Time Course of the Phenotype of Blood and Bone Marrow Monocytes and Macrophages in the Lung after Cigarette Smoke Exposure In Vivo

Alveolar macrophages play a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Monocytes are recruited from blood during inflammation and then mature into alveolar macrophages. The aim of this study was to investigate the effect of cigarette smoke (CS) at different times in lung macrophages and monocytes from blood and bone marrow in mice. Male mice (C57BL/6, n = 45) were divided into groups: control, CS 5 days, CS 14 days and CS 30 days. Five days’ CS exposure induced a pronounced influx of neutrophils and macrophages in the lung associated with increased levels of keratinocyte chemoattractant (KC), tumor necrosis factor-α (TNF-α), nitric oxide (NO) and matrix metalloproteinase (MMP)-12. After 14 days of CS exposure, neutrophil recruitment and cytokine production were greatly reduced. Moreover, chronic CS exposure led to increased recruitment of macrophages (with high expression of CD206), transforming growth factor-β (TGF-β) production as well as no detection of TNF-α, interleukin (IL)-6 and KC. CS can also change the monocyte phenotype in the blood and bone marrow, with an increase in Ly6Clow cells. These results show for the first time that CS can change not only macrophage polarization but also monocyte. These results suggest that continued recruitment of Ly6Clow monocytes may help the distinct renewing macrophage M2 population required for COPD progression

COPD Patients Exhibit Distinct Gene Expression, Accelerated Cellular Aging, and Bias to M2 Macrophages

COPD, one of world’s leading contributors to morbidity and mortality, is characterized by airflow limitation and heterogeneous clinical features. Three main phenotypes are proposed: overlapping asthma/COPD (ACO), exacerbator, and emphysema. Disease severity can be classified as mild, moderate, severe, and very severe. The molecular basis of inflammatory amplification, cellular aging, and immune response are critical to COPD pathogenesis. Our aim was to investigate EP300 (histone acetylase, HAT), HDAC 2 (histone deacetylase), HDAC3, and HDAC4 gene expression, telomere length, and differentiation ability to M1/M2 macrophages. For this investigation, 105 COPD patients, 42 smokers, and 73 non-smoker controls were evaluated. We identified a reduced HDAC2 expression in patients with mild, moderate, and severe severity; a reduced HDAC3 expression in patients with moderate and severe severity; an increased HDAC4 expression in patients with mild severity; and a reduced EP300 expression in patients with severe severity. Additionally, HDAC2 expression was reduced in patients with emphysema and exacerbator, along with a reduced HDAC3 expression in patients with emphysema. Surprisingly, smokers and all COPD patients showed telomere shortening. COPD patients showed a higher tendency toward M2 markers. Our data implicate genetic changes in COPD phenotypes and severity, in addition to M2 prevalence, that might influence future treatments and personalized therapies

Association of markers of endothelial activation and dysfunction with occurrence and outcome of pulmonary hemorrhage in dogs with leptospirosis

BACKGROUND: Endothelial dysfunction might contribute to the development of leptospiral pulmonary hemorrhage syndrome (LPHS). HYPOTHESIS: Serum concentrations of markers of endothelial activation and dysfunction are higher in dogs with leptospirosis and correlate with the occurrence of LPHS and a higher case fatality rate. ANIMALS: Clinically healthy dogs (n = 31; 10/31 dogs confirmed healthy based on no detected abnormalities on blood work), dogs with leptospirosis with LPHS (n = 17) and without LPHS (n = 15), dogs with acute kidney injury not due to leptospirosis (AKI‐nL, n = 34). METHODS: Observational study. Serum concentrations of soluble intercellular adhesion molecule 1 (sICAM‐1), vascular endothelial growth factor (VEGF), and angiopoietin‐2 (Ang‐2) at admission were compared between groups. Correlations with outcome and the accuracy to predict LPHS were examined. RESULTS: Soluble intercellular adhesion molecule (sICAM‐1), VEGF, and Ang‐2 concentrations were higher in dogs with AKI‐nL (sICAM‐1 34.7 ng/mL, interquartile range [IQR] = 24.4‐75.5; VEGF 43.1 pg/mL, IQR = 12.3‐79.2; Ang‐2 8.5 ng/mL, IQR = 6.2‐12.3), leptospirosis without LPHS (sICAM‐1 45.1 ng/mL, IQR = 30.6‐59.0; VEGF 32.4 pg/mL, IQR = 12.5‐62.6; Ang‐2 9.6 ng/mL, IQR = 6.9‐19.3), and LPHS (sICAM‐1 69.7 ng/mL, IQR = 42.1‐89.1; VEGF 51.8 pg/mL, IQR = 26.3‐96.7; Ang‐2 8.0 ng/mL, IQR = 5.6‐12.2) compared to controls (P < .001). In dogs with leptospirosis, VEGF and sICAM‐1 were higher in nonsurvivors (sICAM‐1 89.4 ng/mL, IQR = 76.5‐101.0; VEGF 117.0 pg/mL, IQR = 90.3‐232.4) than survivors (P = .004) and sICAM‐1 predicted the development of LPHS. CONCLUSIONS: Soluble intercellular adhesion molecule 1, VEGF, and Ang‐2 do not discriminate leptospirosis from AKI‐nL. In dogs with leptospirosis, sICAM‐1 and VEGF predict outcome and sICAM‐1 might identify dogs at risk for LPHS