016\/j.immuni.2016.02.014","article-title":"Molecular determinants in phagocyte-bacteria interactions","volume":"44","author":"Kaufmann","year":"2016","journal-title":"Immunity"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2198","DOI":"10.1128\/iai.70.4.2198-2205.2002","article-title":"Pseudomonas aeruginosa ExoT acts in vivo as a GTPase-activating protein for RhoA, Rac1, and Cdc42","volume":"70","author":"Kazmierczak","year":"2002","journal-title":"Infect. Immun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1067\/mai.2001.119025","article-title":"Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma","volume":"108","author":"Knight","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1165\/rcmb.2013-0414OC","article-title":"Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection","volume":"51","author":"Kolli","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1074\/jbc.275.1.141","article-title":"Rac1 and Cdc42 are required for phagocytosis, but not NF-kappaB-dependent gene expression, in macrophages challenged with Pseudomonas aeruginosa","volume":"275","author":"Lee","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1124\/jpet.113.207266","article-title":"NSC23766, a widely used inhibitor of Rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors","volume":"347","author":"Levay","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1111\/imr.12439","article-title":"The life cycle of phagosomes: formation, maturation, and resolution","volume":"273","author":"Levin","year":"2016","journal-title":"Immunol. Rev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"L181","DOI":"10.1152\/ajplung.2001.280.1.L181","article-title":"Muc1 mucins on the cell surface are adhesion sites for Pseudomonas aeruginosa","volume":"280","author":"Lillehoj","year":"2001","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"L591","DOI":"10.1152\/ajplung.00335.2013","article-title":"Mechanisms of phagocytosis and host clearance of Pseudomonas aeruginosa","volume":"306","author":"Lovewell","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1002\/glia.20303","article-title":"cAMP cascade (PKA, Epac, adenylyl cyclase, Gi, and phosphodiesterases) regulates myelin phagocytosis mediated by complement receptor-3 and scavenger receptor-AI\/II in microglia and macrophages","volume":"53","author":"Makranz","year":"2006","journal-title":"Glia"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e00138","DOI":"10.1128\/CMR.00138-18","article-title":"Cystic fibrosis and Pseudomonas aeruginosa: the host-microbe interface","volume":"32","author":"Malhotra","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.4049\/jimmunol.0802280","article-title":"RhoA GTPase activation by TLR2 and TLR3 ligands: connecting via src to NF-kappa B","volume":"182","author":"Manukyan","year":"2009","journal-title":"J. Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1136\/thorax.57.2.146","article-title":"Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers","volume":"57","author":"Miotto","year":"2002","journal-title":"Thorax"},{"key":"B40","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1111\/j.1462-5822.2011.01704.x","article-title":"Pseudomonas aeruginosa Psl polysaccharide reduces neutrophil phagocytosis and the oxidative response by limiting complement-mediated opsonization","volume":"14","author":"Mishra","year":"2012","journal-title":"Cell. Microbiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"L368","DOI":"10.1152\/ajplung.00036.2007","article-title":"Role of PAR2 in murine pulmonary pseudomonal infection","volume":"294","author":"Moraes","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/35014075","article-title":"Latrunculin alters the actin-monomer subunit interface to prevent polymerization","volume":"2","author":"Morton","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"59088","DOI":"10.3791\/59088","article-title":"Alveolar macrophage phagocytosis and bacteria clearance in mice","volume":"145","author":"Nagre","year":"2019","journal-title":"J. Vis. Exp."},{"key":"B44","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/s41586-018-0590-4","article-title":"Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris","volume":"562","author":"Nicholas","year":"2018","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","first-page":"4416","DOI":"10.4049\/jimmunol.171.8.4416","article-title":"Defective phagocytosis and clearance of Pseudomonas aeruginosa in the lung following bone marrow transplantation","volume":"171","author":"Ojielo","year":"2003","journal-title":"J. Immunol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1091\/mbc.02-01-0002","article-title":"Vav regulates activation of Rac but not Cdc42 during FcgammaR-mediated phagocytosis","volume":"13","author":"Patel","year":"2002","journal-title":"Mol. Biol. Cell"},{"key":"B48","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1165\/ajrcmb.20.5.3408","article-title":"Pseudomonas aeruginosa internalization by human epithelial respiratory cells depends on cell differentiation, polarity, and junctional complex integrity","volume":"20","author":"Plotkowski","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e28209","DOI":"10.4161\/sgtp.28209","article-title":"Bacterial factors exploit eukaryotic Rho GTPase signaling cascades to promote invasion and proliferation within their host","volume":"5","author":"Popoff","year":"2014","journal-title":"Small GTPases"},{"key":"B50","doi-asserted-by":"publisher","first-page":"C1161","DOI":"10.1152\/ajpcell.00139.2008","article-title":"Phosphorylation of GTP dissociation inhibitor by PKA negatively regulates RhoA","volume":"295","author":"Qiao","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.celrep.2019.03.053","article-title":"PAR2-Mediated cAMP generation suppresses TRPV4-dependent Ca(2+) signaling in alveolar macrophages to resolve TLR4-induced inflammation","volume":"27","author":"Rayees","year":"2019","journal-title":"Cell Rep."