title: MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration.
abstract: We examined the role of MCP-1, a potent chemotactic and activating factor for macrophages, in perfusion, inflammation, and skeletal muscle regeneration post-ischemic injury. MCP-1-/- or C57Bl/6J control mice [wild-type (WT)] underwent femoral artery excision (FAE). Muscles were collected for histology, assessment of tissue chemokines, and activity measurements of lactate dehydrogenase (LDH) and myeloperoxidase. In MCP-1-/- mice, restoration of perfusion was delayed, and LDH and fiber size, indicators of muscle regeneration, were decreased. Altered inflammation was observed with increased neutrophil accumulation in MCP-1-/- versus WT mice at Days 1 and 3 (P< or =0.003), whereas fewer macrophages were present in MCP-1-/- mice at Day 3. As necrotic tissue was removed in WT mice, macrophages decreased (Day 7). In contrast, macrophage accumulation in MCP-1-/- was increased in association with residual necrotic tissue and impaired muscle regeneration. Consistent with altered inflammation, neutrophil chemotactic factors (keratinocyte-derived chemokine and macrophage inflammatory protein-2) were increased at Day 1 post-FAE. The macrophage chemotactic factor MCP-5 was increased significantly in WT mice at Day 3 compared with MCP-1-/- mice. However, at post-FAE Day 7, MCP-5 was significantly elevated in MCP-1-/- mice versus WT mice. Addition of exogenous MCP-1 did not induce proliferation in murine myoblasts (C2C12 cells) in vitro. MCP-1 is essential for reperfusion and the successful completion of normal skeletal muscle regeneration after ischemic tissue injury. Impaired muscle regeneration in MCP-1-/- mice suggests an important role for macrophages and MCP-1 in tissue reparative processes.
authors.affiliation: Department of Surgery, University of Texas Health Science Center, MC 7741, San Antonio, TX 78229-3900, USA. shireman@uthscsa.edu
authors.forename: Paula K
authors.initials: PK
authors.lastname: Shireman
authors.forename: Verónica
authors.initials: V
authors.lastname: Contreras-Shannon
authors.forename: Oscar
authors.initials: O
authors.lastname: Ochoa
authors.forename: Bijal P
authors.initials: BP
authors.lastname: Karia
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.forename: Linda M
authors.initials: LM
authors.lastname: McManus
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000276:immunology / Q000473:pathology / Q000601:surgery; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000276:immunology* / Q000473:pathology; D012038:Regeneration / Q000235:genetics / Q000276:immunology; D013997:Time Factors
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2