CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity

Abstract

Background Although the development of ileus is widespread and negatively impacts patient outcomes, the mechanism by which ileus develops remains unclear. The purpose of our study was to examine the contribution of myogenic mechanisms to postoperative ileus development and the involvement of inflammation in mediating intestinal smooth muscle dysfunction. Methods Contractile activity and the effects of CXCL1 were studied in a gut manipulation model. Key Results Contraction amplitude in the ileum decreased significantly, while tone increased significantly in response to gut manipulation. Differences in contraction amplitude were affected by tetrodotoxin at earlier time points, but not at later time points. Agonist‐induced contractions in the small intestine decreased significantly with ileus development. Intestinal transit slowed significantly after the induction of ileus. Myosin light chain phosphorylation was significantly decreased and edema increased significantly in the intestinal wall. Conditioned media from mechanically activated macrophages depressed intestinal contractile activity. CXCL1 (GroA) was significantly increased in the mechanically activated macrophages and intestinal smooth muscle within 1 hour after induction of ileus compared with control cells and sham animals, respectively. Treatment with CXCL1 significantly decreased contraction amplitude and agonist‐induced contractile activity and increased tone in the small intestine. In the gut manipulation model, treatment with a CXCR2 antagonist prevented the decrease in agonist‐induced contractile activity but not contraction amplitude. Conclusions & Inferences These data suggest that CXCL1, released from macrophages during intestinal wall stress, can suppress intestinal contractile activity. CXCL1 is a potential target for preventing or treating ileus in trauma patients.

Mechanotransduction at the Plasma Membrane-Cytoskeleton Interface

“…Examples of mechanotransduction include stretch-induced relaxation of the esophageal sphincter and the colon; at the cellular level, increased stretch modulates P21-activated kinase signaling resulting in altered myosin light chain phosphorylation and, consequently, changes in intestinal smooth muscle cell contractility [ 199 , 200 ]. Dysregulation of mechanotransduction contributes significantly to pathology in the gut, ranging from the development of ileus to cancer [ 201 , 202 ]. Thus, understanding mechanotransduction in the gut is crucial for developing successful strategies to treat GI motility disorders and pathologies.…”

“…A wide variety of immune cells reside in the gastrointestinal tract, including resident macrophages in the intestinal wall. These cells may also respond to stretch and release inflammatory mediators [ 201 ]. Macrophages also respond to pressure by increasing phagocytosis and cytokine release, possibly through focal adhesion kinase and extracellular signal-related kinase inhibition [ 222 ].…”

Postoperative Ileus and Postoperative Gastrointestinal Tract Dysfunction: Pathogenic Mechanisms and Novel Treatment Strategies Beyond Colorectal Enhanced Recovery After Surgery Protocols

“…The cytokine CXCL1 released from macrophages during intestinal surgical trauma was shown to suppress intestinal contractility. CXCL1 may provide another target for intervention to ameliorate POI and deserves further investigation (Docsa et al, 2020).…”

Targeting Mechano-Transcription Process as Therapeutic Intervention in Gastrointestinal Disorders

“…This system uses a computer-regulated bioreactor to apply finely controlled multi-axial static or cyclic strains through vacuum pressure to cells cultured on flexible membrane plates. It has been used to study mechano-transcription in vitro in gut smooth muscle cells (SMC) (Wehner et al, 2010;Shi et al, 2011), epithelial cells (Gayer and Basson, 2009), and macrophages (Wehner et al, 2010;Docsa et al, 2020). Another in vitro system applies hydrostatic pressure to stretch cells (e.g., intestinal SMC) cultured on silicon membranes (Gutierrez and Perr, 1999).…”

“…Recent reports suggest that induction of several other proinflammatory molecules by mechanical stress may also contribute to motility abnormalities (Wehner et al, 2010;Lin et al, 2014b;Docsa et al, 2020). It was discovered that mechanical stress in vitro in cultured gut SMCs or in vivo in the model of obstruction significantly induced gene expression of IL-6, chemokine (C-C motif) ligand 2 (CCL-2), iNOS, and several other pro-inflammatory mediators in the muscle cells.…”