Arginine is required for the normal growth and proliferation of lymphocytes in vitro. While the diminished mitogenic response seen in arginine-free conditions was initially attributed to the reduction in protein and polyamine synthesis, the demonstration that normal function and DNA synthesis can be returned by the addition of NO donors (sodium nitroprusside, S-nitrosoacetyl penicillamine) has forced a reconsideration of this premise (Efron et al., 1991).
Tumour growth (C1300 neuroblastoma)
Days post tumour inoculation Fig. 5.4. The effect of supplemental arginine on the growth of a C1300 neuroblastoma in mice with protein-calorie malnutrition (adapted from Reynolds et al., 1988b).
Early mechanistic studies of the in vivo effect of supplemental arginine focused on T-cell activity. Increased delayed-type hypersensitivity responses, measured by foot-pad or ear-lobe thickness following inoculation of foreign material in previously sensitized hosts has been demonstrated in normal mice given supplemental arginine and in the settings of tumour, burn and sepsis (Saito et al., 1987; Reynolds et al., 1988b, 1990; Lewis and Langkamp-Henken, 2000). This has been found to correlate with increased T-cell mitogenesis in response to stimulation by concanavalin A, phytohaemagglutinin or tumour antigens, in addition to increases in specific T-cell cytotoxicity (Reynolds et al., 1988b, 1990). Improvements in mononuclear-cell response to stimulation with concanavalin A have also been demonstrated, using cells from human subjects given arginine (Daly et al., 1988). The mechanisms behind these effects remain unclear. While early reports suggested the involvement of a thymic hormone, similar effects have been produced in athymic nude mice (see Barbul, 1986). Up-regulation of IL-2 receptor expression and, in tumour-bearing mice, IL-2 production have been demonstrated and suggested as a mechanism behind increased T-cell activity (Reynolds et al., 1988b). Gianotti et al. (1993) found that the survival advantage conferred on mice by arginine in the setting of abdominal sepsis was eliminated by the concomitant administration of the NOS inhibitor N-omega-nitro-L-arginine (NNA) and proposed the arginine-NO pathway as the key factor. Meanwhile, the importance of the hypothalamic-pituitary axis in arginine-mediated immune modulation was demonstrated by Barbul et al. (1983), who found that the thymotropic effects of supplemental arginine following injury were not reproduced in hypophysectomized rats.
In addition to the above alterations seen in T-cell functions, supplemental arginine also benefits the innate immune response, with increases in macrophage and natural killer cell cytotoxicity (Reynolds et al., 1988a). The link between arginine metabolism and the tumoricidal activity of macrophages was highlighted by Mills et al. (1992) in a study looking at macrophage function following intraperitoneal implantation of P815 mastocytoma in naive and pre-immunized mice. Tumour rejection was associated with elevated levels of NO production and iNOS expression in peritoneal macrophages and with a reduction in arginase activity. In contrast, during times of exponential tumour growth, arginase activity was increased, with a corresponding elevation in urea and ornithine production, while NO and citrulline production were reduced. The balance between iNOS and arginase activity in macrophages has been demonstrated in many different models and is considered to be central to the shift in phenotype from wound to cytotoxic macrophage.
Both human and animal models have demonstrated the beneficial effect of arginine in wound healing. Arginine supplementation of the diet of injured rats resulted in accelerated wound healing, increased wound tensile strength and increased collagen deposition (see Barbul et al., 1983). Wound healing was assessed by fresh wound strip breaking strength, fixed breaking strength and the amount of reparative collagen deposition indexed by the hydroxypro-line content of implanted sponges. These findings can be explained, in part, by the increased requirement for arginine to synthesize reparative connective tissue. However, as with T-cell mitogenesis, the improvement in wound healing was not reproducible in hypophysectomized animals, suggesting a more complex mechanism.
In human studies, Kirk et al. (1993) examined the effect of arginine supplementation (17 g day-1) on wound healing in an otherwise healthy elderly population. While epithelialization of a partial-thickness wound was not improved, collagen synthesis (as determined by hydroxyproline and protein deposition in subcutaneous polytetrafluroethylene implants) was significantly increased in those subjects given arginine.
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