Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models

Abstract

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 antifibrotic 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.

Xanthohumol alleviates oxidative stress and impaired autophagy in experimental severe acute pancreatitis through inhibition of AKT/mTOR

“…IL-17 affects immune responses and interacts with inflammatory mediators in SAP-related microenvironments ( Li et al, 2021 ). IL-10, a cytokine that combats inflammation, reduces inflammation by inhibiting cytokine production like TNF-α ( Sziksz et al, 2015 ; Palathingal Bava et al, 2022 ). Studies have confirmed that the administration of therapeutic drugs would protect SAP by attenuating the pro-inflammatory cytokine and recovering the IL-10 level, which is in line with our study ( Wang et al, 2011 ; Silva-Vaz et al, 2020 ; Li et al, 2021 ; Palathingal Bava et al, 2022 ).…”

Acute Pancreatitis

“…137 Interestingly, a recent study determined that administration of pirfenidone increases IL-10 production in a mouse model of AP, which may provide an alternative method for increasing circulating IL-10 in SAP patients and should be further explored in humans. 138…”

“…However, a clinical trial performed in 2001 identified no benefit from 8 μg/kg of IL-10 for endoscopic retrograde cholangiopancreatography–induced pancreatitis indicating that alternative cytokine regulators must be identified and targeted to prevent POF in SAP patients 137 . Interestingly, a recent study determined that administration of pirfenidone increases IL-10 production in a mouse model of AP, which may provide an alternative method for increasing circulating IL-10 in SAP patients and should be further explored in humans 138 …”

The role of predictive and prognostic values of inflammatory markers in acute pancreatitis: a narrative review

“…[72] Despite extensive research efforts, there is currently no specific treatment available for AP. Palathingal Bava et al [73] examined the effectiveness of pirfenidone, a Food and Drug Administration (FDA)-approved anti-inflammatory and antifibrotic drug used for treating idiopathic pulmonary fibrosis (IPF) in alleviating both local and systemic damage in AP. The findings indicate that therapeutic administration of pirfenidone, even when initiated at the peak of injury, significantly reduces the severity of local and systemic damage and inflammation in various AP models.…”

“…Considering that pirfenidone was already approved by the FDA for IPF, it would be feasible to initiate a clinical trial promptly to assess the efficacy of pirfenidone in patients with moderate to severe AP. [73] Clinical studies IL-10 has recently been recognized as an anti-inflammatory cytokine that hinders the production of pro-inflammatory cytokines by monocytes and/or macrophages, as well as the release of harmful oxygen radicals. Studies have indicated that IL-10 treatment reduces the severity of experimental pancreatitis primarily by suppressing cellular necrosis.…”