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Despite decades of research there is no specific therapy for Acute Pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an anti-inflammatory and anti-fibrotic agent which is FDA-approved for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (i.e. after initiation of injury), even when administered at the peak of injury, reduces severity of local and systemic injury and inflammation in multiple models of AP. In-vitro evaluation suggests that pirfenidone decreases cytokine release from acini and macrophages and disrupts acinar-macrophage crosstalk. Therapeutic pirfenidone treatment increases IL-10 secretion from macrophages preceding changes in histology and modulates the immune phenotype of inflammatory cells with decreased levels of inflammatory cytokines. Antibody-mediated IL-10 depletion, use of IL-10 Knock Out mice, and macrophage depletion experiments confirmed the role of IL-10 and macrophages in its mechanism of action, as pirfenidone was unable to reduce severity of AP in these scenarios. Since pirfenidone is FDA approved for IPF, a trial evaluating the efficacy of pirfenidone in patients with moderate to severe AP can be initiated expeditiously.Key Words: Acute Pancreatitis, Pirfenidone, Interleukin-10, L-arginine pancreatitis, Systemic inflammation, lung injury.

The nonimmune roles of Tregs have been described in various tissues, including the BM. In this study, we comprehensively phenotyped marrow Tregs, elucidating their key features and tissue-specific functions. We show that marrow Tregs are migratory and home back to the marrow. For trafficking, marrow Tregs use S1P gradients, and disruption of this axis allows for specific targeting of the marrow Treg pool. Following Treg depletion, the function and phenotype of both mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs) was impaired. Transplantation also revealed that a Treg-depleted niche has a reduced capacity to support hematopoiesis. Finally, we found that marrow Tregs are high producers of IL-10 and that Treg-secreted IL-10 has direct effects on MSC function. This is the first report to our knowledge revealing that Treg-secreted IL-10 is necessary for stromal cell maintenance, and our work outlines an alternative mechanism by which this cytokine regulates hematopoiesis., Bone marrow Tregs regulate stromal cell function to maintain hematopoiesis through IL-10 and provide a potential therapeutic avenue for stromal manipulation.