How nitric oxide helps regulate biological function

Speeding or restarting wound healing after injury, surgery, or disease is a primary goal in veterinary care

By Jacob Adams Ph.D. •  Noxsano

FIGURE 1

What do wound healing, medications for ED, biofilm quorum sensing, fruit ripening, and the 1998 Nobel Prize for Physiology and Medicine have in common? Nitric oxide. This remarkable diatomic gas plays an oversized function in regulating biological processes everywhere from bacteria to animals to humans. Nitric oxide is implicated in everything from memory and learning to skin tone and most importantly, wound healing.

Speeding or restarting wound healing after injury, surgery, or disease, and returning the animal to full health as quickly as possible is a primary goal in veterinary care. Rapid healing means lower stress on the animal, reduced risk of infection, and lower stress and cost to the animal’s owner. Nitric oxide is known to be a critical part of the normal wound healing cascade- a discovery that resulted in the aforementioned Nobel Prize. The therapeutic value of nitric oxide in wound healing comes from regulating inflammatory response, cell proliferation, collagen formation, antimicrobial action and angiogenesis (Figure 1).

Nitric Oxide- Biologic

The enzyme, nitric oxide synthase, converts L-arginine to L-citrulline releasing nitric oxide in vivo. Three isoforms of the enzyme have been characterized. Wound healing is primarily controlled by endothelial nitric oxide synthase which is primarily expressed in the skin and blood vessels. Endothelial nitric oxide synthase is activated by thrombin when a wound occurs and then orchestrates the cascade of processes necessary for wound closure.

Nitric Oxide-Natural Antimicrobial

Nitric oxide is utilized in two ways by the body post-coagulation to kill or remove any pathogens in the wound bed to prevent infection. At low concentrations, nitric oxide acts as a signaling molecule that promotes the growth and activity of immune cells. At high concentrations, nitric oxide induces broad spectrum damage to pathogens caused by nitrosative and oxidative reactions. The damage sustained by the pathogens subject to these chemical processes is extensive. Few bacteria are able to escape the antimicrobial effect of nitric oxide. Nitric oxide further controls immune cell signaling and the biochemical reactions which are used to defend against bacteria, fungi, viruses, and parasites.

Nitric oxide is a biological signal that controls the dispersal of biofilms to the more susceptible form of planktonic bacteria. Biofilms are notoriously persistent and generally very resistant to antimicrobials and antibiotics. Planktonic bacteria are much more sensitive to antimicrobials and antibiotics. Nitric oxide upregulates expression of endogenous collagenase, which autolytically debrides the wound, to further promote the healing process.

Nitric Oxide-Wound Repair

Nitric oxide acts to coordinate proliferation, differentiation, and apoptosis in a number of cell types involved in wound healing. In testing, nitric oxide donors significantly increase fetal bovine serum-induced thymidine incorporation into the DNA of human dermal fibroblasts and enhance fibroblast growth factor- or platelet-derived growth factor-induced DNA synthesis. Nitric oxide has been shown to stimulate the proliferation of endothelial cells, protect endothelial cells from apoptosis, and mediate vascular endothelial growth factor (VEGF) production. These effects of nitric oxide on endothelial cells guide angiogenesis, the formation of new capillaries. The resulting increased blood flow boosts the transport of proteins into the wound bed facilitating wound healing. Low levels of nitric oxide increase keratinocyte proliferation. Nitric oxide coordinates increased collagen synthesis and deposition in the final phases of wound healing. Treatment with nitric oxide donors has been shown to increase collagen formation from fibroblasts and conversely collagen formation decreases following nitric oxide synthase inhibition.

The role of nitric oxide in wound healing is multifaceted, its presence and amount delivered are critical in every stage of wound healing. The challenge in medicine has been to safely, efficiently, and effectively deliver the correct amount of nitric oxide at the point of need, the wound bed, to control and drive the healing process.

Nitric Oxide-Delivery Systems

Multiple nitric oxide delivery systems for wound care have been developed. The success of nitric oxide delivery systems in treating laboratory models of wounds and infection spurs continued development of this promising technology.

  • Gaseous Nitric Oxide

Nitric oxide containing gas flows have proven to be effective in a long term clinical practice for therapy of wounds and inflammatory diseases. Delivery to the wound bed may require immobilizing the patient during treatment. Nitric oxide in this form is supplied in gas cylinders and requires proper storage. Intermittent exposure may be practiced to avoid long immobilization periods with administration occurring over multiple visits.

  • Generation of Nitric Oxide by Acidified Nitrite

Nitric oxide can be produced when combined with a weak acid such as citric acid with wound healing studies showing promising results. Length of exposure time and skin sensitivity to low pH must be managed. Consistent biologically appropriate dosing requires care as the reaction generates an immediate spike in nitric oxide concentration. Progress has been made on this approach by immobilizing the acid to carefully control mixing nitrite salts. Long-term controlled delivery at biologically appropriate levels is the current focus to improve this delivery method.

  • Low Molecular Weight and Macromolecular Nitric Oxide Donors

Nitric oxide donors in many forms, including organic nitrates, nitrites, S-nitrosothiols, nitrosamines, N-diazeniumdiolates, and metal–nitric oxide complexes, have been developed to release nitric oxide on demand. The donors are often encapsulated in or conjugated onto a variety of biomaterial vectors to develop delivery systems. Nitric oxide release relies on ambient conditions in the wound to activate the delivery system though combination with a release agent may be used to improve control. Nitric oxide synthase mimics to catalyze the production and release of nitric oxide from L-arginine have also been developed. Each approach comes with its own method of activation and delivery and most have demonstrated at least laboratory promise for improved wound healing.

  • Nitric Oxide by Electrochemical Activation

Nitric oxide can be generated from sodium nitrite via electrochemical reduction. This system has the ability to deliver nitric oxide at a steady, biologically relevant concentration over long time periods. To date the use of powered systems or expensive electrodes has limited the utility of the system. A new electrochemical system has been introduced that is activated by the addition of water. Once activated, the electrochemical system will generate a biologically relevant level of nitric oxide over multiple days. The first practical application of this approach has just been released by Noxsano in wound dressings that are optimized to deliver nitric oxide at a level that drives increased blood flow, angiogenesis, proliferation, and epithelialization resulting in improved wound healing (Figure 2).

This Education Center article was underwritten by Noxsano.

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