Acceleration of wound healing by growth hormone-releasing hormone and its agonists

Abstract

Despite the well-documented action of growth hormone-releasing hormone (GHRH) on the stimulation of production and release of growth hormone (GH), the effects of GHRH in peripheral tissues are incompletely explored. In this study, we show that GHRH plays a role in wound healing and tissue repair by acting primarily on woundassociated fibroblasts. Mouse embryonic fibroblasts (MEFs) in culture and wound-associated fibroblasts in mice expressed a splice variant of the receptors for GHRH (SV1). Exposure of MEFs to 100 nM and 500 nM GHRH or the GHRH agonist JI-38 stimulated the expression of α-smooth muscle actin (αSMA) based on immunoblot analyses as well as the expression of an αSMA-β-galactosidase reporter transgene in primary cultures of fibroblasts isolated from transgenic mice. Consistent with this induction of αSMA expression, results of transwellbased migration assays and in vitro wound healing (scratch) assays showed that both GHRH and GHRH agonist JI-38 stimulated the migration of MEFs in vitro. In vivo, local application of GHRH or JI-38 accelerated healing in skin wounds of mice. Histological evaluation of skin biopsies showed that wounds treated with GHRH and JI-38 were both characterized by increased abundance of fibroblasts during the early stages of wound healing and accelerated reformation of the covering epithelium at later stages. These results identify another function of GHRH in promoting skin tissue wound healing and repair. Our findings suggest that GHRH may have clinical utility for augmenting healing of skin wounds resulting from trauma, surgery, or disease.smooth muscle | actin | fibroblast proliferation | growth hormone G rowth hormone-releasing hormone (GHRH) is produced by the hypothalamus and acts on the pituitary, stimulating the production and release of growth hormone (GH) (1). Much evidence suggests that besides its hypophyseal action, GHRH plays a role in extrapituitary tissues and importantly in cancers stimulating tumor growth by paracrine and/or autocrine mechanisms (2, 3). Conversely, antagonistic analogs of GHRH potently inhibit the growth of various experimental human cancers in vitro and in vivo, suggesting that GHRH antagonists could serve as another specific class of anticancer agents (4).In addition to the hypothalamus, expression of GHRH has been reported in several nonhypothalamic tissues including placenta, ovaries, testes, lymphocytes, and others (5-14), but the physiological significance of this ectopic production of GHRH remains poorly elucidated. However, it has been suggested that locally produced GHRH promotes follicular maturation by paracrine modulation of the stimulatory action of follicle stimulating hormone on granulosa cell function (12), whereas in Leydig cells, GHRH contributes to spermatogenesis (9). Recent evidence also demonstrates that this neuropeptide can induce cardiac repair after myocardial infarction, by mechanisms involving a direct action on the cardiomyocytes (15, 16). Lately, it was also reported that GHRH agonists stimulate the proliferation...

Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation

“…The extrapituitary functions of GHRH are mediated through GHRH-R and its splice variants, particularly SV-1 (23)(24)(25). However, the pituitary-type GHRH-R rather than SV-1 is the predominant form of receptor expressed in normal ocular tissues (26).…”

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

“…Although peripheral tissues rarely express full-length GHRH-R, splice variants can also be found (21). Thus, GHRH-R and splice variant SV1 are present not only in tumors but also in myocardium, pancreatic β-islet cells, and fibroblasts (22)(23)(24). Nonpituitary GHRH can modulate cell proliferation, especially in malignant tissues (18), promote healing of skin wounds, inhibit cardiomyocyte apoptosis, and reduce infarct size in isolated rat heart after ischemia reperfusion and in vivo after myocardial infarction (21)(22)(23)(24)(25).…”

“…Thus, GHRH-R and splice variant SV1 are present not only in tumors but also in myocardium, pancreatic β-islet cells, and fibroblasts (22)(23)(24). Nonpituitary GHRH can modulate cell proliferation, especially in malignant tissues (18), promote healing of skin wounds, inhibit cardiomyocyte apoptosis, and reduce infarct size in isolated rat heart after ischemia reperfusion and in vivo after myocardial infarction (21)(22)(23)(24)(25). Moreover, GHRH agonists were shown to stimulate cardiac myocytes, to accelerate regeneration of the heart in rats after myocardial infarct, to stimulate pancreatic β-islet cells, and to accelerate wound healing in mice (21)(22)(23)(24).…”

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

“…Pretreatment with JI-36 also improves the engraftment and the metabolic function of islets following transplantation to STZ-induced diabetic mice (12). GHRH agonist, JI-38, has been shown to have a cardioprotective effect after myocardial infarction, and to accelerate wound healing (14,18). In view of these findings of stimulatory effects of GHRH agonists of the JI series, still more potent analogs of GHRH(1-29) have been developed in our laboratory (19).…”