Mechanisms underlying mustard gas-induced conjunctival injury and use of lipid mediators as medical countermeasures

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PROJECT SUMMARY Mustard gas (MG, most commonly sulfur and nitrogen mustard) is a highly toxic vesicant that causes ocular injuries in over 90% of exposed victims with symptoms lasting from minutes to years. These symptoms include conjunctivitis in addition to eye pain, photophobia and corneal epitheliopathy. Moderate to severe exposure to MG results in chronic or latent (delayed-onset) forms of symptoms that include changes in the conjunctiva such as vascular abnormalities and histopathology including reduced goblet cell (GC) density and lymphocytic infiltration. However, mechanisms of toxicity and therapeutic targets in the conjunctiva remain largely unknown. We reported that in addition to protective soluble mucin, MUC5AC,GCs are a source of pro-inflammatory IL-1β as well as immunomodulatory TGFβ and therefore play a role in shaping both local innate and adaptive immune responses. The contribution of GC secretory products to ocular mucosal homeostasis is further underscored by the observed chronic inflammation and related epitheliopathy associated with loss of GCs or GC-derived regulatory factors. Specialized pro-resolving mediators (SPM) like D-series resolvins RvD1 are endogenous lipid derivatives produced during inflammation are known to accelerate its resolution and restoration of tissue architecture. We reported that RvD1 can inhibit secretion of GC-derived IL-1β. In this proposal we will identify mechanisms underlying MG toxicity in the conjunctiva and its contribution to chronic pathology. We will determine if SPMs restore homeostasis in the conjunctiva to prevent chronic damage caused by MG and serve as effective medical counter measure (MCM) for ocular toxicity of MG. We hypothesize that SPMs promote resolution of MG-induced ocular damage by modulating secretory and homeostatic function of conjunctival GCs. To address this hypothesis, the following three specific aims are proposed. Aim 1: Identify nitrogen mustard (NM)-induced alteration in conjunctival epithelial GC function and the potential of SPMs to resolve NM toxicity and restore GC function in vitro; Aim 2: Determine if NM exposure disrupts immune homeostatic function of GCs in vitro and if SPMs can restore it; and Aim3: Determine therapeutic efficacy of RvD1 as a MCM, in vivo, using a mouse model of NM toxicity. Conjunctival and corneal damage as well as ocular surface innervation will be evaluated. Our anticipated results from these studies can reveal the potential of conjunctival GCs as a MG injury site and therefore a therapeutic target and provide critical insights into developing novel strategies to promote mucosal and immune homeostasis in clinical management of MG-induced ocular toxicity.