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The role of neutrophils in corneal wound healing in HO-2 mice.

Marrazzo G, Bellner L, Halilovic A, Li Volti G, Drago F, Dunn MW, Schwartzman ML - PLoS ONE (2011)

Bottom Line: Our studies demonstrated that Heme oxygenase (HO), in particular, the constitutive HO-2, is critical for a self-resolving inflammatory and repair response in the cornea.Moreover, endothelial cells lacking HO-2 expressed higher levels of the Midkine and VE-cadherin and displayed strong adhesion to neutrophils suggesting that perturbation in endothelial cell function caused by HO-2 depletion underlies the increased infiltration of neutrophils into the HO-2(-/-) cornea.Moreover, the fact that neutropenia worsened epithelial healing of the injured cornea in both WT and HO-2(-/-) mice suggest that cells other than neutrophils contribute to the exaggerated inflammation and impaired wound healing seen in the HO-2 cornea.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Ophthalmology, New York Medical College, Valhalla, New York, United States of America. giuseppina_marrazzo@nymc.edu

ABSTRACT
Our studies demonstrated that Heme oxygenase (HO), in particular, the constitutive HO-2, is critical for a self-resolving inflammatory and repair response in the cornea. Epithelial injury in HO-2 mice leads to impaired wound closure and chronic inflammation in the cornea. This study was undertaken to examine the possible relationship between HO-2 and the recruitment of neutrophils following a corneal surface injury in wild type (WT) and HO-2 knockout (HO-2(-/-)) mice treated with Gr-1 monoclonal antibody to deplete peripheral neutrophils. Epithelial injury was performed by removing the entire corneal epithelium. Infiltration of inflammatory cell into the cornea in response to injury was higher in HO-2(-/-) than in WT. However, the rate of corneal wound closure following neutrophil depletion was markedly inhibited in both WT and HO-2(-/-) mice by 60% and 85%, respectively. Neutropenia induced HO-1 expression in WT but not in HO-2(-/-) mice. Moreover, endothelial cells lacking HO-2 expressed higher levels of the Midkine and VE-cadherin and displayed strong adhesion to neutrophils suggesting that perturbation in endothelial cell function caused by HO-2 depletion underlies the increased infiltration of neutrophils into the HO-2(-/-) cornea. Moreover, the fact that neutropenia worsened epithelial healing of the injured cornea in both WT and HO-2(-/-) mice suggest that cells other than neutrophils contribute to the exaggerated inflammation and impaired wound healing seen in the HO-2 cornea.

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Real-time PCR analysis of mRNA expression of (A) midkine (Mdk) and (B) VE-Cadherin in untreated aortic endothelial cells (mAEC) from WT and HO-2−/−.Results are the mean ± SE; n = 4 to 5; *p<0.005 from WT mAEC.
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pone-0021180-g006: Real-time PCR analysis of mRNA expression of (A) midkine (Mdk) and (B) VE-Cadherin in untreated aortic endothelial cells (mAEC) from WT and HO-2−/−.Results are the mean ± SE; n = 4 to 5; *p<0.005 from WT mAEC.

Mentions: Migration of neutrophils through the blood vessel wall is highly regulated by endothelial cells adhesion molecules. The role of HO-2 in neutrophil adhesion was examined using aortic endothelial cells lacking the HO-2 gene [18]. As seen in Figure 5, neutrophils adhere significantly more to HO-2−/− endothelial cells compared to WT mAEC. Moreover, this adhesion was enhanced in the in mAEC treated with TNF-α. Interestingly, mAEC from HO-2−/− mice showed a marked increase in the expression of Mdk, a 13-kDa multifunctional heparin-binding protein that promotes migration of neutrophils, macrophages, and neurons [21] (Figure 6A). The HO-2−/− mAEC also expressed significantly higher levels of VE-cadherin (Figure 6B), a key junctional molecule for transendothelial migration of neutrophils [22].


