Our laboratory research group investigates the mechanisms that regulate inflammatory processes using different models of pancreatic diseases. During the acute pancreatitis, premature digestive enzyme activation occurs inside pancreatic acinar cells. This fact, as well as causing the self-digestion of the tissue, is accompanied by an inflammatory process that, in severe cases, is extended to distant organs and leads to the development of multiorgan failure with considerable morbidity and mortality. Experimental acute pancreatitis models have allowed us to approach some strategies to reduce the inflammation-related problems. Therefore, we use a broad range of techniques, including different "in vivo" models, primary cell cultures, established human or other animal cell lines, evaluation of signal transduction mechanisms, analytical and biophysical approaches.
We present some of the research studies we are currently developing.
* Phenotypic analysis of different macrophage populations during the development of the systemic inflammatory response.
Macrophages can be activated by different mechanisms triggering several physiological processes (defense, repair, inactivation). During the systemic inflammatory processes, macrophage populations (peritoneal, hepatic, and alveolar) combine different degrees on inflammatory phenotypes, thus indicating that the signaling among these cells is regulated by a wide range of mediators (TNFa;, IL-4, IL13, IL-10, PAP). At present, we are designing strategies to modulate the activation mechanism of some of these populations in order to prevent or minimize the progression of inflammation in different affected organs.
* “Pancreatitis Associated Protein" (PAP): a pivotal regulator of inflammation
PAP, also known as HIP/PAP or Reg2 protein, has been recently described as a part of an endogenous mechanism involved in the regulation of the inflammatory response. Although initially it was characterized as an overexpressed protein during the course of acute pancreatitis, PAP has also been associated with many inflammatory diseases, such as Crohn’s disease, ulcerative colitis and different types of cancer. We have observed that PAP reduces the synthesis of inflammatory mediators (TNFa; or IL-6) on different cell types. In the functional characterization of this protein, our group has established that PAP inhibits the inflammatory response by blocking NFkB activation through an STAT3-dependent mechanism suggesting a crosstalk between these two signaling pathways. At present, we are particularly interested in exploring the mechanism involved in the NFkB blockade through PAP as well as the identification of PAP receptor.
* Oxidized fatty acids in the control of inflammation.
It is known that fatty acids not only modulate the production of lipid but also alter expression of different inflammatory genes. The synthesis of some of these lipids (prostaglandins, leukotrienes, lipoxins, HETEs,…) is well regulated by the cell and their mechanisms as well as its receptors are well known. However, other fatty acids showing different degrees of oxidation can act as agonists or antagonists of these receptors. In pathologies such as pancreatitis, with severe white adipose tissue affected, we demonstrated that the generation of these fatty acids seriously affects the development of the inflammation by acting on regulatory nuclear factors like PPARg;. To characterize the lipid profile involved in these effects may offer new diagnostic and therapeutical tools for the treatment of inflammatory diseases.