Citation

Blockade of the larger renin-angiotensin-aldosterone system (RAAS) has been shown to have anti-fibrotic effects in ocular tissue [18]. Topical angiotensin receptor blockade has been shown to be associated with inhibition of decreased opacity, corneal scarring, and decreased myofibroblast activity after descemetorrhexis in animal models [19]. Further, the presence of RAAS components has been documented throughout the eye. Expression of angiotensin-converting enzyme isoforms [20], angiotensin II, and angiotensin II receptors have been demonstrated in lacrimal gland tissue in mice [21]. Bulbar conjunctiva and cornea also express angiotensin II and angiotensin-converting enzyme [20], further providing rationale for the observed anti-fibrotic effect seen with upstream RAAS blockade and downstream mineralocorticoid receptor blockade. In a cGVHD mouse model, upregulation of angiotensinogen mRNA in lacrimal glands has been demonstrated [21], further implicating RAAS components in the pathophysiology of ocular GVHD. As pathogenic fibrosis and inflammation are thought to be closely linked to the development of the sicca syndrome in oGVHD [22], RAAS and mineralocorticoid receptor blockade present novel therapeutic approaches in managing this complex disease. The pathophysiology of oGVHD has been described by Ogawa as a cycle of inflammation, fibrosis, and ocular surface pathology arising out of T-cell autoactivity, cellular senescence, tissue renin-angiotensin system (RAS), and endoplasmic reticulum stress (Figure _5_) [23]. Treatments targeting the RAS and RAAS, like topical losartan and spironolactone, are directed to disrupt cyclic inflammatory processes that result in surface barrier dysfunction, keratitis, and tear film abnormalities.