Nitric oxide, an autocrine regulator of wound fibroblast synthetic function
Abstract
Nitric oxide (NO) is synthesized in wounds, but its exact role and cellular source are not known. Wound fibroblasts (WF) are phenotypically characterized by increased collagen synthesis and contractility. We hypothesized that WF may be also phenotypically altered during wound healing to synthesize NO. WF were isolated from polyvinyl alcohol sponges implanted in male Lewis rats and harvested 10 days later. Proliferation in response to 10% fetal bovine serum was assessed by [3H]thymidine incorporation in a microculture system. A fibroblast-populated collagen lattice was used for assaying contractility. Collagen synthesis was determined by measuring the collagenase-sensitive fraction of protein-incorporated [3H]proline. Fibroblasts were incubated in the presence or the absence of 0.5 mM S-methyl-isothio-uronium or 0.5 mM N-monomethyl-L-arginine, both competitive inhibitors of NO synthase. WF spontaneously synthesize and release NO (4.60 +/- 0.29 nmol nitrite/microg DNA/48 h). Normal dermal fibroblasts do not synthesize NO. WF NO synthesis was limited to the first and second passages postharvest and was inhibitable by S-methyl-isothio-uronium (96%) and N-monomethyl-L-arginine (84%). In vivo iNOS expression by WF was confirmed by in situ hybridization and immunohistochemistry. Inhibition of endogenous NO synthesis had no effect on fibroblast proliferation. However, fibroblast-mediated collagen contraction was enhanced (p < 0.01), and collagen synthesis was significantly decreased (p < 0.05) by inhibiting NO synthase. The data show that WF are phenotypically altered during the healing process to synthesize NO, which, in turn, regulates their collagen synthetic and contractile activities.
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The Basic Science of Wound Healing
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Schäffer, M. R., Schier, R., Napirei, M., et al. (2007) · Langenbeck s Archives of Surgery · doi:10.1007/s00423-007-0174-5 · Cited by 58 · see citing works
Self-citationMorgun, E. I., & Vorotelyak, E. A. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.581697 · Cited by 56 · see citing works
Nitric oxide regulates prolidase activity by serine/threonine phosphorylation
Surażyński, A., Liu, Y., Miltyk, W., et al. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20631 · Cited by 55 · see citing works
“Additionally, fibroblasts isolated from healing wounds synthesize NO autonomously and spontaneously [Schaffer et al., 1997].”
BackgroundBurrow, J. W., Koch, J. A., Chuang, H.-H., et al. (2007) · Journal of Surgical Research · doi:10.1016/j.jss.2006.11.010 · Cited by 55 · see citing works
“Nitric oxide (NO) is significantly reduced in chronic ulcers and impaired healing of diabetic wounds is thought to be related to diminished NO production [15–18].”
BackgroundTACROLIMUS IMPAIRS WOUND HEALING
ffer, M. R. S., Fuchs, N., Proksch, B., et al. (1998) · Transplantation · doi:10.1097/00007890-199803270-00008 · Cited by 55 · see citing works
Phosphoinositide 3-Kinase in Nitric Oxide Synthesis in Macrophage
Sakai, K., Suzuki, H., Oda, H., Akaike, T., Azuma, Y., Murakami, T., Sugi, K., Ito, T., Ichinose, H., Koyasu, S., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601896200 · Cited by 53 · see citing works
Cell-mediated biotransformation of S-nitrosoglutathione
Gordge, M. P., Addis, P., Noronha-Dutra, A. A., & Hothersall, J. S. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(97)00498-x · Cited by 54 · see citing works
Kulkarni, M. M., O’Loughlin, A., Vazquez, R., Mashayekhi, K., Rooney, P., Greiser, U., O’Toole, E. A., O’Brien, T., Malagón, M. M., & Pandit, A. S. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.11.003 · Cited by 53 · see citing works
“The relationship between NO and diabetic wound healing has been supported by several reports showing enhanced wound healing after NO treatment [27e30] via a number of mechanisms, such as altering matrix metalloproteinase (MMP) expression [31,32], affecting the synthesis function of fibroblasts [33,34], or acting as an…”
BackgroundBrewer, S., Desneves, K. J., PEARCE, L. M., et al. (2010) · Journal of Wound Care · doi:10.12968/jowc.2010.19.7.48905 · Cited by 53 · see citing works
He, M., Sun, L., Fu, X., McDonough, S. P., & Chu, C. (2018) · Acta Biomaterialia · doi:10.1016/j.actbio.2018.11.053 · Cited by 53 · see citing works
COBBOLD, C. A., & Sherratt, J. A. (2000) · Journal of Theoretical Biology · doi:10.1006/jtbi.2000.2012 · Cited by 52 · see citing works
“This is due to the fact that TGF-b has been suggested to stimulate the phenotypic change of "broblast to myo"broblasts (Desmouliere et al., 1993) and nitric oxide has been implicated in inhibiting such a transition (Schaffer et al., 1997a).”
BackgroundMethodDisorders of the Gastrointestinal System
Sanchez, L. (2017) · Equine Internal Medicine · doi:10.1016/b978-0-323-44329-6.00012-7 · Cited by 12 · see citing works
“Recent studies indicate that nitric oxide is critical to both of these processes, 835, 885 which likely explains the reparative properties of it in the stomach.”
McCallum, S., Paoloni, J., & Murrell, G. A. C. (2009) · British Journal of Sports Medicine · doi:10.1136/bjsm.2009.061002 · Cited by 50 · see citing works
Emerging Nitric Oxide and Hydrogen Sulfide Releasing Carriers for Skin Wound Healing Therapy
Pinto, R. V., Carvalho, S., Antunes, F., Pires, J., & Pinto, M. L. (2021) · ChemMedChem · doi:10.1002/cmdc.202100429 · Cited by 50 · see citing works
Low-Dose Propranolol Improves Cutaneous Wound Healing of Burn-Injured Rats
Romana‐Souza, B., do Nascimento, A. P., & Monte‐Alto‐Costa, A. (2008) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0b013e31818cbf67 · Cited by 47 · see citing works
- Authors
- Schäffer, M. R., Efron, P. A., Thornton, F. J., Klingel, K., Gross, S. S., & Barbul, A.
- Affiliations
- Johns Hopkins University (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-03-01
- Volume
- 158
- Issue
- 5
- Pages
- 2375-2381
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2113127336
- Cited by
- 260
- References
- 0
- Citations by year
- 2025: 2 · 2024: 6 · 2023: 3 · 2022: 8 · 2021: 5 · 2020: 4 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 10 · 2015: 5 · 2014: 6 · 2013: 11 · 2012: 9
- FWCI
- 17.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- nitric oxide, wound healing, collagen synthesis, collagen contraction, nitric oxide synthase, inducible nitric oxide synthase, L-NMMA, fibroblast proliferation, autocrine regulation
- MeSH terms
- Animals, Cell Division, Cell Line, Collagen, DNA, Fibroblasts, Male, Nitric Oxide, Phenotype, Rats, Inbred Lew, Wound Healing, In Situ Hybridization, Mice, Rats
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