Tissue Repair: An Important Determinant of Final Outcome of Toxicant-Induced Injury

Tissue repair is a dynamic compensatory cell proliferation and tissue regeneration response stimulated in order to overcome acute toxicity and recover organ/tissue structure and function. Extensive evidence in rodent models using structurally and mechanistically diverse hepatotoxicants such as acetaminophen (APAP), carbon tetrachloride (CCl4), chloroform (CHCl3), thioacetamide (TA), trichloroethylene (TCE), and allyl alcohol (AA) have demonstrated that tissue repair plays a critical role in determining the final outcome of toxicity, i.e., recovery from injury and survival or progression of injury leading to liver failure and death. Tissue repair is a complex process governed by intricate cellular signaling involving a number of chemokines, cytokines, growth factors, and nuclear receptors leading to promitogenic gene expression and cell division. Tissue repair also encompasses regeneration of hepatic extracellular matrix and angiogenesis, the processes necessary to completely restore the structure and function of the liver tissue lost to toxicant-induced initiation followed by progression of injury. New insights have emerged over the last quarter century indicating that tissue repair follows a dose response. Tissue repair increases with dose until a threshold dose, beyond which it is delayed and impaired due to inhibition of cellular signaling resulting in runaway secondary events causing tissue destruction, organ failure, and death. Prompt and adequately stimulated tissue repair response to toxic injury is critical for recovery from toxic injury. Tissue repair is modulated by a variety of factors including species, strain, age, nutrition, and disease condition causing marked changes in susceptibility and toxic outcome. This review focuses on the properties of tissue repair, different factors affecting tissue repair, and the mechanisms that govern tissue repair and progression of injury. It also highlights the significance of tissue repair as a target for drug development strategies and an important consideration in the assessment of risk from exposure to toxicants.