The role of neutrophils in corneal wound healing in HO-2 mice.

Marrazzo G, Bellner L, Halilovic A, Li Volti G, Drago F, Dunn MW, Schwartzman ML - PLoS ONE (2011)

Real-time PCR analysis of mRNA expression of (A) midkine (Mdk) and (B) VE-Cadherin in untreated aortic endothelial cells (mAEC) from WT and HO-2−/−.Results are the mean ± SE; n = 4 to 5; *p<0.005 from WT mAEC.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117875&req=5

pone-0021180-g006: Real-time PCR analysis of mRNA expression of (A) midkine (Mdk) and (B) VE-Cadherin in untreated aortic endothelial cells (mAEC) from WT and HO-2−/−.Results are the mean ± SE; n = 4 to 5; *p<0.005 from WT mAEC.
Mentions: Migration of neutrophils through the blood vessel wall is highly regulated by endothelial cells adhesion molecules. The role of HO-2 in neutrophil adhesion was examined using aortic endothelial cells lacking the HO-2 gene [18]. As seen in Figure 5, neutrophils adhere significantly more to HO-2−/− endothelial cells compared to WT mAEC. Moreover, this adhesion was enhanced in the in mAEC treated with TNF-α. Interestingly, mAEC from HO-2−/− mice showed a marked increase in the expression of Mdk, a 13-kDa multifunctional heparin-binding protein that promotes migration of neutrophils, macrophages, and neurons [21] (Figure 6A). The HO-2−/− mAEC also expressed significantly higher levels of VE-cadherin (Figure 6B), a key junctional molecule for transendothelial migration of neutrophils [22].

Bottom Line: Our studies demonstrated that Heme oxygenase (HO), in particular, the constitutive HO-2, is critical for a self-resolving inflammatory and repair response in the cornea.Moreover, endothelial cells lacking HO-2 expressed higher levels of the Midkine and VE-cadherin and displayed strong adhesion to neutrophils suggesting that perturbation in endothelial cell function caused by HO-2 depletion underlies the increased infiltration of neutrophils into the HO-2(-/-) cornea.Moreover, the fact that neutropenia worsened epithelial healing of the injured cornea in both WT and HO-2(-/-) mice suggest that cells other than neutrophils contribute to the exaggerated inflammation and impaired wound healing seen in the HO-2 cornea.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Ophthalmology, New York Medical College, Valhalla, New York, United States of America. giuseppina_marrazzo@nymc.edu

ABSTRACT
Our studies demonstrated that Heme oxygenase (HO), in particular, the constitutive HO-2, is critical for a self-resolving inflammatory and repair response in the cornea. Epithelial injury in HO-2 mice leads to impaired wound closure and chronic inflammation in the cornea. This study was undertaken to examine the possible relationship between HO-2 and the recruitment of neutrophils following a corneal surface injury in wild type (WT) and HO-2 knockout (HO-2(-/-)) mice treated with Gr-1 monoclonal antibody to deplete peripheral neutrophils. Epithelial injury was performed by removing the entire corneal epithelium. Infiltration of inflammatory cell into the cornea in response to injury was higher in HO-2(-/-) than in WT. However, the rate of corneal wound closure following neutrophil depletion was markedly inhibited in both WT and HO-2(-/-) mice by 60% and 85%, respectively. Neutropenia induced HO-1 expression in WT but not in HO-2(-/-) mice. Moreover, endothelial cells lacking HO-2 expressed higher levels of the Midkine and VE-cadherin and displayed strong adhesion to neutrophils suggesting that perturbation in endothelial cell function caused by HO-2 depletion underlies the increased infiltration of neutrophils into the HO-2(-/-) cornea. Moreover, the fact that neutropenia worsened epithelial healing of the injured cornea in both WT and HO-2(-/-) mice suggest that cells other than neutrophils contribute to the exaggerated inflammation and impaired wound healing seen in the HO-2 cornea.

Show MeSH
Related in: MedlinePlus