Desiccating Stress-Induced MMP Production and Activity Worsens Wound Healing in Alkali-Burned Corneas

Eye injuries in the military and civilian population are frequent events.1–4 The main causes of eye injuries in the military has changed with changes in strategy and weaponry. These include sharp, blast fragmentation, penetrating, and perforating injuries of the globe, occasionally with intraocular foreign bodies to ocular surface chemical, thermal, nuclear, and laser burns.5,6 Sulfur mustard gas can potentially cause severe ocular surface injury, including blepharospasm, lid edema, and corneal ulceration. This chemical warfare agent has been in several military conflicts, including the recent Iran–Iraq War.7,8 Barely detected in an unwounded cornea, matrix metalloproteinases (MMPs) are strongly induced during wound healing and chemical burns. The MMP family includes more than 25 members that can be divided into collagenases (MMPs-1, -8, and -13, that degrades collagen types I, II, and III); gelatinases (MMP-2 and -9 that degrade collagen types IV, V, VII, and X as well as decorin, fibronectin, and laminin); stromelysins (MMP-3 and -10); matrilysins (MMP-7 and -26 that degrade proteoglycans, laminin, and glycoproteins substrates); and the membrane-type MMPs that are bound to epithelial cell membranes, and can activate MMPs, according to their structure and substrate specificity (MMP-14 to -17 and -24).9–12 Collectively, these MMPs are able to degrade the entire extracellular matrix and basement membranes components. Both chemical and thermal injuries to the surface of the eye have a high potential to cause blindness. These injuries often damage the epithelium covering the cornea, conjunctiva, and eyelid margins and in more severe cases destroy the stem cells that renew these epithelia. In many cases, the supporting stromal cells and matrix are damaged and chronic inflammation is induced. Furthermore, most patients with severe ocular surface injuries develop a secondary dry eye due to destruction of tear producing cells, which has the potential to worsen the outcome. In addition to lubricating the ocular surface, the tears contain numerous growth and anti-inflammatory factors that are essential for wound repair and suppressing inflammation and tissue destruction. The controlled desiccating environment many of us live in is under recognized as an initiator of dry eye–induced ocular surface inflammation. Virtually all modern office buildings are air-conditioned, often with high flow, low humidity air. Low humidity (in offices, aircraft cabins, deserts, and winter season) impacts tear film and ocular health.13 While it is currently known that low humidity exposure increases tear evaporation rate and increases frequency of eye irritation,14,15 specific inflammatory pathways/mediators that are stimulated are poorly understood. The purpose of this study was to study the effects of dry eye on ocular surface protease activity following corneal chemical injury. A combined model of alkali burn (AB) and dry eye was used to evaluate the effects of experimental dry eye on inflammatory cytokines, chemokines, and MMPs (-1, -2, -3, -8, -9, -12, and -13) after ocular surface chemical injury and the consequences of increase protease activity on corneal epithelial healing.