Regulation of YKL-40 expression by corticosteroids: effect on pro-inflammatory macrophages in vitro and its modulation in COPD in vivo.

BACKGROUND: Macrophages constitute a heterogeneous cell population with pro- (MΦ1) and anti-inflammatory (MΦ2) cells. The soluble chitinase-like-protein YKL-40 is expressed in macrophages and various other cell types, and has been linked to a variety of inflammatory diseases, including COPD. Dexamethasone strongly reduces YKL-40 expression in peripheral blood mononuclear cells (PBMC) in vitro. We hypothesized that: a) YKL-40 is differentially expressed by MΦ1 and MΦ2, b) is decreased by corticosteroids and c) that long-term treatment with inhaled corticosteroids (ICS) affects YKL-40 levels in serum and sputum of COPD patients. METHODS: Monocytes of healthy subjects were cultured in vitro for 7 days with either GM-CSF or M-CSF (for MΦ1 and MΦ2, respectively) and stimulated for 24 h with LPS, TNFα, or oncostatin M (OSM). MΦ1 and MΦ2 differentiation was assessed by measuring secretion of IL-12p40 and IL-10, respectively. YKL-40 expression in macrophages was measured by quantitative RT-PCR (qPCR) and ELISA; serum and sputum YKL-40 levels were analyzed by ELISA. RESULTS: Pro-inflammatory MΦ1 cells secreted significantly more YKL-40 than MΦ2, which was independent of stimulation with LPS, TNFα or OSM (p < 0.001) and confirmed by qPCR. Dexamethasone dose-dependently and significantly inhibited YKL-40 protein and mRNA levels in MΦ1. Serum YKL-40 levels of COPD patients were significantly higher than sputum YKL-40 levels but were not significantly changed by ICS treatment. CONCLUSIONS: YKL-40 secretion from MΦ1 cells is higher than from MΦ2 cells and is unaffected by further stimulation with pro-inflammatory agents. Furthermore, YKL-40 release from cultured monocyte-derived macrophages is inhibited by dexamethasone especially in MΦ1, but ICS treatment did not change YKL-40 serum and sputum levels in COPD. These results indicate that YKL-40 expression could be used as a marker for MΦ1 macrophages in vitro, but not for monitoring the effect of ICS in COPD. TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT00158847.

The global peripheral chemoreflex drive in patients with systemic sclerosis: a rebreathing and exercise study.

BACKGROUND: Exercise intolerance (EI) in systemic sclerosis (SSc) is difficult to manage by the clinician. The peripheral chemoreflex drive compensates for metabolic acidosis during exercise and may be related to EI. AIM: To assess the global peripheral chemoreflex drive (GPCD) in patients with SSc at rest and during exercise. METHODS: Consecutively tested SSc patients (n = 49) were evaluated by pulmonary function tests, carbon dioxide (CO2) rebreathing studies and non-invasive cardiopulmonary exercise testing (CPET). Results of their CO2 rebreathing tests were compared with those of controls (n = 32). Respiratory compensation for metabolic acidosis during CPET was defined by the occurrence of a sharp increase in minute ventilation (VdotE) and the ventilatory equivalent for CO2 (V'E and V'CO2) at the end of the isocapnic buffer phase. Euoxic (eVHR) and hyperoxic (hVHR) ventilatory responses to hypercapnia were measured and its difference (eVHR - hVHR) was considered to reflect the GPCD. RESULTS: In 45 patients with SSc, CPET results showed respiratory compensation at the occurrence of metabolic acidosis. eVHR - hVHR in patients with diffuse cutaneous SSc (dcSSc) differed significantly from that in patients with limited cutaneous SSc (lcSSc) and from that in controls (0.47 ± 0.38 (dcSSc) vs. 0.90 ± 0.77 (lcSSc) and 0.90 ± 0.49 (controls) l/min/mmHg; P = 0.04 and P = 0.03, respectively). CONCLUSIONS: Respiratory compensation for metabolic acidosis occurred in all patients. However, the GPCD was diminished in dcSSc patients, suggesting an altered control of breathing. Its assessment may help the clinician to better understand reported EI and exertional dyspnea in dcSSc patients.