Intestinal Contractility

Intestinal Contractility

Feeding intolerance and ileus, caused by slowed gastrointestinal motility, are common complications in surgical patients, and critically ill and trauma patients. Feeding intolerance and ileus cause delayed enteral feeding, prolonged hospital stays, and increased complications; however, there are no effective pharmacological treatments for ileus. Existing prokinetic drugs, drugs that increase gastrointestinal motility, target the enteric nervous system. However, we and others have shown that gastrointestinal smooth muscle is dysfunctional in ileus animal models. Phosphorylation of myosin light chain is the rate-limiting step in smooth muscle contraction; thus, our research is focused on the dysregulation of myosin light chain (MLC) phosphorylation during the development of ileus. Our long term goal is to identify drug targets in intestinal smooth muscle for the treatment of postoperative and trauma-induced ileus.

Inflammation is a key component of ileus and one of our objectives is to determine the mechanism by which inflammatory cytokines affect the regulation of MLC phosphorylation. We found that CXCL1 and LIX are both upregulated early in the development of ileus. Thus, we are investigating how these cytokines which signal via C-X-C Motif receptor 2 (CXCR2), decrease MLC phosphorylation to inhibit smooth muscle function. The results of these studies will improve our understanding of how cytokines can affect gastrointestinal motility and provide a basis for pursuing novel drug targets in the CXCR2 signaling cascade for the treatment of ileus.

Another avenue of research is the role of p21-activated kinase (PAK1) in the regulation of myosin light chain phosphorylation. We found that PAK1 activity is upregulated in an animal model of ileus. We also showed that increased PAK1 activity can decrease MLC phosphorylation in intestinal smooth muscle cells. We are currently using a PAK1 knockout animal model to understand how PAK1 affects MLC phosphorylation and smooth muscle contraction. These studies will improve our understanding of the regulation of MLC phosphorylation and help in identifying new drug targets for the treatment of feeding intolerance and ileus. Effective treatment of ileus will shorten hospital and intensive care stays and reduce infectious and thromboembolic complications, thus improving patient outcomes and reducing patient care costs.

Frissítés dátuma: 2017.03.27.