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Division of Digestive Diseases, Department of Internal Medicine, and Departments of Pharmacology and Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612
Using
oxidant-induced hyperpermeability of monolayers of intestinal (Caco-2)
cells as a model for the pathophysiology of inflammatory bowel disease
(IBD), we previously showed that oxidative injury to the F-actin
cytoskeleton is necessary for the disruption of monolayer barrier
integrity. We hypothesized that this cytoskeletal damage is caused by
upregulation of an inducible nitric oxide (NO) synthase (iNOS)-driven
pathway that overproduces reactive nitrogen metabolites (RNMs) such as
NO and peroxynitrite (OONO
), which cause actin nitration
and disassembly. Monolayers were exposed to
H2O2 or to RNMs with and without pretreatment
with antioxidants or iNOS inhibitors. H2O2
concentrations that disassembled and/or disrupted the F-actin
cytoskeleton and barrier integrity also caused rapid iNOS
activation, NO overproduction, and actin nitration. Added
OONO mimicked H2O2; iNOS
inhibitors and RNM scavengers were protective. Our results show that
oxidant-induced F-actin and intestinal barrier disruption are caused by
rapid iNOS upregulation that further increases oxidant levels; a
similar positive feedback mechanism may underlie the episodic
recurrence of the acute IBD attack. Confirming these mechanisms in vivo
would provide a rationale for developing novel anti-RNM therapies for IBD.
inflammatory bowel disease; G-actin; nitration; oxidation; disassembly; nitric oxide; peroxynitrite; Caco-2 cells; inducible nitric oxide synthase
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