IL-18-mediated neutrophil recruitment promotes acute lung injury in inflammation-mediated chronic pancreatitis.

Abstract

Lung injury is the most common secondary complication of pancreatitis and pancreatic malignancy. Around 60-70% of pancreatitis-related deaths are caused by lung injury; however, there is no animal model of the inflammation-mediated progressive pulmonary pathological events that contribute to acute lung injury in chronic pancreatitis (CP). Hence, we developed an inflammation-mediated mouse model and studied the pathological events that have a critical role in promoting the pathogenesis of lung injury. Our proteomic analysis of lung tissue revealed neutrophil-associated induction of neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase enzyme, further supporting a role for neutrophils in promoting IL-18-associated lung injury. We show that neutrophils released IL-18-induced p-NF-κB along with profibrotic and oncogenic proteins like TTF1, PDX1, and SOX9 in lung tissues of a mouse model of chronic pancreatitis. We also show that neutrophil infiltration induces TGF-β and SMAD4 and activates epithelial cells to produce other profibrotic proteins like ZO-1 and MUC2, along with the fibroblast markers FGF-1 and αSMA, that cause mesenchymal transition and accumulation of extracellular matrix collagen. Most importantly, we present evidence that IL-18 inhibition significantly alleviates CP-induced lung injury. This was further established by the finding that IL-18 gene-deficient mice showed improved lung injury by inhibition of TGF-β and fibroblast to mesenchymal transition and reduced collagen accumulation. The present study suggests that inhibition of IL-18 may be a novel treatment for CP-associated induced acute lung injury.