},{"key":"B52","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.intimp.2015.03.035","article-title":"Therapeutic effects of R8, a semi-synthetic analogue of Vasicine, on murine model of allergic airway inflammation via STAT6 inhibition","volume":"26","author":"Rayees","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.3389\/fimmu.2020.02091","article-title":"Macrophage TLR4 and PAR2 signaling: Role in regulating vascular inflammatory injury and repair","volume":"11","author":"Rayees","year":"2020","journal-title":"Front. Immunol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1165\/ajrcmb.21.5.3334","article-title":"Surfactant protein D stimulates phagocytosis of Pseudomonas aeruginosa by alveolar macrophages","volume":"21","author":"Restrepo","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"861","DOI":"10.3892\/or_00000708","article-title":"Pharmacological inhibition of Rho-kinase signaling with Y-27632 blocks melanoma tumor growth","volume":"23","author":"Routhier","year":"2010","journal-title":"Oncol. Rep."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1056\/NEJMoa050333","article-title":"Incidence and outcomes of acute lung injury","volume":"353","author":"Rubenfeld","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1164\/rccm.200408-1044SO","article-title":"Pathogen-host interactions in Pseudomonas aeruginosa pneumonia","volume":"171","author":"Sadikot","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1007\/s00441-013-1755-y","article-title":"cAMP with other signaling cues converges on Rac1 to stabilize the endothelial barrier- a signaling pathway compromised in inflammation","volume":"355","author":"Schlegel","year":"2013","journal-title":"Cell Tissue Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1165\/rcmb.2007-0153OC","article-title":"Prostaglandin E2 suppresses bacterial killing in alveolar macrophages by inhibiting NADPH oxidase","volume":"37","author":"Serezani","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"16860","DOI":"10.1073\/pnas.1415712111","article-title":"Surface attachment induces Pseudomonas aeruginosa virulence","volume":"111","author":"Siryaporn","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B61","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1242\/jcs.064964","article-title":"Rho GTPases and their role in organizing the actin cytoskeleton","volume":"124","author":"Sit","year":"2011","journal-title":"J. Cell Sci."},{"key":"B62","doi-asserted-by":"publisher","first-page":"e1007684","DOI":"10.1371\/journal.ppat.1007684","article-title":"The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2","volume":"15","author":"Skjesol","year":"2019","journal-title":"PLoS Pathog."},{"key":"B63","doi-asserted-by":"crossref","first-page":"5514","DOI":"10.4049\/jimmunol.160.11.5514","article-title":"Nonopsonic and opsonic association of Mycobacterium tuberculosis with resident alveolar macrophages is inefficient","volume":"160","author":"Stokes","year":"1998","journal-title":"J. Immunol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"2249","DOI":"10.1172\/JCI89652","article-title":"Bispecific antibody targets multiple Pseudomonas aeruginosa evasion mechanisms in the lung vasculature","volume":"127","author":"Thanabalasuriar","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B65","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.4049\/jimmunol.1302863","article-title":"Differential role for p120-catenin in regulation of TLR4 signaling in macrophages","volume":"193","author":"Yang","year":"2014","journal-title":"J. Immunol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1165\/ajrcmb.16.3.9070615","article-title":"Purification, characterization, and localization of a novel trypsin-like protease found in the human airway","volume":"16","author":"Yasuoka","year":"1997","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"42758","DOI":"10.1038\/srep42758","article-title":"STIM1 phosphorylation at Y361 recruits Orai1 to STIM1 puncta and induces Ca(2+) entry","volume":"7","author":"Yazbeck","year":"2017","journal-title":"Sci. Rep."},{"key":"B68","doi-asserted-by":"publisher","first-page":"13875","DOI":"10.1074\/jbc.M115.642736","article-title":"Neutrophil elastase activates protease-activated receptor-2 (PAR2) and transient receptor potential vanilloid 4 (TRPV4) to cause inflammation and pain","volume":"290","author":"Zhao","year":"2015","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.874197\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,19]],"date-time":"2023-02-19T17:01:32Z","timestamp":1676826092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.874197\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,20]]},"references-count":66,"alternative-id":["10.3389\/fphar.2022.874197"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.874197","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,20]]},"article-number":"874197"}}