Biphasic changes in TGF-1 signaling drive NSAID-induced multi-organ damage

The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs), used extensively worldwide, is limited by adverse cardiac events resulting from chronic drug exposure. Here, we provide evidence identifying transforming growth factor beta (TGF-beta 1), released from multiple tissues, as a critical driver of NSAID-induced multi organ damage. Biphasic changes in TGF-beta 1 levels in liver and heart were accompanied by ROS generation, cell death, fibrotic remodeling, compromised cardiac contractility and elevated liver enzymes. Pharmacological inhibition of TGF-beta RI signaling markedly improved heart and liver function and increased overall survival of animals exposed to multiple NSAIDs, effects likely mediated by reductions in NOX-dependent ROS generation. Notably, the beneficial impact of TGF-beta RI blockade was confined to a critical window wherein consecutive, but not concurrent, inhibitor administration improved cardiac and hepatic endpoints. Remarkably, in addition to ameliorating indomethacin-mediated myofilament disruptions, cardiac TGF-beta RI knockdown lead to drastic reductions in TGF-beta 1 production accompanied by lessening in intestinal lesioning underscoring the importance of endocrine TGF-beta 1 signaling in NSAID-driven tissue injury. Indeed, gastric ulceration was associated with a higher incidence of cardiac complications in a human cohort underscoring the critical importance of circulation facilitated peripheral organ system interconnectedness in efforts seeking to mitigate the toxic side effects of chronic NSAID use.