title: Mast cell protease 5 mediates ischemia-reperfusion injury of mouse skeletal muscle.
abstract: Ischemia with subsequent reperfusion (IR) injury is a significant clinical problem that occurs after physical and surgical trauma, myocardial infarction, and organ transplantation. IR injury of mouse skeletal muscle depends on the presence of both natural IgM and an intact C pathway. Disruption of the skeletal muscle architecture and permeability also requires mast cell (MC) participation, as revealed by the fact that IR injury is markedly reduced in c-kit defective, MC-deficient mouse strains. In this study, we sought to identify the pathobiologic MC products expressed in IR injury using transgenic mouse strains with normal MC development, except for the lack of a particular MC-derived mediator. Histologic analysis of skeletal muscle from BALB/c and C57BL/6 mice revealed a strong positive correlation (R(2) = 0.85) between the extent of IR injury and the level of MC degranulation. Linkage between C activation and MC degranulation was demonstrated in mice lacking C4, in which only limited MC degranulation and muscle injury were apparent. No reduction in injury was observed in transgenic mice lacking leukotriene C(4) synthase, hemopoietic PGD(2) synthase, N-deacetylase/N-sulfotransferase-2 (enzyme involved in heparin biosynthesis), or mouse MC protease (mMCP) 1. In contrast, muscle injury was significantly attenuated in mMCP-5-null mice. The MCs that reside in skeletal muscle contain abundant amounts of mMCP-5 which is the serine protease that is most similar in sequence to human MC chymase. We now report a cytotoxic activity associated with a MC-specific protease and demonstrate that mMCP-5 is critical for irreversible IR injury of skeletal muscle.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Abonia
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Friend
authors.forename: William G
authors.initials: WG
authors.lastname: Austen
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.forename: Rodney
authors.initials: R
authors.lastname: Chan
authors.forename: Jalil
authors.initials: J
authors.lastname: Afnan
authors.forename: Alison
authors.initials: A
authors.lastname: Humbles
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Pamela
authors.initials: P
authors.lastname: Knight
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kanaoka
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yasuda
authors.forename: Nasa
authors.initials: N
authors.lastname: Morokawa
authors.forename: K Frank
authors.initials: KF
authors.lastname: Austen
authors.forename: Richard L
authors.initials: RL
authors.lastname: Stevens
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gurish
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D015926:Complement C3a / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015936:Complement C5a / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003171:Complement Pathway, Classical / Q000235:genetics / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000201:enzymology / Q000503:physiopathology*; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D012206:Rhabdomyolysis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D022142:Secretory Vesicles / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D003181:Complement C4; D015926:Complement C3a; D015936:Complement C5a; D012697:Serine Endopeptidases