Impaired Healing of a Cutaneous Wound in an Inducible Nitric Oxide Synthase-Knockout Mouse

Overview

Journal Dermatol Res Pract

Publisher Wiley

Specialty Dermatology

Date 2017 May 11

PMID 28487726

Citations 19

Authors

Takashi Kitano

Hiroshi Yamada

Maki Kida

Yuka Okada

Shizuya Saika

Munehito Yoshida

Affiliations

Soon will be listed here.

Abstract

. We investigated the effects of loss of inducible nitric oxide synthase (iNOS) on the healing process of cutaneous excisional injury by using iNOS-null (KO) mice. Population of granulation tissue-related cell types, that is, myofibroblasts and macrophages, growth factor expression, and reepithelialization were evaluated. . KO and wild type (WT) mice of C57BL/6 background were used. Under general anesthesia two round full-thickness excision wounds of 5.0 mm in diameter were produced in dorsal skin. After specific intervals of healing, macroscopic observation, histology, immunohistochemistry, and real-time reverse transcription-polymerase chain reaction (RT-PCR) were employed to evaluate the healing process. . The loss of iNOS retards granulation tissue formation and reepithelialization in excision wound model in mice. Detailed analyses showed that myofibroblast appearance, macrophage infiltration, and mRNA expression of transforming growth factor b and of collagen 12 were all suppressed by lacking iNOS. . iNOS is required in the process of cutaneous wound healing. Lacking iNOS retards macrophage invasion and its expression of fibrogenic components that might further impair fibrogenic behaviors of fibroblasts.

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References

Shi H, Most D, Efron D, Tantry U, Fischel M, Barbul A . The role of iNOS in wound healing. Surgery. 2001; 130(2):225-9. DOI: 10.1067/msy.2001.115837. View

Singer A, Clark R . Cutaneous wound healing. N Engl J Med. 1999; 341(10):738-46. DOI: 10.1056/NEJM199909023411006. View

Saika S, Ikeda K, Yamanaka O, Flanders K, Ohnishi Y, Nakajima Y . Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. Am J Physiol Cell Physiol. 2005; 290(1):C282-9. DOI: 10.1152/ajpcell.00306.2005. View

Most D, Efron D, Shi H, Tantry U, Barbul A . Characterization of incisional wound healing in inducible nitric oxide synthase knockout mice. Surgery. 2002; 132(5):866-76. DOI: 10.1067/msy.2002.127422. View

Mori R, Kondo T, Ohshima T, Ishida Y, Mukaida N . Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration. FASEB J. 2002; 16(9):963-74. DOI: 10.1096/fj.01-0776com. View

Saika S, Shiraishi A, Liu C, Funderburgh J, Kao C, Converse R . Role of lumican in the corneal epithelium during wound healing. J Biol Chem. 2000; 275(4):2607-12. PMC: 3580337. DOI: 10.1074/jbc.275.4.2607. View

Dovi J, He L, DiPietro L . Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol. 2003; 73(4):448-55. DOI: 10.1189/jlb.0802406. View

Nussler A, Billiar T . Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993; 54(2):171-8. View

Lizarbe T, Garcia-Rama C, Tarin C, Saura M, Calvo E, Lopez J . Nitric oxide elicits functional MMP-13 protein-tyrosine nitration during wound repair. FASEB J. 2008; 22(9):3207-15. DOI: 10.1096/fj.07-103804. View

10.

Schaffer M, Tantry U, Ahrendt G, Wasserkrug H, Barbul A . Acute protein-calorie malnutrition impairs wound healing: a possible role of decreased wound nitric oxide synthesis. J Am Coll Surg. 1997; 184(1):37-43. View

11.

Shi H, Efron D, Most D, Tantry U, Barbul A . Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice. Surgery. 2000; 128(2):374-8. DOI: 10.1067/msy.2000.107372. View

12.

Swift M, Kleinman H, DiPietro L . Impaired wound repair and delayed angiogenesis in aged mice. Lab Invest. 2000; 79(12):1479-87. View

13.

Saika S . TGFbeta pathobiology in the eye. Lab Invest. 2005; 86(2):106-15. DOI: 10.1038/labinvest.3700375. View

14.

Saika S, Shirai K, Yamanaka O, Miyazaki K, Okada Y, Kitano A . Loss of osteopontin perturbs the epithelial-mesenchymal transition in an injured mouse lens epithelium. Lab Invest. 2007; 87(2):130-8. DOI: 10.1038/labinvest.3700508. View

15.

Cohen B, Danon D, Roth G . Wound repair in mice as influenced by age and antimacrophage serum. J Gerontol. 1987; 42(3):295-301. DOI: 10.1093/geronj/42.3.295. View

16.

Lee R, Efron D, Tantry U, Barbul A . Nitric oxide in the healing wound: a time-course study. J Surg Res. 2001; 101(1):104-8. DOI: 10.1006/jsre.2001.6261. View

17.

Jang J, Ko M, Yun J, Kim M, Kim J, Park H . Nitric Oxide Produced by Macrophages Inhibits Adipocyte Differentiation and Promotes Profibrogenic Responses in Preadipocytes to Induce Adipose Tissue Fibrosis. Diabetes. 2016; 65(9):2516-28. DOI: 10.2337/db15-1624. View

18.

Zhou J, Dehne N, Brune B . Nitric oxide causes macrophage migration via the HIF-1-stimulated small GTPases Cdc42 and Rac1. Free Radic Biol Med. 2009; 47(6):741-9. DOI: 10.1016/j.freeradbiomed.2009.06.006. View

19.

Saika S, Ikeda K, Yamanaka O, Flanders K, Okada Y, Miyamoto T . Loss of tumor necrosis factor alpha potentiates transforming growth factor beta-mediated pathogenic tissue response during wound healing. Am J Pathol. 2006; 168(6):1848-60. PMC: 1606617. DOI: 10.2353/ajpath.2006.050980. View

20.

Saika S, Miyamoto T, Yamanaka O, Kato T, Ohnishi Y, Flanders K . Therapeutic effect of topical administration of SN50, an inhibitor of nuclear factor-kappaB, in treatment of corneal alkali burns in mice. Am J Pathol. 2005; 166(5):1393-403. PMC: 1606394. DOI: 10.1016/s0002-9440(10)62357-7. View