scholarly journals Topical 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice

Endocrinology ◽  
2017 ◽  
Vol 159 (1) ◽  
pp. 547-556 ◽  
Author(s):  
Ana Tiganescu ◽  
Melanie Hupe ◽  
Yoshikazu Uchida ◽  
Theadora Mauro ◽  
Peter M Elias ◽  
...  
Keyword(s):  
Wound Healing ◽  
Matrix Metalloproteinase ◽  
Chronic Wounds ◽  
Keratinocyte Growth Factor ◽  
Hydroxysteroid Dehydrogenase ◽  
Impaired Wound Healing ◽  
Expression Studies ◽  
Gene Expression Studies ◽  
Skin Function

Abstract Glucocorticoid (GC) excess drives multiple cutaneous adverse effects, including skin thinning and poor wound healing. The ubiquitously expressed enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates mouse corticosterone from 11-dehydrocorticosterone (and human cortisol from cortisone). We previously demonstrated elevated 11β-HSD1 activity during mouse wound healing, but the interplay between cutaneous 11β-HSD1 and systemic GC excess is unexplored. Here, we examined effects of 11β-HSD1 inhibition by carbenoxolone (CBX) in mice treated with corticosterone (CORT) or vehicle for 6 weeks. Mice were treated bidaily with topical CBX or vehicle (VEH) 7 days before wounding and during wound healing. CORT mice displayed skin thinning and impaired wound healing but also increased epidermal integrity. 11β-HSD1 activity was elevated in unwounded CORT skin and was inhibited by CBX. CORT mice treated with CBX displayed 51%, 59%, and 100% normalization of wound healing, epidermal thickness, and epidermal integrity, respectively. Gene expression studies revealed normalization of interleukin 6, keratinocyte growth factor, collagen 1, collagen 3, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 4 by CBX during wound healing. Importantly, proinflammatory cytokine expression and resolution of inflammation were unaffected by 11β-HSD1 inhibition. CBX did not regulate skin function or wound healing in the absence of CORT. Our findings demonstrate that 11β-HSD1 inhibition can limit the cutaneous effects of GC excess, which may improve the safety profile of systemic steroids and the prognosis of chronic wounds.

scholarly journals Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review

Antioxidants ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 98 ◽  
Author(s):  
Mariola Cano Sanchez ◽  
Steve Lancel ◽  
Eric Boulanger ◽  
Remi Neviere
Keyword(s):  
Wound Healing ◽  
Mitochondrial Dysfunction ◽  
Chronic Wounds ◽  
Ros Generation ◽  
Nuclear Factor ◽  
Impaired Wound Healing ◽  
Pyrin Domain ◽  
Low Concentrations ◽  
Pathway Inhibition ◽  
Healing Processes

Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

Role of Nitric Oxide in Wound Healing

2002 ◽  
Vol 4 (1) ◽  
pp. 5-15 ◽  
Author(s):  
Beverly B. Childress ◽  
Joyce K. Stechmiller
Keyword(s):  
Nitric Oxide ◽  
Wound Healing ◽  
Growth Factors ◽  
Animal Studies ◽  
Chronic Wounds ◽  
Current Knowledge ◽  
Wound Care ◽  
Impaired Wound Healing ◽  
Normal Wound Healing ◽  
Age Related

Chronic wounds mainly affect elderly individuals and persons with comorbid diseases due to a compromised immune status. An age-related decline in immune function deters proper healing of wounds in an orderly and timely manner. Thus, older adults with 1 or more concomitant illnesses are more likely to experience and suffer from a nonhealing wound, which may drastically decrease their quality of life and financial resources. Novel therapies in wound care management rely heavily on our current knowledge of wound healing physiology. It is well established that normal wound healing occurs sequentially and is strictly regulated by pro-inflammatory cytokines and growth factors. A multitude of commercial products such as growth factors are available; however, their effectiveness in healing chronic wounds has yet to be proven. Recently, investigators have implicated nitric oxide (NO) in the exertion of regulatory forces on various cellular activities of the inflammatory and proliferative phases of wound healing. Gene therapy in animal studies has shown promising results and is furthering our understanding of impaired wound healing. The purpose of this article is to review the literature on NO and its role in wound healing. A discussion of the physiology of normal healing and the pathophysiology of chronic wounds is provided.

scholarly journals The Small Molecule NLRP3 Inflammasome Inhibitor MCC950 Does Not Alter Wound Healing in Obese Mice

