Inositol phosphates and phosphoinositides are integral to a number of critical intracellular signaling pathways in epithelia, endothelia and immune cells that are fundamental to GI health and can contribute to GI pathology when disrupted. These pathways broadly pervade almost every aspect of GI function including, secretion, absorption, innate and adaptive immunities, and are present in all cell types. Examples include excessive or insufficient fluid secretion through disregulation of ion channel function that can lead to diarrhea, constipation, or abnormal secretion of bile or pancreatic enzymes. Importantly, infectious bacteria such as Salmonella highjack inositide metabolic pathways that cause changes in both inositol polyphosphate and phosphoinositide metabolism that contribute to pathogenicity. Phosphoinositides play multiple roles in inflammatory reactions by regulating the function of immune cells involved in both innate and acquired immunity. These range from controlling cell movement and secretion of oxygen radicals from neutrophils to modulation of macrophage, B-cell and T-cell function. More specifically, phosphatidylinositol 3 kinase (PI3K) isoforms control inflammation at many levels, from the generation of inflammatory cells to the migration/adhesion and infiltration of these cells to injured tissues. The abnormal PI3K-associated signaling networks can lead to dysregulation of the inflammatory response and are important in the pathogenesis of pancreatitis and inflammatory bowel diseases (IBD). In addition, hyperproliferative GI diseases such as cancer are linked to PI3K pathway abnormalities that figure into every aspect of oncogenesis from the regulation of cell division and apoptosis to epithelia to mesenchymal transitions and cancer cell migration/metastasis. PI3K also plays an indirect role in cancer through its involvement in chronic inflammation that is associated with the pathogenesis of GI and pancreatic cancers. The PI3K pathways are one of the common signaling pathways that link inflammation with cancer. This includes the PI3K-mediated regulatory effects on the tumor stroma, tumor-associated macrophages, cytokines and chemokines. A hallmark of inflammatory responses is the infiltration of leukocytes to the inflammatory lesion in response to chemokines and other chemoattractants. Excessive infiltration of activated leukocytes into the GI tract or pancreas is a prerequisite for the development of chronic inflammation that predispose to cancer. Many studies indicate that the polarized activation of PI3K at the leading edge of a migrating cell is a crucial and early event in the detection of a chemokine gradient. Therefore, inositide signaling pathways encompass numerous potential targets relevant to GI disorders that demand focused analysis.
Panceratic Disorder and Therapy