title: Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.
abstract: Previously, we reported that murine gammaherpesvirus-68 (M1-MHV-68) induces pulmonary artery (PA) neointimal lesions in S100A4-overexpressing, but not in wild-type (C57), mice. Lesions were associated with heightened lung elastase activity and PA elastin degradation. We now investigate a direct relationship between elastase and PA neointimal lesions, the nature and source of the enzyme, and its presence in clinical disease. We found an association exists between the percentage of PAs with neointimal lesions and elastin fragmentation in S100A4 mice 6 months after viral infection. Confocal microscopy documented the heightened susceptibility of S100A4 versus C57 PA elastin to degradation by elastase. A transient increase in lung elastase activity occurs in S100A4 mice, 7 days after M1-MHV-68, unrelated to inflammation or viral load and before neointimal lesions. Administration of recombinant elafin, an elastase-specific inhibitor, ameliorates early increases in serine elastase and attenuates later development of neointimal lesions. Neutrophils are the source of elevated elastase (NE) in the S100A4 lung, and NE mRNA and protein levels are greater in PA smooth muscle cells (SMC) from S100A4 mice than from C57 mice. Furthermore, elevated NE is observed in cultured PA SMC from idiopathic PA hypertension versus that in control lungs and localizes to neointimal lesions. Thus, PA SMC produce NE, and heightened production and activity of NE is linked to experimental and clinical pulmonary vascular disease.
authors.affiliation: Department of Pediatrics and the Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yu-Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: Leila
authors.initials: L
authors.lastname: Haghighat
authors.forename: Edda
authors.initials: E
authors.lastname: Spiekerkoetter
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alvira
authors.forename: Lingli
authors.initials: L
authors.lastname: Wang
authors.forename: Swati
authors.initials: S
authors.lastname: Acharya
authors.forename: Gabriela
authors.initials: G
authors.lastname: Rodriguez-Colon
authors.forename: Andrew
authors.initials: A
authors.lastname: Orton
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004279:DNA, Viral / Q000378:metabolism; D053492:Elafin / Q000494:pharmacology; D018142:Gammaherpesvirinae; D006566:Herpesviridae Infections / Q000201:enzymology; D006976:Hypertension, Pulmonary / Q000201:enzymology*; D019272:Leukocyte Elastase / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D058426:Neointima / Q000201:enzymology; D011480:Protease Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000201:enzymology*; D012367:RNA, Viral / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D019562:Viral Load
chemical_list: D004279:DNA, Viral; D053492:Elafin; D011480:Protease Inhibitors; D012367:RNA, Viral; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D019272:Leukocyte Elastase