Pirfenidone ameliorates chronic pancreatitis in mouse models through immune and cytokine modulation

Macrophages are mononuclear phagocytes that are widely distributed throughout the body. These cells can contribute to development and homeostasis and participate in innate and adaptive immune responses. The physiology of macrophages can vary tremendously depending on the environment in which they reside and the local stimuli to which they are exposed. Macrophages are prodigious secretory cells, and in that role can promote and regulate immune responses and contribute to autoimmune pathologies. Macrophages are highly phagocytic, and in this capacity have long been considered to be essential immune effector cells. The important roles of macrophages in maintaining homeostasis and in contributing to tissue remodeling and wound healing is sometimes overlooked because of their vital role in host defense. Copyright 2008 by John Wiley & Sons, Inc.

The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells (vitamin A storing cells) play a significant role in the development of fibrosis. To determine whether cells resembling hepatic stellate cells are present in rat pancreas, and if so, to compare their number with the number of stellate cells in the liver, and isolate and culture these cells from rat pancreas. Liver and pancreatic sections from chow fed rats were immunostained for desmin, glial fibrillary acidic protein (GFAP), and alpha smooth muscle actin (alpha-SMA). Pancreatic stellate shaped cells were isolated using a Nycodenz gradient, cultured on plastic, and examined by phase contrast and fluorescence microscopy, and by immunostaining for desmin, GFAP, and alpha-SMA. In both liver and pancreatic sections, stellate shaped cells were observed; these were positive for desmin and GFAP and negative for alpha-SMA. Pancreatic stellate shaped cells had a periacinar distribution. They comprised 3.99% of all pancreatic cells; hepatic stellate cells comprised 7.94% of all hepatic cells. The stellate shaped cells from rat pancreas grew readily in culture. Cells cultured for 24 hours had an angular appearance, contained lipid droplets manifesting positive vitamin A autofluorescence, and stained positively for desmin but negatively for alpha-SMA. At 48 hours, cells were positive for alpha-SMA. Cells resembling hepatic stellate cells are present in rat pancreas in a number comparable with that of stellate cells in the liver. These stellate shaped pancreatic cells can be isolated and cultured in vitro.

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression. All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol. A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation. Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.