Efficacy of gaseous nitric oxide in the treatment of skin and soft tissue infections

Abstract

Bacterial burden significantly interferes with the healing process in chronic ulcers. Nitric oxide (NO) plays a key role in regulating skin's response to infection and wound healing. In previous studies, we demonstrated that exogenous NO gas (gNO) at 200 parts per million (ppm) exhibits potent antimicrobial effects against a representative range of pathogens. The aim of the present study is to explore the antimicrobial properties of gNO in vivo and to determine skin cells' sensitivity to the cytotoxic effects of gNO. To test gNO's antimicrobial effects, full-thickness wounds were infected with Staphylococcus aureus on the dorsal skin surface of New Zealand White rabbit and treated with 200 ppm gNO for 8 hours/day for 3 consecutive days. Significant reduction in wound bacterial content was observed in the presence of gNO. In a separate experiment, primary cultures of human fibroblasts, keratinocytes, and endothelial cells were established to test gNO's cytotoxicity in the skin. Methyl thiazolyl tetrazolium proliferation assays demonstrated that human skin cells, unlike bacterial cells, exhibited significant resistance toward gNO cytotoxicity. In vitro migration studies on keratinocytes and endothelial cells revealed that gNO treatment does not seem to interfere with reepithelialization and angiogenesis during the process of wound healing. Following 24 hours of gNO treatment, fibroblasts expressed significantly higher levels of procollagen and, to a lesser degree, a decrease in matrix metalloproteinase -1 mRNA. In conclusion, the present study provides evidence for the potential application of high doses of gNO as an antimicrobial agent for the treatment of infection in chronic nonhealing ulcers or burn patients, without compromising the viability, and function of skin cells.

A phase I clinical study of inhaled nitric oxide in healthy adults

“…Here we provide evidence that 160 ppm NO, a concentration previously identified as an effective antimicrobial dose against various microorganisms in vitro, ex vivo and in animal models [16,17,19], can be safely delivered to healthy human lungs in a pulsed manner for 5 consecutive days. No significant adverse events occurred and only three minor adverse events, not attributable to NO, were reported.…”

“…At 160-200 ppm, NO has also been shown in vitro, ex vivo and in animal models [14][15][16][17][18][19][20] to exert potent antimicrobial effects against a broad range of microbes, suggesting its use in appropriate concentrations in CF patients. At present, however, inhalation of NO as a selective, short acting vasodilator is approved only at 80 ppm for use in full term infants with hypoxic respiratory failure associated with pulmonary hypertension [21,22].…”

Apyrase Elicits Host Antimicrobial Responses and Resolves Infection in Burns

“…Not only is NO antimicrobial at concentrations of 200 ppm but also it has been shown to improve the healing of burns. 19,20 In addition to its direct activity as an antimicrobial, NO has been implicated in gene regulation. We sought to identify NO-regulated molecules that could affect the host response to infectious agents.…”

Topical Antimicrobials for Burn Infections – An Update

“…In a study by Ghaffari et al [284] exogenous NO in gaseous state was directly administered to puncture wounds without any carriers in which the treatment achieved significant reduction in inoculated S. aureus numbers. It was also reported that gaseous NO (gNO) treatment did not cause any cytotoxic effects to skin cells tested such as fibroblasts and keratinocytes and thus did not hinder the wound healing process [284]. A topical formulation comprising gNO carriers has been patented by Av-Gay et al [285] which are capable of releasing therapeutically effective amounts of the gas when applied to a wound.…”