Hydrostatic intestinal edema induced signaling pathways: Potential role of mechanical forces

Abstract

Background-Hydrostatic intestinal edema initiates a signal transduction cascade that results in smooth muscle contractile dysfunction. Given the rapid and concurrent alterations in the mechanical properties of edematous intestine observed with the development of edema, we hypothesize that mechanical forces may serves as a stimulus for activation of certain signaling cascades. We sought to examine if isolated similar magnitude mechanical forces induced the same signal transduction cascades associated with edema.

Biphasic Regulation of Myosin Light Chain Phosphorylation by p21-activated Kinase Modulates Intestinal Smooth Muscle Contractility

“…Thus, this is a mechanotransduction cell model only. Nevertheless, the regulation of MLC phosphorylation in the ECS model parallels observations in edematous intestinal smooth muscle tissue in vivo (12)(13)(14)(15). Importantly, PAK negatively regulates MLC phosphorylation in hISMCs subjected to ECS just as in the in vivo edematous intestinal smooth muscle (Fig.…”

“…We have shown previously that MLC phosphorylation was significantly decreased in edematous intestinal smooth muscle compared with non-edematous tissue (12)(13)(14)(15). As shown in Fig.…”

“…Intestinal edema causes a 6-fold increase in strain in the smooth muscle layer of the intestine compared with non-edematous tissue (11). This increased strain, resulting in increased stretching force to the intestinal smooth muscle cells, is associated with decreased intestinal contractile activity via decreased myosin light chain (MLC) 2 phosphorylation (12)(13)(14)(15). This is accomplished by edema-induced attenuation of the constitutive inhibition of MLC phosphatase in intestinal smooth muscle (7).…”

A murine model for the study of edema induced intestinal contractile dysfunction

“…We have increasingly noted the potential role of early mechanical changes to the pathogenesis of intestinal edema. (3, 4, 19–23) The 6-hour timepoint allows us the ability to examine potential contributions of mechanical changes on intestinal contractility and transit which may be initiators for signal transduction cascades culminating in intestinal contractile dysfunction. (23)…”

“…3,4,19-23 The 6-h time point allows us the ability to examine potential contributions of mechanical changes on intestinal contractility and transit which may be initiators for signal transduction cascades culminating in intestinal contractile dysfunction. 23 In summary, we have developed a novel murine model for the study of intestinal edema and subsequent contractile dysfunction. The elimination of factors classically associated with inflammation and ischemia/reperfusion injury, such as neutrophil infiltration and mucosal injury allows us to target the signal transduction cascades affected by edema alone and further clarifies the importance of intestinal edema as a potential initiation and/or propagator of dysfunctional signaling pathways leading to the functional endpoint of ileus.…”