Nitric oxide and airway epithelial barrier function: Regulation of tight junction proteins and epithelial permeability

Abstract

Acute airway inflammation is associated with enhanced production of nitric oxide (NO • ) and altered airway epithelial barrier function, suggesting a role of NO • or its metabolites in epithelial permeability. While high concentrations of S-nitrosothiols disrupted transepithelial resistance (TER) and increased permeability in 16HBE14o-cells, no significant barrier disruption was observed by NONOates, in spite of altered distribution and expression of some TJ proteins. Barrier disruption of mouse tracheal epithelial (MTE) cell monolayers in response to inflammatory cytokines was independent of NOS2, based on similar effects in MTE cells from NOS2-/-mice and a lack of effect of the NOS2-inhibitor 1400W. Cell pre-incubation with LPS protected MTE cells from TER loss and increased permeability by H 2 O 2 , which was independent of NOS2. However, NOS2 was found to contribute to epithelial wound repair and TER recovery after mechanical injury. Overall, our results demonstrate that epithelial NOS2 is not responsible for epithelial barrier dysfunction during inflammation, but may contribute to restoration of epithelial integrity.

Cytokines induce tight junction disassembly in airway cells via an EGFR-dependent MAPK/ERK1/2-pathway

“…In fact, the specific different concentrations of TNF-a, IL-4 or INF-g used to exanimate the effect on TJ protein reduction demonstrated a significant different decrease in TER in response to all three cytokines. In agreement with the results of the present paper, treatment of mouse tracheal epithelial cell monolayers with TNF-a, IFN-g and IL-1b resulted in a markedly decreased TER after 24 h. 19 However, we also found a dissociation between the degree of cytokine-induced TJ disruption (highest for IFN-g) and TER decrease (highest for IL-4), unexpected because of the importance ascribed to ZO-1 and occludin in the regulation of TJ function. In a different experimental model, exposure of primary human airway epithelial cells (16HBE14o-) to the nitric oxide donor (DETA-NO) resulted in an altered distribution and expression of TJ proteins (claudin-1 and occludin), not associated with significant barrier disruption.…”

“…At these possibly clinically relevant doses, 18 these cytokines were reported to induce barrier breakdown in a rapid, dose-dependent fashion in Calu-3. [16][17][18][19]31 Preliminary experiments in our lab confirmed the results reported by others. Cells were then permeabilized and stained as previously described.…”

“…3 Several mechanisms can be responsible for the cytokineinduced disruption of epithelial barriers, including expressional downregulation of junctional proteins. A variety of mediators possess the capability to alter TJ structure and barrier function on a variety of epithelial cell types, 11,14,15 but few studies have been performed on the bronchial epithelial cells, [16][17][18][19][20][21][22][23] exploring the signaling pathways involved. 19,21 Specifically, it has never been evaluated the possible engagement of the epidermal growth factor receptor (EGFR) signaling pathways, known to promote various cellular processes by phosphorylation of mitogen-activated protein (MAP) kinases.…”

“…A variety of mediators possess the capability to alter TJ structure and barrier function on a variety of epithelial cell types, 11,14,15 but few studies have been performed on the bronchial epithelial cells, [16][17][18][19][20][21][22][23] exploring the signaling pathways involved. 19,21 Specifically, it has never been evaluated the possible engagement of the epidermal growth factor receptor (EGFR) signaling pathways, known to promote various cellular processes by phosphorylation of mitogen-activated protein (MAP) kinases. 24 Activation of the MAP kinases-extracellular signalregulated kinases 25 (MAPK/ERK)1/2 has been associated not only with cell survival, proliferation, growth and differentiation 24 but also with TJ protein disruption.…”

Vitreous levels of somatostatin in patients with chronic uveitic macular oedema

“…SST may be involved in regulating the permeability of endothelial and epithelial barriers. SST inhibits nitric oxide production, 16,17 which was found to be involved in disruption of tight junctions in Chinese hamster ovary endothelial cells. 18 The human receptor of SST 3, a subtype of SST receptor, physically interacts with an epithelial tight junction protein known as MUPP1 (multiple PDZ domain protein-1), which enables SST to regulate transepithelial permeability.…”