Role of intestinal inflammation in oxidized lipid induced pulmonary hypertension

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SUMMARY Pulmonary arterial hypertension (PAH) is a chronic lung disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular (RV) heart failure and death. Over the last five years, our group and others have demonstrated the critical role of oxidized fatty acids in the pathogenesis of PAH. Levels of oxidized fatty acids of the lipoxygenase (LOX) pathway; hydroxyeicosatetraenoic acids (HETEs) are upregulated in the lungs of patients with PAH as well as in rats with pulmonary hypertension (PH). We were the first to establish that dietary supplementation of a single oxidized fatty acid (15HETE) of the LOX pathway is sufficient to cause PH in wild type mice in the absence of any other PH stimulus. In our very recent publication in Hypertension, we reported T cell-dependent endothelial cell apoptosis as one of the mechanisms underlying 15HETE induced PH. However, the exact molecular mechanisms leading to PAEC apoptosis and onset of PH are not known. To unravel the molecular mechanisms, we performed RNA-Seq on the lungs and intestine of mice on 15HETE diet and integrated our RNA-Seq data with online microarrays of human PAH lungs and identified IFI44 (IFN inducible protein 44) as the only novel common gene that was significantly upregulated. IFI44 is an interferon inducible protein and our preliminary data shows that IFNα4 is specifically increased in the small intestine of mice on 15HETE diet. Our preliminary time course experiments revealed increased expression of IFI44 in the small intestine, which precedes its upregulation in the lung, suggesting that 15HETE may act on the small intestine initially. In addition, our pilot data shows that IFI44 is expressed in the immune cells in the lungs of human PAH patients and in T cells in mouse lungs on 15HETE diet. Our bioinformatic analysis also revealed that expression of IFI44 in immune cells in the lungs correlates with CXCL10 (a proinflammatory cytokine) and TRAIL (Tumor Necrosis Factor Related Apoptosis Inducing Ligand). TRAIL and CXCL10 are both known to induce endothelial cell apoptosis. Our preliminary data also shows i) Knockdown of IFI44 in the lungs of mice on 15HETE diet prevented development of PH, and ii) blocking the pathologic action of Cxcl10 rescues PH development. Taken together, our overall hypotheses are i) dietary 15HETE acts on intestinal epithelial cells to produce IFN4, which induces IFI44 in specific immune cells of the Lamina Propria. IFI44 positive immune cells migrate to the lungs and in coordination with CXCL10/TRAIL trigger PAEC death, causing PH; and ii) IFI44 and CXCL10 can serve as novel therapeutic targets in the lungs to prevent or even rescue development of PH in mice on 15HETE diet. Aim 1 will determine the mechanisms by which 15HETE activates the intestinal epithelium resulting in the development of PH; Aim 2 will examine how activation of IFI44 in immune cells in the small intestine induces endothelial cell apoptosis in the lungs through CXC10 and/or TRAIL dependent mechanisms causing pulmonary hypertension; and Aim 3 will examine whether IFI44 and CXCL10 can serve as novel therapeutic targets in the lungs to prevent or rescue development of PH in mice on 15HETE diet.