Stress impairs wound healing of cutaneous lesions; however, the mechanism is still unclear. The aim of this study was to evaluate the effects of rotational stress on cutaneous wound healing in mice and propose a mechanism. Male mice were spun at 45 rpm for 15 min every hour beginning 3 days before wounding until euthanasia. Control animals were not subjected to stress. To confirm that catecholamines participate in stress-induced delay of wound healing, mice were treated daily with propranolol. An excisional lesion was created and measured. Seven and 14 days later, animals were killed and lesions collected. Sections were stained with hematoxylin-eosin and immunostained for alpha-smooth muscle actin and proliferating cell nuclear antigen. Matrix metalloproteinase (MMP)-2 and -9 activity, nitrite levels, and tumor necrosis factor-alpha (TNF-alpha) expression were measured in the wounds. In addition, murine skin fibroblast cultures were treated with high levels of epinephrine and fibroblast activity was evaluated. Stressed mice exhibited reduced locomotor activity and increased normetanephrine plasma levels. Rotational stress was associated with decreased wound contraction, reduced re-epithelialization, reduced MMP-2 and MMP-9 activation, but with strongly increased nitrite levels. Furthermore, inflammatory cell infiltration, TNF-alpha expression, myofibroblastic differentiation, and angiogenesis were all delayed in the stress group. Propranolol administration reversed the deleterious effects of stress on wound contraction and re-epithelialization. High epinephrine concentrations increased murine skin fibroblast proliferation and nitric oxide synthesis, and strongly inhibited skin fibroblast migration and both pro- and active MMP-2. In conclusion, rotational stress impairs cutaneous wound healing due to epinephrine increased levels.

Stress impairs cutaneous wound healing; however, it is unclear how beta-adrenoceptors participates in alterations induced by stress on skin wound repair. Therefore, the aim of this study was to investigate the effects of propranolol, a non-selective beta-blocker, administration on cutaneous wound healing of chronically stressed mice. Male mice were spun at 115 rpm for 15 min every hour from three days before wounding until euthanasia. Control animals were not submitted to stress. Stressed and control animals were treated with propranolol dissolved in water; controls received only water. Propranolol administration began one day before wounding and was continued daily until euthanasia. A full-thickness excisional lesion was performed. Seven and fourteen days later, animals were killed, and lesions were formalin-fixed and paraffin-embedded. Sections were stained with hematoxylin-eosin and immunostained against F4/80 to quantify macrophages, alpha-smooth muscle actin to quantify the myofibroblast density and proliferating cell nuclear antigen to quantify the cell proliferation. Furthermore, matrix metalloproteinases (MMP)-2 and MMP-9 activity, nitrite and hydroxyproline levels and tumor necrosis factor-alpha (TNF-alpha) expression were measured in wound. Stress and control + propranolol groups presented a delay in wound contraction, re-epithelialization, F4/80-positive macrophages, neutrophils and mast cells infiltration, cellular proliferation, angiogenesis, myofibroblastic differentiation, MMP-2 and MMP-9 activation and TNF-alpha expression, whereas an increase in the nitrite levels. Stress + propranolol group presented results similar to control group. In conclusion, stress impairs cutaneous wound healing in mice through beta1- adrenoceptors and beta2-adrenoceptors activation.

Sympathetic nerve failure has been proposed as a contributing factor in impaired cutaneous wound healing in diabetes mellitus. Nevertheless, no studies have shown whether beta-adrenoceptor blockade through beta-blocker (e.g., propranolol) administration may alter healing of diabetic cutaneous lesions. This study evaluated macro- and microscopically the effects of propranolol administration on cutaneous wound healing in streptozotocin-induced diabetic rats. Acute diabetes was induced by a single intraperitoneal injection of streptozotocin 14 days before wounding. Animals were treated with propranolol (50 mg/kg) dissolved in drinking water; controls received water only. Administration of beta-receptor antagonist began 1 day before wounding and was continued daily until euthanasia. A full-thickness excisional lesion (1 cm(2)) was created. The wound area was measured weekly and the animals were killed 14 days after wounding. Lesions and adjacent skin were formalin-fixed and paraffin-embedded. Sections were stained with hematoxylin-eosin, Sirius red, and toluidine blue, and immunostained for CD-68, alpha-smooth muscle actin and proliferating cell nuclear antigen. The wound area was significantly smaller in the propranolol-treated group than in the control group 7 and 14 days after wounding. Inflammatory cell numbers and metalloproteinase-9 levels were reduced in the propranolol-treated group compared to the control group 14 days after wounding. Cell proliferation, mast cell number, collagen deposition, blood vessel density, and nitric oxide levels were increased in the propranolol-treated group compared to the control group 14 days after wounding. Propranolol administration improves cutaneous wound healing of hyperglycemic diabetic rats by reducing the local inflammatory response and improving subsequent phases of the repair process.

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