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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 H 2 O 2  or to RNMs with and without pretreatment with antioxidants or iNOS inhibitors. H 2 O 2 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 H 2 O 2 ; 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.

iNOS upregulation mediates oxidant-induced disruption of F-actin and barrier of intestinal monolayers