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1 Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
2 Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States
3 Cell Biology and Physiology, University of PIttsburgh School Medicine, PGH, Pennsylvania, United States
4 Orthopaedic Surgery, Bioengineering and Mechanical Engineering, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
5 Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States; Cell Biology and Physiology, University of PIttsburgh School Medicine, PGH, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: david.hackam{at}chp.edu.
Diseases of intestinal inflammation like necrotizing enterocolitis (NEC) are associated with impaired epithelial barrier integrity and the sustained release of intestinal nitric oxide (NO). NO modifies the cytoskeletal regulator RhoA-GTPase, suggesting that NO could affect barrier healing by inhibiting intestinal restitution. We now hypothesize that NO inhibits enterocyte migration through RhoA-GTPase, and sought to determine the pathways involved. The induction of NEC was associated with increased enterocyte NO release, and impaired migration of BrDU-labeled enterocytes from terminal ileal crypts to villus tips. In IEC-6 enterocytes, NO significantly inhibited enterocyte migration and activated RhoA-GTPase while increasing the formation of stress fibers. In parallel, exposure of IEC-6 cells to NO increased the phosphorylation of focal adhesion kinase (pFAK) and a striking increase in cell-matrix adhesiveness, suggesting a mechanism by which NO could impair enterocyte migration. NEC was associated with increased expression of pFAK in the terminal ileal mucosa of wild-type mice and a corresponding increase in disease severity compared with iNOS-/- mice , confirming the dependence of NO for FAK phosphorylation in vivo and its role in the pathogenesis of NEC. Strikingly, inhibition of the protein tyrosine phosphatase SHP-2 in IEC-6 cells prevented the activation of RhoA by NO, restored focal adhesions, and reversed the inhibitory effects of NO on enterocyte migration. These data indicate that NO impairs mucosal healing by inhibiting enterocyte migration through activation of RhoA in a SHP-2-dependent manner, and support a possible role for SHP-2 as a therapeutic target in diseases of intestinal inflammation like NEC.
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