Molecular mechanisms of pharmaconutrients

Abstract

Nutritional supplementation has become the standard of care for management of critically ill patients. Traditionally, nutritional support in this patient population was intended to replete substrate deficiencies secondary to stress-induced catabolism. Recognition of the influence of certain nutrients on the immune and inflammatory response of the critically ill has led to the evolution of more sophisticated nutritional strategies and concepts. Administration of immune-enhancing formulas supplemented with a combination of glutamine, arginine, omega-3 fatty acids (omega-3 FA), and nucleotides have been shown in most studies to reduce infectious outcomes. More recently, the separation of nutritional support from the provision of key nutrients has led to a further appreciation of the immunomodulatory and anti-inflammatory benefits of isolated nutrients, such as glutamine and antioxidants. The purpose of this article is to review the molecular mechanisms that are unique to each class of frequently utilized nutrients. A better understanding of the specific molecular targets of immunonutrients will facilitate application of more refined nutritional therapies in critically ill patients.

Fig. 1. Overview of the proposed mechanisms for differential modulation of gut function by enteral glutamine and arginine in the hypoperfused gut

Following gut ischemia/reperfusion (IR), the proinflammatory transcription factor, AP-1, is increased, as is the downstream, proinflammatory enzyme iNOS. Both are associated with gut inflammation, mucosal injury, and dysfunction. When the enteral nutrient, arginine, is added to the hypoperfused gut, iNOS expression and AP-1 DNA-binding activity are further increased. Arginine is a known precursor to iNOS, but the mechanism by which arginine increases AP-1 is unknown. There is a recently described, NO-mediated protein kinase G pathway that may explain the increase in AP-1 by arginine. PPARγ is believed to inhibit the proinflammatory pathway at the level of AP-1, protecting the hypoperfused gut. Glutamine increases PPARγ DNA-binding activity and may be a novel PPARγ agonist. When PPAR γ is activated, it heterodimerizes with the retinoic acid receptor (RXR) and then binds to the peroxisome proliferator response element (PPRE), resulting in target gene expression.

Fig. 2. Differential pathways for arginine metabolism

L-Arginine is differentially metabolized based on the predominant cytokine profile. Th-1 cytokines that accompany the pro-inflammatory response lead to nitric oxide and reactive oxygen species as by-products of arginine. When a TH-2 cytokine profile exists, arginine is metabolized by arginase-1 into proline and polyamines, which promotes cell division and collagen synthesis. IL-1 (interleukin 1), IFN-γ (interferon gamma), iNOS (inducible nitric oxide synthase), NO (nitric oxide), ROS (reactive oxygen species). IL-10 (interkeukin 10), IL-4 (interleukin 4), TGF-β (tumor growth factor beta).

Fig 3. Antioxidant enzymes catalyze the breakdown of reactive oxygen species (ROS)

Antioxidant enzymes are the first line of defense against free radical damage. Superoxide dismutase (SOD) is associated with various cofactors, selenium (Se), zinc (Zn) and manganese (Mn); it initiates the breakdown of free radicals into hydrogen peroxide (H202). Hydrogen peroxide, which is also harmful to the host, is further catabolized into water and oxygen by catalase and glutathione peroxidase (GPX).