2018 ◽  
Vol 19 (11) ◽  
pp. 3289 ◽  
Author(s):  
James Lee ◽  
Avril Robertson ◽  
Matthew Cooper ◽  
Kiarash Khosrotehrani
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Nlrp3 Inflammasome ◽  
Chronic Wounds ◽  
Inflammatory Diseases ◽  
Healing Process ◽  
Obese Mice ◽  
Impaired Wound Healing ◽  
Macrophage Polarisation ◽  
Inflammatory Conditions

The incidence of chronic wounds is escalating, and the associated healing process is especially problematic in an aging population with increased morbidity. Targeting increased inflammation in chronic wounds is a promising but challenging therapeutic strategy. Indeed, inflammation and especially macrophages are required for wound healing. As the NLRP3 inflammasome has been implicated with various other inflammatory diseases, in this study, we used MCC950—a selective NLRP3 small molecule inhibitor—on murine models of both acute and chronic wounds. This molecule, while tested for other inflammatory conditions, has never been investigated to reduce topical inflammation driving chronic wounds. We found that there were no significant differences when the treatment was applied either topically or orally in wild-type C57Bl/6 mice and that it even impaired wound healing in obese mice. The treatment was also unable to improve re-epithelialisation or angiogenesis, which are both required for the closure of wounds. We are inclined to believe that MCC950 may inhibit the closure of chronic wounds and that it does not alter wound-associated macrophage polarisation.

scholarly journals Inhibition of 11β-HSD1 Expression by Insulin in Skin: Impact for Diabetic Wound Healing

2020 ◽  
Vol 9 (12) ◽  
pp. 3878
Author(s):  
Christina B. Brazel ◽  
Jan C. Simon ◽  
Jan P. Tuckermann ◽  
Anja Saalbach
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Health Care Systems ◽  
Stress Hormones ◽  
Myeloid Cells ◽  
Inhibitory Effect ◽  
Related Factors ◽  
Delayed Wound Healing ◽  
Impaired Wound Healing ◽  
Obesity And Diabetes

Chronic, non-healing wounds impose a great burden on patients, professionals and health care systems worldwide. Diabetes mellitus (DM) and obesity are globally highly prevalent metabolic disorders and increase the risk for developing chronic wounds. Glucocorticoids (GCs) are endogenous stress hormones that exert profound effects on inflammation and repair systems. 11-beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is the key enzyme which controls local GC availability in target tissues such as skin. Since treatment with GCs has detrimental side effects on skin integrity, causing atrophy and delayed wound healing, we asked whether the dysregulated expression of 11β-HSD1 and consequently local GC levels in skin contribute to delayed wound healing in obese, diabetic db/db mice. We found increased expression of 11β-HSD1 during disturbed wound healing and in the healthy skin of obese, diabetic db/db mice. Cell analysis revealed increased expression of 11β-HSD1 in fibroblasts, myeloid cells and dermal white adipose tissue from db/db mice, while expression in keratinocytes was unaffected. Among diabetes- and obesity-related factors, insulin and insulin-like growth factor 1 down-regulated 11β-HSD1 expression in fibroblasts and myeloid cells, while glucose, fatty acids, TNF-α and IL-1β did not affect it. Insulin exerted its inhibitory effect on 11β-HSD1 expression by activating PI3-kinase/Akt-signalling. Consequently, the inhibitory effect of insulin is attenuated in fibroblasts from insulin-resistant db/db mice. We conclude that insulin resistance in obesity and diabetes prevents the down-regulation of 11β-HSD1, leading to elevated endogenous GC levels in diabetic skin, which could contribute to impaired wound healing in patients with DM.

scholarly journals The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

2020 ◽  
Vol 13 (4) ◽  
pp. 60 ◽  
Author(s):  
Simona Federica Spampinato ◽  
Grazia Ilaria Caruso ◽  
Rocco De Pasquale ◽  
Maria Angela Sortino ◽  
Sara Merlo
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Negative Consequences ◽  
Impaired Wound Healing ◽  
Patients With Diabetes ◽  
Reparative Process ◽  
Dipeptidylpeptidase 4 ◽  
Therapeutic Alternatives ◽  
Near Future ◽  
Old Drugs

Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing.

scholarly journals The potential of human induced pluripotent stem cells for modelling diabetic wound healing in vitro

