PPARgamma and PPARgamma agonists in septic shock

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DESCRIPTION (provided by applicant): Sepsis is a systemic response to infection characterized by hemodynamic and metabolic derangements that may result in septic shock, multiple organ system failure and death. Although it occurs in people of all ages, there is clinical evidence that the incidence and mortality of sepsis is disproportionately increased in elderly adults. Antibiotic therapy may effectively treat an underlying infection. However, this treatment is not sufficient to reverse the systemic inflammation and its consequences. In the previous funding period, we have observed that the peroxisome proliferator activated receptor-3 (PPAR3), a nuclear receptor with anti-inflammatory properties, declines progressively in several organs and tissues during sepsis. The extent of PPAR3 downregulation correlates with the severity of the inflammatory response. On the contrary, treatment of rodents with PPAR3 ligands improves survival, ameliorates lung injury and cardiovascular derangement. The sepsis- induced decline in PPAR3 expression and function inversely correlates with phosporylation of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinases known to be capable of modifying PPAR3 activity. Our studies have also demonstrated that other nuclear receptors may regulate PPAR3 activation and modulate the inflammatory response. For example, we have observed that PPAR3 may interact with liver X receptor-1 (LXR1) a similar nuclear ligand-activated transcription factor, in controlling the inflammatory response in macrophages in vitro. Other in vivo studies have demonstrated that activation of PPAR4, another receptor of the PPAR family, reduces the severity of the inflammatory response in endotoxic shock and polymicrobial sepsis. Interestingly, we have observed that lung expression of PPAR3, PPAR4 and LXR1 is also a function of the aging process and it declines in mature mice (11-12 months old), which appear to be more susceptible to polymicrobial sepsis. Thus, our preliminary data have identified the existence of a complex signaling network that is important to the anti-inflammatory role of PPAR3. Our hypothesis is that downregulation of the expression and anti-inflammatory function of the nuclear receptors PPAR3, PPAR4 and LXR1 plays an important role in the systemic inflammatory response of sepsis. On the contrary, coordinate upregulation of these receptors is beneficial in sepsis. Three specific aims will test this hypothesis. (1) We will define the age-dependency of the PPAR3, PPAR4 and LXR1 expression and function under normal physiological conditions and under pathological conditions secondary to polymicrobial sepsis in vivo. (2) With "gain-of-function" and "loss-of-function" studies, we will evaluate the precise role of PPAR4 and LXR1 in coordinating the PPAR3-dependent anti-inflammatory function during polymicrobial sepsis in vivo. (3) With in vitro studies we will further identify the molecular mechanisms by which PPAR3, LXR1 or PPAR4 may induce transrepression at promoter sites of key inflammatory genes. PUBLIC HEALTH RELEVANCE Sepsis and septic shock resulting from Gram-negative or Gram-positive infection are frequent complications secondary to trauma, hemorrhage or burns in patients, and are leading causes of morbidity and mortality in critical care units. There are over 750,000 cases of sepsis resulting in 215,000 deaths each year in the USA. The incidence and mortality of sepsis increase with age from 10% in children to 38.4% in those >85 yrs old. Unfortunately, the conventional antibiotic therapies, circulatory and respiratory support are not always sufficient to reverse the systemic inflammation. Our project is aimed to understand the role of the nuclear receptors PPAR3, PPAR4 and LXR1 in regulating the inflammatory response during sepsis. This competitive renewal represents a logical extension of our previous application and will provide valuable information for the developing of novel experimental approaches to complement antibiotic therapy after sepsis.