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* Department of Medical Ecology and Informatics,
Department of Gastroenterology, and
Research Institute, International Medical Center of Japan, Tokyo, Japan;
Department of Pharmacokinetics and Pharmacodynamics, Hospital Pharmacy, Tokyo Medical and Dental University Graduate School, Tokyo, Japan;
¶ G.S. Platz Company, Tokyo, Japan;
|| Department of Pathology and Experimental Medicine, Graduate School of Medical, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan; and
# Immunology Center, Mount Sinai School of Medicine, New York, NY 10029
Peritoneal adhesions are a significant complication of surgery and visceral inflammation; however, the mechanism has not been fully elucidated. The aim of this study was to clarify the mechanism of peritoneal adhesions by focusing on the cell trafficking and immune system in the peritoneal cavity. We investigated the specific recruitment of peritoneal macrophages (PM
) and their expression of chemokine receptors in murine models of postoperative and postinflammatory peritoneal adhesions. PM aggregated at the site of injured peritoneum in these murine models of peritoneal adhesions. The chemokine receptor CCR8 was up-regulated in the aggregating PM when compared with naive PM. The up-regulation of CCR8 was also observed in PM, but not in bone marrow-derived M, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PM and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. Cell aggregation involving PM and PMCs was induced in vitro in the presence of CCL1. CCL1 also up-regulated mRNA levels of plasminogen activator inhibitor-1 in both PM and PMCs. CCR8 gene-deficient mice or mice treated with anti-CCL1-neutralizing Ab exhibited significantly reduced postoperational peritoneal adhesion. Our study now establishes a unique autocrine activation system in PM and the mechanism for recruitment of PM together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity, which triggers peritoneal adhesions.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Medical Techniques Promotion Research Grant H14-nano-004 from the Ministry of Health, Labor, and Welfare of Japan; grants and contracts from the Ministry of Health, Labor, and Welfare; the Ministry of Education, Culture, Sports, Science, and Technology; the Japan Health Sciences Foundation; and the Japan Science and Technology Agency.
2 Address correspondence and reprint requests to Dr. Taeko Dohi, Department of Gastroenterology, Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku, Tokyo 162-8655, Japan. E-mail address: dohi{at}ri.imcj.go.jp
3 Abbreviations used in this paper: M, macrophage; BM, bone marrow-derived M; PM, peritoneal M; QD, quantum dot; PGN, peptidoglycan; pAb, polyclonal Ab; TNBS, 2,4,6-trinitrobenzene sulfonic acid; PTX, pertussis toxin; CIMA, chemokine-induced macrophage aggregation; PMC, peritoneal mesothelial cell; tPA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1.
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