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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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Effect of neutrophil depletion on wound healing.(A) Representative images of fluorescein-stained corneas at day 0 and day 2 after injury in control and neutrophil (N)-depleted WT and HO-2−/− mice. (B) Wound closure as percent change from day 0. Results are mean ± SE; n = 5–7; *p<0.005 from control WT mice; **p<0.005 from control HO-2−/− mice; † p<0.01 from control WT mice; ‡ p<0.005 from neutrophil-depleted WT mice.
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pone-0021180-g001: Effect of neutrophil depletion on wound healing.(A) Representative images of fluorescein-stained corneas at day 0 and day 2 after injury in control and neutrophil (N)-depleted WT and HO-2−/− mice. (B) Wound closure as percent change from day 0. Results are mean ± SE; n = 5–7; *p<0.005 from control WT mice; **p<0.005 from control HO-2−/− mice; † p<0.01 from control WT mice; ‡ p<0.005 from neutrophil-depleted WT mice.

Mentions: The corneal epithelial injury model is a well-established model in which the inflammatory and reparative response has been well characterized [13], [19]. Wound healing was assessed in control and neutrophil-depleted WT and HO-2−/− mice. As seen in Figure 1, epithelial injury in WT mice produced a consistent wound in control mice (6.6±0.3 mm2, n = 6) that exhibited 44.2%±5.2% re-epithelialization by day 2 after injury. In contrast, wound closure in neutrophil-depleted WT mice (7.2±0.2 mm2, n = 6) was markedly inhibited displaying re-epithelialization of 20.5%±4.0% at day 2 after injury. Similar results were obtained in the HO-2−/− mice in which wound closure was further impaired following neutrophil depletion. Thus, epithelial injury in HO-2−/− mice produced a consistent wound in control (7.4±0.1 mm2, n = 5) and neutrophil-depleted mice (7.6±0.2 mm2, n = 5) that was closed by 22.6%±4.9% and 4.5%±2.6%, respectively, at day 2 after injury (Figure 1 A and B).


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)

Effect of neutrophil depletion on wound healing.(A) Representative images of fluorescein-stained corneas at day 0 and day 2 after injury in control and neutrophil (N)-depleted WT and HO-2−/− mice. (B) Wound closure as percent change from day 0. Results are mean ± SE; n = 5–7; *p<0.005 from control WT mice; **p<0.005 from control HO-2−/− mice; † p<0.01 from control WT mice; ‡ p<0.005 from neutrophil-depleted WT mice.
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Related In: Results  -  Collection

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

pone-0021180-g001: Effect of neutrophil depletion on wound healing.(A) Representative images of fluorescein-stained corneas at day 0 and day 2 after injury in control and neutrophil (N)-depleted WT and HO-2−/− mice. (B) Wound closure as percent change from day 0. Results are mean ± SE; n = 5–7; *p<0.005 from control WT mice; **p<0.005 from control HO-2−/− mice; † p<0.01 from control WT mice; ‡ p<0.005 from neutrophil-depleted WT mice.
Mentions: The corneal epithelial injury model is a well-established model in which the inflammatory and reparative response has been well characterized [13], [19]. Wound healing was assessed in control and neutrophil-depleted WT and HO-2−/− mice. As seen in Figure 1, epithelial injury in WT mice produced a consistent wound in control mice (6.6±0.3 mm2, n = 6) that exhibited 44.2%±5.2% re-epithelialization by day 2 after injury. In contrast, wound closure in neutrophil-depleted WT mice (7.2±0.2 mm2, n = 6) was markedly inhibited displaying re-epithelialization of 20.5%±4.0% at day 2 after injury. Similar results were obtained in the HO-2−/− mice in which wound closure was further impaired following neutrophil depletion. Thus, epithelial injury in HO-2−/− mice produced a consistent wound in control (7.4±0.1 mm2, n = 5) and neutrophil-depleted mice (7.6±0.2 mm2, n = 5) that was closed by 22.6%±4.9% and 4.5%±2.6%, respectively, at day 2 after injury (Figure 1 A and B).

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