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Calpains in fibrosis
Dimeric calpains (CAPN’s 1, 2, 9) are calcium-activated cysteine proteases that regulate cellular function. Calpain over-activation promotes signaling processes foundational to cell/tissue damage responses that eventually lead to fibrosis.
Mechanism of calpain-targeted inhibition
Dimeric calpain activity is required for differentiation/activation of myofibroblast cells that lay down extracellular collagen matrix (ECM, or scarring) that disrupts normal organ function.
An inhibitor (calpastatin) exists to counterbalance calpain activity and maintain the system in equilibrium. In the diseased state, calpastatin levels can become inadequate and dimeric calpains remain “turned on” (overactivated). Persistent overactivation contributes to tissue damage and pro-inflammatory responses and underlies key steps in the fibrosis process (highlighted in red below).
Calpain Activity is Implicated in Tissue Damage Response
In response to cellular/tissue injury, calpain signaling triggers release of calprotectin, a damage associated molecular pattern (DAMP) protein, from multiple cell types. Calprotectin in turn catalyzes tissue-damage responses and enables cell resuscitation or destruction. Elevated calprotectin levels often correlate with disease severity and progression.
In preclinical models of acute lung injury and fibrosis, calpain inhibition has been demonstrated to downregulate production of calprotectin and other pro-inflammatory proteins including IL-6, IL-1beta, LIF, and Oncostatin M. Inhibition of calpains has also been shown to interrupt the early steps of myofibroblast activation and differentiation, thereby attenuating the production of extracellular matrix proteins (e.g. collagen) central to the fibrosis process.
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