Sirolimus suppresses circulating fibrocytes in idiopathic pulmonary fibrosis in a randomized controlled crossover trial.

Abstract

Fibrocytes are bone marrow-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF). We conducted a short-term randomised double-blind placebo-controlled crossoverpilot trial to assess the safety and tolerability of sirolimus in IPF. Subjects were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4 week washout, assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment. In the 28 study subjects, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing ɑ-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment with the exception of a small decline in gas transfer during treatment with placebo. As compared with placebo, short-term treatment with sirolimus resulted inreduction of circulating fibrocyte concentrations in subjects with IPF with an acceptable safety profile. gov identifier number NCT01462006FUNDING. NIH R01HL098329 and American Heart Association 18TPA34170486.