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Kansas State University

Dr. James Lillich

This is a photograph of James Lillich   Dr. James Lillich
  Associate Professor
  Department of Clinical Sciences
  Phone: (785) 532-5700

Mentor : Dr. Lisa Freeman

Intestinal Epithelial Wound Healing: NSAIDs and Calpain Inhibition:
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications worldwide despite their well-documented gastrointestinal (GI) toxicity. The GI epithelium has several functions, the most important of which are nutrient absorption and barrier function, separating the internal milieu from the external environment. Mucosal restitution represents a primary repair modality in the GI tract, and allows resealing of the epithelial barrier in minutes to hours via reformation of tight junctions between cells. Restitution requires cell migration, but not cell proliferation nor differentiation and it is a well coordinated event relying on numerous cellular pathways. Recent evidence suggests that calpains (cysteine proteases) are vital to several key pathways of cell migration. Recently we have shown that: a) irrespective of COX selectivity, ulcerogenic NSAIDs inhibit cell migration after wounding; b) individual NSAIDs differ significantly in their effects on the cellular signals that modulate cell migration; and c) ulcerogenic NSAIDs either down-regulate calpain gene expression or up-regulate the constituent inhibitor, calpastatin. Project experiments are specifically designed to link NSAID inhibition of cell migration with NSAID effects on events vital to calpain function within differentiated intestinal epithelial cells (IECs).

    The specific aims of this project are to:
  • Demonstrate that calpains are critical to normal IEC migration.
  • Confirm that calpains are a target for NSAID-toxicity and disruption of intestinal epithelial wound healing.
  • Determine the effects of NSAIDs on calpain-mediated adhesion dynamics.
The results of this project will provide valuable data immediately useful not only to the health care providers who need to make rational decisions about prescribing NSAIDs, but also to the industrial scientists who strive to develop less toxic alternatives to the drugs currently available. In addition, the knowledge gained from these studies may suggest novel strategies for the prevention and treatment of NSAID-induced GI ulcers, identify novel targets for new drug design, and initiate novel safety testing of new NSAIDs.