Mammalian Target of Rapamycin Inhibitors and Wound Healing Complications in Kidney Transplantation: Old Myths and New Realities

Table 1

Animal studies on mTOR-I to study its impact on wound healing.

Reference	Journal/year	Objective	Intervention	Finding
Dantal et al. [10]	Faseb Journal/2002	Hypoxia increases DNA synthesis and proliferative response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) in rat and human smooth muscle and endothelial cells. It is dependent on mTOR activation downstream enzyme phosphatidyl inositol 3-kinase. Rapamycin blocks these effects and inhibits fibrogenesis and angiogenesis.	Primary cultures of rat aortic smooth muscle cells were isolated from fresh rat aortas. Aortas were denuded from endothelium and adventitia and the aortic media was fragmented mechanically and subcultured. Effect of hypoxia and activity of PI3K were analyzed. Effect of rapamycin on hypoxia induced proliferation was also analyzed.	Hypoxia increases PDGF- and FGF-induced proliferation of vascular wall cells. PI3K activity is required for the proliferative response of vascular cells and angiogenesis in vitro under normoxia and hypoxia. Rapamycin specifically inhibits the hypoxia-mediated increase in growth factor-mediated vascular cell proliferation.
Vitko et al. [11]	Journal of Immunology/2008	Intraepithelial lymphocytes, γδT cells in the skin helps in tissue repair via cytokine and growth factor. The function of this T cell was analyzed as rapamycin treatment in a mouse model of wound repair.	Wildtype C57BL/6J mice were given daily rapamycin or vehicle control for three days before wounding. This treatment was continued after wound for total of 14 days.	Fewer wounds were closed on day 10 in rapamycin-treated mice as compared to vehicle control treated animals. Delay on day 3 wound closure was found which was similar mice lacking γδT cells (TCRδ−/− mice).
Durrbach et al. [12]	Transplantation/2006	To study the effect of EVL on wound healing in rat intestine.	4 groups of male Wistar rats were given 0 mg (group 1, control), 0.5 mg (group 2), 1 mg (group 3), and 3 mg (group 4) starting 4 hours before colonic and iliac anastomosis until killing on day 3 or day 7 of operation.	There was no difference on day 3. Breaking strength and bursting pressure were reduced on day 7 in EVL group. There was reduction in hydroxyproline content and there was less collagen deposition in the wound. The effects were more pronounced in higher EVL group of 3 mg.
Vitko et al. [13]	Wound repair and regeneration/2009	To study the effect of EVL in both intestine and abdominal wall in rats over a period of 4 weeks.	Wistar rats received a daily dose of 1 or 2 mg/kg EVL orally, from the operation day and control was given saline onwards.. Controls received saline. All rats have resection of ileum and colon with end-to-end anastomosis, and on day 7, 14, and 28, animals were killed. Their abdominal and anastomotic wounds were assessed for wound strength.	Wistar rats received a daily dose of 1 or 2 mg/kg EVL orally, from the operation day onwards. Controls received saline. In each rat, a resection of ileum and colon was performed, and end-to-end anastomoses were constructed. On day 7, 14, and 28, the animals were killed and anastomoses and abdominal wall wounds were analyzed, wound strength being the primary parameter. Breaking strength of ileum, colon, and fascia was consistently and significantly reduced in the experimental groups. Anastomotic bursting pressures followed the same pattern. Loss of strength was accompanied by a decrease in hydroxyproline content after 7 days. Thus, the negative effect of EVL on wound repair persists for at least 4 weeks after operation in this rodent model. This protracted effect may have clinical consequences and cause surgical morbidity.
Salvadori et al. [14]	Transplantation Proceeding/2007	To see the effects of rapamycin on the healing of bladder and abdominal wound closures.	Study was done in 14 male rats. Rapamycin (3 mg/d) or placebo was given to them. Midline abdominal incision was given and bladder was cut and closed with 4–0 vicryl.	Eosinophil and neutrophil infiltration and myofibroblast proliferation were significantly higher in bladder, fascia, and dermis of the control group. Lymphocyte’s infiltration was the same in both groups. Mean microvessel density as well as the percentage of cells expressing vascular endothelial growth factor in the bladder, fascia, and dermis were significantly lower among rapamycin.
Büchler et al. [15]	Transplantation Proceeding/2005	To see the effect of rapamycin on wound healing and the healing of the ureteric anastomosis.	Pigs underwent laparotomy and excision of the ureter followed by anastomosis of the ureter. The animals were randomly allocated to receive either rapamycin or placebo. The animals were sacrificed on postoperative day 5. Skin, fascia, and ureteric tissues were assessed for the tensile strength, hydroxyproline levels, and histological changes.	The tensile strength and the hydroxyproline levels in the ureter and fascia were lower in the rapamycin-treated group. However, there was no difference in the tensile strength in the skin, although the hydroxyproline levels were lower.
Flechner et al. [16]	European Journal of Cardiothoracic Surgery/2003	SDZ RAD (40–0 (2-hydroxyethyl)-rapamycin), a rapamycin derivative, inhibits fibroblast proliferation and may limit development of bronchiolitis obliterans. But, it may impair the healing of the bronchial anastomoses.	The cervical trachea in pigs was divided and reanastomosis was done. One group was given SDZ RAD for 14 days and control group was given none.	SDZ RAD significantly reduced the breaking strength of the tracheal anastomosis. However, no differences in histological samples were found between two groups.