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Heme oxygenase-1 protects corexit 9500A-induced respiratory epithelial injury across species.

Li FJ, Duggal RN, Oliva OM, Karki S, Surolia R, Wang Z, Watson RD, Thannickal VJ, Powell M, Watts S, Kulkarni T, Batra H, Bolisetty S, Agarwal A, Antony VB - PLoS ONE (2015)

Bottom Line: CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production.Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis.Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.

ABSTRACT
The effects of Corexit 9500A (CE) on respiratory epithelial surfaces of terrestrial mammals and marine animals are largely unknown. This study investigated the role of CE-induced heme oxygenase-1 (HO-1), a cytoprotective enzyme with anti-apoptotic and antioxidant activity, in human bronchial airway epithelium and the gills of exposed aquatic animals. We evaluated CE-mediated alterations in human airway epithelial cells, mice lungs and gills from zebrafish and blue crabs. Our results demonstrated that CE induced an increase in gill epithelial edema and human epithelial monolayer permeability, suggesting an acute injury caused by CE exposure. CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production. Importantly, CE induced caspase-3 activation and subsequent apoptosis of epithelial cells. The expression of the intercellular junctional proteins, such as tight junction proteins occludin, zonula occludens (ZO-1), ZO-2 and adherens junctional proteins E-cadherin and Focal Adhesion Kinase (FAK), were remarkably inhibited by CE, suggesting that these proteins are involved in CE-induced increased permeability and subsequent apoptosis. The cytoskeletal protein F-actin was also disrupted by CE. Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis. Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK. These observations suggest that CE activates CRP and NOX4-mediated ROS production, alters permeability by inhibition of junctional proteins, and leads to caspase-3 dependent apoptosis of epithelial cells, while HO-1 and its reaction products protect against oxidative stress and apoptosis.

No MeSH data available.


Related in: MedlinePlus

Proposed schematic: HO-1 contributes to protection of epithelium from CE-induced injury, ROS and apoptosis.CE exposure triggers oxidative stress, which induced cleavage of ZO-1, ZO-2, occludin, F-actin, E-cadherin, FAK cleavage, permeability increase, and activation of CRP, NOX4 and HO-1. ROS production and subsequent caspase-3 dependent apoptosis attribute to the induction of both CRP and NOX4. HO-1 and/or CORM-2 are in charge of the protection of CE-induced injury, ROS generation and apoptosis.
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pone.0122275.g009: Proposed schematic: HO-1 contributes to protection of epithelium from CE-induced injury, ROS and apoptosis.CE exposure triggers oxidative stress, which induced cleavage of ZO-1, ZO-2, occludin, F-actin, E-cadherin, FAK cleavage, permeability increase, and activation of CRP, NOX4 and HO-1. ROS production and subsequent caspase-3 dependent apoptosis attribute to the induction of both CRP and NOX4. HO-1 and/or CORM-2 are in charge of the protection of CE-induced injury, ROS generation and apoptosis.

Mentions: The respiratory epithelium in mammals and aquatic animals is constantly exposed to the environment either through inhalation or through the movement of water through gills. These structures have developed evolutionarily and phylogentically conserved mechanisms to protect them from injury. Cellular responses to the accumulation of ROS generated by oxidative stress can lead to several forms of injury with activation of defense mechanisms to counter the injury, including activation of the antioxidant, anti-inflammatory systems. Cells also respond to ROS-induced DNA damage through caspase-3-dependent apoptosis in the case of unrepairable DNA damage [57,59]. In this study, we addressed these two responses in epithelial cells exposed to CE in vitro and in vivo. We showed that CE-induced apoptosis is caspase-3 dependent and that ROS play an important role in this pathway (Fig. 9). We confirmed our hypothesis that HO-1 activation is important in protecting epithelial cells against injury by CE and HO-1 decreased the inflammation and apoptosis induced in epithelial cells by CE through ROS scavenging mechanism mediated by both CRP and NOX4. Finally, we showed for the first time that disruption of intercellular junctional proteins and cytoskeletal proteins is involved in CE-induced apoptosis and that HO-1 can significantly protect against these processes.


