Dessication And Inflammatory Stress Model And Its Translational Implication In Ocular Surface Conditions

Aberrant immuno-inflammatory factors and responses have been critical contributors towards disease pathogenesis for a wide variety of ocular surface conditions including dry eye disease (DED) and keratoconus (KC). One of the successful therapeutic strategies that facilitates resolution of disease is dampening of inflammation by a different agents with specific mechanisms of action. Cyclosporine A (CsA) is one of the critical agent in the armamentarium that has been approved for the management of specific ocular surface conditions. This study investigates cellular effects and characteristics along with additional mechanism which may aid in its use for ocular surface conditions, as new indication

Tertiary Eye Care Centre

A detailed in vitro investigation using the human corneal epithelial cells (HCE) was performed to study the effects of desiccation stress (DS) and inflammatory stress (InS, using TNF alpha) in the presence and absence of topical CsA formulations. Cell viability was performed using trypan blue assay. The mRNA expression status of inflammatory factors including, IL-6, MCP1, MMP9 and TIMP1 was determined using quantitative PCR. Inflammatory- and stress-associated intracellular signaling events were determined using immunoblotting. The dynamics of lysosome (a critical intracellular machinery that regulates cell function and fate) following the DS or InS in HCE was studied by live cell imaging using holotomography (NanoLive^TM). 

CsA significantly reduced the DS- and/or InS-induced expression of MCP1 and MMP9 along with the induction of TIMP1 in HCE. In addition, CsA exhibited to rescue DS-induced reduction in cell viability in HCE. CsA was also observed to inhibit DS- and/or InS induced phosphorylation of p38 and/or p65 in HCE. Holotomography based live cell imaging revealed that CsA facilitated the regain of normal lysosomal dynamics in HCE exposed to DS or InS. It was noted that the pattern and magnitude of cell protective and anti-inflammatory effect varied among the different CsA formulation.

Current findings confirm the regulatory potential of CsA on beneficial cellular mechanisms that are essential for the management of epitheliopathy, epithelial dysfunction and inflammation in a variety of ocular surface conditions. This opens the options of CsA use as a newer indication as part of mechanism specific targeting for ocular surface conditions.