CRTH2 Mediates Profibrotic Macrophage Differentiation and Promotes Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a particularly deadly form of pulmonary fibrosis of unknown cause. In patients with IPF, high serum and lung concentrations of CHI3L1 (chitinase 3 like 1) can be detected and are associated with poor survival. However, the roles of CHI3L1 in these diseases have not been fully elucidated. We hypothesize that CHI3L1 interacts with CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) to stimulate profibrotic macrophage differentiation and the development of pulmonary fibrosis and that circulating blood monocytes from patients with IPF are hyperresponsive to CHI3L1-CRTH2 signaling. We used murine pulmonary fibrosis models to investigate the role of CRTH2 in profibrotic macrophage differentiation and fibrosis development and primary human peripheral blood mononuclear cell culture to detect the difference of monocytes in the responses to CHI3L1 stimulation and CRTH2 inhibition between patients with IPF and normal control subjects. Our results showed that null mutation or small-molecule inhibition of CRTH2 prevents the development of pulmonary fibrosis in murine models. Furthermore, CHI3L1 stimulation induces a greater increase in CD206 expression in IPF monocytes than control monocytes. These results demonstrated that monocytes from patients with IPF appear to be hyperresponsive to CHI3L1 stimulation. These studies support targeting the CHI3L1-CRTH2 pathway as a promising therapeutic approach for IPF and that the sensitivity of blood monocytes to CHI3L1-induced profibrotic differentiation may serve as a biomarker that predicts responsiveness to CHI3L1- or CRTH2-based interventions.

The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study.

OBJECTIVES: It is unclear if a low- or high-volume IV fluid resuscitation strategy is better for patients with severe sepsis and septic shock. DESIGN: Prospective randomized controlled trial. SETTING: Two adult acute care hospitals within a single academic system. PATIENTS: Patients with severe sepsis and septic shock admitted from the emergency department to the ICU from November 2016 to February 2018. INTERVENTIONS: Patients were randomly assigned to a restrictive IV fluid resuscitation strategy (≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care. MEASUREMENTS AND MAIN RESULTS: We enrolled 109 patients, of whom 55 were assigned to the restrictive resuscitation group and 54 to the usual care group. The restrictive group received significantly less resuscitative IV fluid than the usual care group (47.1 vs 61.1 mL/kg; p = 0.01) over 72 hours. By 30 days, there were 12 deaths (21.8%) in the restrictive group and 12 deaths (22.2%) in the usual care group (odds ratio, 1.02; 95% CI, 0.41-2.53). There were no differences between groups in the rate of new organ failure, hospital or ICU length of stay, or serious adverse events. CONCLUSIONS: This pilot study demonstrates that a restrictive resuscitation strategy can successfully reduce the amount of IV fluid administered to patients with severe sepsis and septic shock compared with usual care. Although limited by the sample size, we observed no increase in mortality, organ failure, or adverse events. These findings further support that a restrictive IV fluid strategy should be explored in a larger multicenter trial.