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Mast Cell Protease 5 Mediates Ischemia-Reperfusion Injury of Mouse Skeletal Muscle¹

J. Pablo Abonia^2,*, Daniel S. Friend, William G. Austen, Jr., Francis D. Moore, Jr., Michael C. Carroll^¶, Rodney Chan, Jalil Afnan, Alison Humbles^||, Craig Gerard^||, Pamela Knight^#, Yoshihide Kanaoka^*, Shinsuke Yasuda^*, Nasa Morokawa^*, K. Frank Austen^*, Richard L. Stevens^* and Michael F. Gurish^3,*

Departments of^* Medicine, Pathology, and Surgery, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115; Department of Surgery, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02129; ^¶ Department of Pediatrics, CBR Institute for Biomedical Research, and Harvard Medical School, Boston, MA, 02115; ^|| Department of Pediatrics, Beth Israel Hospital, Children’s Hospital, and Harvard Medical School, Boston, MA, 02115; and ^# Department of Veterinary Clinical Studies, Royal School of Veterinary Studies, University of Edinburgh, Easter Bush, United Kingdom

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 (R² = 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 C₄ synthase, hemopoietic PGD₂ 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.

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