The inflammatory response and its resolution are necessary for efficient healing of corneal injuries. The inflammation develops as a cascade of sequentially dependent cellular emigrations, and the precise temporal and molecular relationships within this cellular trafficking are critical. There are unique features in the cornea not predictable from studies of other vascular beds, and dysregulation of this cascade diminishes the efficiency of or actively delays corneal wound healing. Research design: The proposed studies are limited to an animal model: corneal epithelial abrasion in C57BL/6 mice. A mouse model provides access to molecular reagents and resources for mechanistic studies (e.g., transgenic and knockout mice). The injury is standardized -- removal of a defined area of epithelium with no or minimal direct stromal injury, and analysis of inflammation at 6 hour intervals over an observation period of 48 hours defines the kinetics of cellular trafficking.
The specific aims deal with previously unrecognized aspects of corneal epithelial wound repair -- specifically, the involvement of ?/? T cells and platelets in facilitating healing.
Aim 1. Define mechanisms for the accumulation of platelets in limbal vessels and peripheral corneal stroma following central corneal epithelial abrasion. Hypothesis: Platelet accumulation depends on adhesion to leukocytes in limbal vessels and in turn augments leukocyte accumulation. Our published work shows that depletion of circulating platelets significantly reduces corneal healing.
Aim 2. Define mechanisms by which ?/? T cells influence the inflammatory response to central corneal epithelial abrasion. Hypothesis: Resident and emigrated ?/? T cells are necessary for efficient epithelial healing through their control of the inflammatory process including the accumulation of platelets. Preliminary data in this application reveal that depletion of ?/? T cells significantly reduces corneal healing and significantly reduces platelet and neutrophil localization in the limbus. Epithelium on the surface of the cornea plays important roles in the maintenance of corneal function and optimal healing, a major concern for efficacy and safety of refractive surgical procedures and the treatment of corneal injury. The proposed research defines mechanisms by which inflammation in response to corneal injury promotes or retards healing, revealing potential targets for therapeutic intervention.
|Zhang, Wanyu; Magadi, Sri; Li, Zhijie et al. (2017) IL-20 promotes epithelial healing of the injured mouse cornea. Exp Eye Res 154:22-29|
|Dai, Yu-Bing; Miao, Yi-Fei; Wu, Wan-Fu et al. (2016) Ablation of Liver X receptors ? and ? leads to spontaneous peripheral squamous cell lung cancer in mice. Proc Natl Acad Sci U S A 113:7614-9|
|Lam, Fong W; Phillips, Jenny; Landry, Paul et al. (2015) Platelet recruitment promotes keratocyte repopulation following corneal epithelial abrasion in the mouse. PLoS One 10:e0118950|
|Knight, John M; Lee, Seung-Hyo; Roberts, Luz et al. (2014) CD11a polymorphisms regulate TH2 cell homing and TH2-related disease. J Allergy Clin Immunol 133:189-97.e1-8|
|Hanlon, Samuel D; Smith, C Wayne; Sauter, Marika N et al. (2014) Integrin-dependent neutrophil migration in the injured mouse cornea. Exp Eye Res 120:61-70|
|Gao, Yuan; Li, Zhijie; Hassan, Nida et al. (2013) NK cells are necessary for recovery of corneal CD11c+ dendritic cells after epithelial abrasion injury. J Leukoc Biol 94:343-51|
|Liu, Qiong; Smith, C Wayne; Zhang, Wanyu et al. (2012) NK cells modulate the inflammatory response to corneal epithelial abrasion and thereby support wound healing. Am J Pathol 181:452-62|
|Lam, Fong W; Burns, Alan R; Smith, C Wayne et al. (2011) Platelets enhance neutrophil transendothelial migration via P-selectin glycoprotein ligand-1. Am J Physiol Heart Circ Physiol 300:H468-75|
|Li, Zhijie; Burns, Alan R; Han, Lei et al. (2011) IL-17 and VEGF are necessary for efficient corneal nerve regeneration. Am J Pathol 178:1106-16|
|Li, Zhijie; Burns, Alan R; Miller, Sarah Byeseda et al. (2011) CCL20, ýýýý T cells, and IL-22 in corneal epithelial healing. FASEB J 25:2659-68|
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