MECHANISMS DRIVING THE FORMATION OF POST-OPERATIVE PERITONEAL ADHESIONS

The wound healing process that follows intra-abdominal surgery results in the formation of peritoneal adhesions
which occurs in over 90% percent of patients who undergo this type of procedure. Peritoneal adhesions are
fibrotic tissue that contains significant numbers of myofibroblasts and vascular smooth muscle cells (VSMCs).
Peritoneal adhesions can lead to a multitude of complications, including bowel obstructions. Bowel obstructions
have been implicated in severe morbidity and create a risk of mortality. Surgical interventions can be used to
remove peritoneal adhesions, but there is a risk of recurrence of adhesive disease in these patients. Therefore,
new therapies for the prevention and/or reversal of peritoneal adhesions are urgently needed.
Myofibroblasts and VSMCs have the capacity to secrete and remodel extracellular matrix. These processes have
been implicated as an important function to aid in fibrotic diseases. Platelet derived growth factor receptors α
and β (PDGFRα and PDGFRβ) are involved in many diseases including fibrosis. PDGFRα is typically expressed
in fibroblastic cells, whereas PDGFRβ is expressed in mural cells such as VSMCs. PDGF signaling in these cells
has been shown to induce mechanotransduction pathways by promoting actin assembly. Actin assembly can
induce the activity of Myocardin-Related Transcriptions Factors (MRTFs) and the YAP1 transcriptional cofactor.
The goal of this research program is to examine whether PDGF signaling promotes the formation of peritoneal
adhesions by activating actin assembly and thereby inducing the activity of MRTFs and YAP1. We will
accomplish this goal by using novel in vivo approaches such as cell ablation techniques in PDGFR+ positive cells
in mice. These cell types will also be molecularly characterized using NuTrap technology that allows us to identify
novel pathways that may promote the formation of peritoneal adhesions. Moreover, we will investigate the
consequences of inhibiting mechanotransduction pathways in these same cell types. Lastly, we will validate our
findings in cells isolated from patients’ peritoneal adhesion tissue.
At the end of these studies, we will have gained new insights into molecular mechanisms that drive the formation
of peritoneal adhesions. Specifically, we will learn whether the interplay between PDGF signaling and the
mechanotransduction pathways in PDGFRα+ and/or PDGFRβ+ cells. This knowledge may enable us to identify
novel approaches to prevent or reduce the formation of peritoneal adhesions and potentially other forms of
fibrosis.

Grant Number: 5R35GM142786-05
NIH Institute/Center: NIH
Principal Investigator: William Berry