Russell L. Delude, Associate Professor
Ph.D., Vanderbilt University, 1992
E-mail: deluder@ccm.upmc.edu
During septic or hemorrhagic shock, pro- and antiinflammatory cytokines are released systemically, where they bind to target receptors on a wide variety of cells. An important consequence of this systemic inflammatory response is the multiple organ dysfunction syndrome (MODS), which causes morbidity and mortality in over 750,000 people annually in the United States alone.
One goal of my research is to gain a better molecular understanding of the pathogenesis of MODS. Although the clinical manifestations of MODS can be quite varied, the organs involved typically include the lungs, gut, kidneys, and liver. The normal functioning of these organs depends on the establishment and maintenance of compositionally distinct compartments that are lined by sheets of epithelial cells. An essential element in this process is the formation of tight junctions (TJ) between adjacent cells making up the epithelial sheet. The TJ acts as a regulated semi-permeable barrier that limits the passive diffusion of solutes across the paracellular pathway between adjacent cells. In addition, the TJ serves as a fence that divides the plasma membrane into apical and basolateral domains. These barrier and fence functions, in combination with transcellular vectorial transport processes, generate distinct internal environments in the opposing compartments. In some organs, notably the gut and the lung, this barrier function is also important to prevent systemic contamination by microbes and toxins that are present in the external environment
During shock, increased production of proinflammatory mediators leads to decreased paracellular barrier function of epithelial monolayers. One working hypothesis is that proinflammatory cytokines upregulate the expression of inducible nitric oxide synthase, which causes the generation of excessive amounts of nitric oxide (NO.). We and others have used a variety of genetic and pharmacologic approaches to show that NO?is both sufficient and necessary to cause increased paracellular permeability of epithelial cells grown in cell culture and in epithelia of various organs in animal models.
We and others have shown that NO?decreases the expression and interferes with the proper targeting of TJ proteins in cultured epithelial cells. Furthermore, we have shown that epithelial barrier function decreases in an NO?dependent manner in the liver, lung, ileum, and colon of mice during a systemic inflammatory response (manuscripts submitted). We are currently attempting to identify the targets of NO?that are responsible for destruction of the TJ complex in cultured human intestinal epithelial cells. To do this, we plan to employ cell fractionation and biochemical methods to study the targeting and assembly of TJ proteins in normal and immunostimulated cells.
Our group is currently studying the antiinflammatory properties of two distinct agents, which were shown to preserve epithelial barrier function both in tissue cultured cells and in animal models of intestinal inflammation. We showed that ethyl pyruvate and nicotinamide adenine dinucleotide (NAD+) effectively blocked the production of NO?in immunostimulated enterocytes, and it also prevented nuclear translocation of NF- B. We are currently pursuing studies to understand the molecular basis for the protective effect of these compounds on epithelial function.
Recent Publication
Macias CA, Chiao JW, Xiao J, et al. Treatment with a novel hemigramicidin-TEMPO conjugate prolongs survival in a rat model of lethal hemorrhagic shock. Ann Surg. 2007; 245:305-314.
Angus DC, Yang L, Kong L, et al. Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med. 2007; 35:1061-1067.
Liu S, Stolz DB, Sappington PL, et al. HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers. Am J Physiol Cell Physiol. 2006; 290:C990-999.
Han Y, Englert JA, Yang R, Delude RL, Fink MP. Ethyl pyruvate inhibits nuclear factor-kB-dependent signaling by directly targeting p65. J Pharmacol Exp Ther. 2005; 312:1097-1105.
Fink MP, Delude RL. Epithelial barrier dysfunction: a unifying theme to explain the pathogenesis of multiple organ dysfunction at the cellular level. Crit Care Clin. 2005; 21:177-196.
Han X, Fink MP, Uchiyama T, Yang R, Delude RL. Increased iNOS activity is essential for pulmonary epithelial tight junction dysfunction in endotoxemic mice. Am J Physiol Lung Cell Mol Physiol. 2004; 286:L259-267.
Han X, Fink MP, Uchiyama T, Yang R, Delude RL. Increased iNOS activity is essential for hepatic epithelial tight junction dysfunction in endotoxemic mice. Am J Physiol Gastrointest Liver Physiol. 2004; 286:G126-136.
Han X, Fink MP, Yang R, Delude RL. Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice. Shock. 2004; 21:261-270.