Heme oxygenase-1 protects corexit 9500A-induced respiratory epithelial injury across species.

Li FJ, Duggal RN, Oliva OM, Karki S, Surolia R, Wang Z, Watson RD, Thannickal VJ, Powell M, Watts S, Kulkarni T, Batra H, Bolisetty S, Agarwal A, Antony VB - PLoS ONE (2015)

Proposed schematic: HO-1 contributes to protection of epithelium from CE-induced injury, ROS and apoptosis.CE exposure triggers oxidative stress, which induced cleavage of ZO-1, ZO-2, occludin, F-actin, E-cadherin, FAK cleavage, permeability increase, and activation of CRP, NOX4 and HO-1. ROS production and subsequent caspase-3 dependent apoptosis attribute to the induction of both CRP and NOX4. HO-1 and/or CORM-2 are in charge of the protection of CE-induced injury, ROS generation and apoptosis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383564&req=5

pone.0122275.g009: Proposed schematic: HO-1 contributes to protection of epithelium from CE-induced injury, ROS and apoptosis.CE exposure triggers oxidative stress, which induced cleavage of ZO-1, ZO-2, occludin, F-actin, E-cadherin, FAK cleavage, permeability increase, and activation of CRP, NOX4 and HO-1. ROS production and subsequent caspase-3 dependent apoptosis attribute to the induction of both CRP and NOX4. HO-1 and/or CORM-2 are in charge of the protection of CE-induced injury, ROS generation and apoptosis.
Mentions: The respiratory epithelium in mammals and aquatic animals is constantly exposed to the environment either through inhalation or through the movement of water through gills. These structures have developed evolutionarily and phylogentically conserved mechanisms to protect them from injury. Cellular responses to the accumulation of ROS generated by oxidative stress can lead to several forms of injury with activation of defense mechanisms to counter the injury, including activation of the antioxidant, anti-inflammatory systems. Cells also respond to ROS-induced DNA damage through caspase-3-dependent apoptosis in the case of unrepairable DNA damage [57,59]. In this study, we addressed these two responses in epithelial cells exposed to CE in vitro and in vivo. We showed that CE-induced apoptosis is caspase-3 dependent and that ROS play an important role in this pathway (Fig. 9). We confirmed our hypothesis that HO-1 activation is important in protecting epithelial cells against injury by CE and HO-1 decreased the inflammation and apoptosis induced in epithelial cells by CE through ROS scavenging mechanism mediated by both CRP and NOX4. Finally, we showed for the first time that disruption of intercellular junctional proteins and cytoskeletal proteins is involved in CE-induced apoptosis and that HO-1 can significantly protect against these processes.

Bottom Line: CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production.Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis.Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.

ABSTRACT
The effects of Corexit 9500A (CE) on respiratory epithelial surfaces of terrestrial mammals and marine animals are largely unknown. This study investigated the role of CE-induced heme oxygenase-1 (HO-1), a cytoprotective enzyme with anti-apoptotic and antioxidant activity, in human bronchial airway epithelium and the gills of exposed aquatic animals. We evaluated CE-mediated alterations in human airway epithelial cells, mice lungs and gills from zebrafish and blue crabs. Our results demonstrated that CE induced an increase in gill epithelial edema and human epithelial monolayer permeability, suggesting an acute injury caused by CE exposure. CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production. Importantly, CE induced caspase-3 activation and subsequent apoptosis of epithelial cells. The expression of the intercellular junctional proteins, such as tight junction proteins occludin, zonula occludens (ZO-1), ZO-2 and adherens junctional proteins E-cadherin and Focal Adhesion Kinase (FAK), were remarkably inhibited by CE, suggesting that these proteins are involved in CE-induced increased permeability and subsequent apoptosis. The cytoskeletal protein F-actin was also disrupted by CE. Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis. Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK. These observations suggest that CE activates CRP and NOX4-mediated ROS production, alters permeability by inhibition of junctional proteins, and leads to caspase-3 dependent apoptosis of epithelial cells, while HO-1 and its reaction products protect against oxidative stress and apoptosis.

No MeSH data available.


Related in: MedlinePlus