2018 ◽  
Vol 132 (15) ◽  
pp. 1629-1643 ◽  
Author(s):  
Patricia E. Martin ◽  
Erin M. O’Shaughnessy ◽  
Catherine S. Wright ◽  
Annette Graham
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Chronic Wounds ◽  
Healing Process ◽  
Diabetic Patients ◽  
Impaired Wound Healing ◽  
Induced Pluripotent

Impaired wound healing and ulceration caused by diabetes mellitus, is a significant healthcare burden, markedly impairs quality of life for patients, and is the major cause of amputation worldwide. Current experimental approaches used to investigate the complex wound healing process often involve cultures of fibroblasts and/or keratinocytes in vitro, which can be limited in terms of complexity and capacity, or utilisation of rodent models in which the mechanisms of wound repair differ substantively from that in humans. However, advances in tissue engineering, and the discovery of strategies to reprogramme adult somatic cells to pluripotency, has led to the possibility of developing models of human skin on a large scale. Generation of induced pluripotent stem cells (iPSCs) from tissues donated by diabetic patients allows the (epi)genetic background of this disease to be studied, and the ability to differentiate iPSCs to multiple cell types found within skin may facilitate the development of more complex skin models; these advances offer key opportunities for improving modelling of wound healing in diabetes, and the development of effective therapeutics for treatment of chronic wounds.

scholarly journals Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing

1996 ◽  
Vol 320 (2) ◽  
pp. 659-664 ◽  
Author(s):  
Marianne MADLENER ◽  
Cornelia MAUCH ◽  
Walter CONCA ◽  
Maria BRAUCHLE ◽  
William C. PARKS ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Healing Process ◽  
Branching Morphogenesis ◽  
Transforming Growth Factor Β1 ◽  
Impaired Wound Healing ◽  
Factor Α

Keratinocyte growth factor (KGF) has been implicated in wound re-epithelialization and branching morphogenesis of several organs. To determine whether KGF induces these effects via induction of matrix metalloproteinase expression we have analysed the effect of KGF on the expression of stromelysin-2 in cultured HaCaT keratinocytes. Here we show a strong induction of stromelysin-2 mRNA within 5–8 h of stimulation of these cells with KGF. The degree of induction was similar to that achieved by treatment with epidermal growth factor or tumour necrosis factor α, whereas the stimulatory effect of transforming growth factor β1 was even stronger. To determine whether the induction of stromelysin-2 expression by growth factors and cytokines might be important for wound healing, we analysed the expression of this gene during the healing process of full-thickness excisional wounds in mice. Whereas stromelysin-2 mRNA could hardly be detected in unwounded skin, a biphasic induction was seen after injury and highest levels were found at days 1 and 5 after wounding. Hybridization in situ revealed the presence of stromelysin-2 mRNA in basal keratinocytes at the wound edge but not in the underlying mesenchymal tissue. During impaired wound healing as seen in glucocorticoid-treated mice, stromelysin-2 expression was significantly increased compared with untreated control mice. Taken together, these results suggest that correct regulation of this broad-spectrum metalloproteinase might be important for normal repair.

The Role of Matrix Metalloproteinases in Wound Healing

2002 ◽  
Vol 92 (1) ◽  
pp. 12-18 ◽  
Author(s):  
David G. Armstrong ◽  
Edward B. Jude
Keyword(s):  
Wound Healing ◽  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Chronic Wounds ◽  
Basic Knowledge ◽  
Collagenolytic Activity ◽  
Tissue Inhibitors Of Metalloproteinase ◽  
High Prevalence ◽  
Healing Wounds

The structure, classification, function, and regulation of matrix metalloproteinases in normal and abnormal wound healing is discussed. Results from key studies suggest that neutrophil-derived matrix metalloproteinase 8 (MMP-8) is the predominant collagenase present in normal healing wounds, and that overexpression and activation of this collagenase may be involved in the pathogenesis of nonhealing chronic leg ulcers. Excessive collagenolytic activity in these chronic wounds is possible because of the reduced levels of tissue inhibitor metalloproteinase 1 (TIMP-1). However, until recently, there have been no studies evaluating levels of matrix metalloproteinase or tissue inhibitors of metalloproteinase activity in chronic diabetic foot wounds. Improving basic knowledge and pharmaceutical intervention in this area ultimately may help clinicians identify and proactively intervene in an effort to prevent normal wounds from becoming chronic. This may prevent the high prevalence of morbidity associated with this significant health problem. (J Am Podiatr Med Assoc 92(1): 12-18, 2002)

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