Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD.

BACKGROUND: In models of COPD, environmental stressors induce innate immune responses, inflammasome activation and inflammation. However, the interaction between these responses and their role in driving pulmonary inflammation in stable COPD is unknown. OBJECTIVES: To investigate the activation of innate immunity and inflammasome pathways in the bronchial mucosa and bronchoalveolar lavage (BAL) of patients with stable COPD of different severity and control healthy smokers and non-smokers. METHODS: Innate immune mediators (interleukin (IL)-6, IL-7, IL-10, IL-27, IL-37, thymic stromal lymphopoietin (TSLP), interferon γ and their receptors, STAT1 and pSTAT1) and inflammasome components (NLRP3, NALP7, caspase 1, IL-1ß and its receptors, IL-18, IL-33, ST2) were measured in the bronchial mucosa using immunohistochemistry. IL-6, soluble IL-6R, sgp130, IL-7, IL-27, HMGB1, IL-33, IL-37 and soluble ST2 were measured in BAL using ELISA. RESULTS: In bronchial biopsies IL-27+ and pSTAT1+ cells are increased in patients with severe COPD compared with control healthy smokers. IL-7+ cells are increased in patients with COPD and control smokers compared with control non-smokers. In severe stable COPD IL-7R+, IL-27R+ and TSLPR+ cells are increased in comparison with both control groups. The NALP3 inflammasome is not activated in patients with stable COPD compared with control subjects. The inflammasome inhibitory molecules NALP7 and IL-37 are increased in patients with COPD compared with control smokers. IL-6 levels are increased in BAL from patients with stable COPD compared with control smokers with normal lung function whereas IL-1ß and IL-18 were similar across all groups. CONCLUSIONS: Increased expression of IL-27, IL-37 and NALP7 in the bronchial mucosa may be involved in progression of stable COPD.

Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis.

BACKGROUND: It is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses. METHODS AND RESULTS: Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE) caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H2O2. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H2O2 treatment in the absence of cell death. CONCLUSIONS: This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COPD.

Stepwise increase of angiopoietin-2 serum levels is related to haemodynamic and functional impairment in stable chronic heart failure.

BACKGROUND: A reciprocal link between inflammation, oxidative/nitrosative stress, and endothelial dysfunction has been postulated in chronic heart failure (CHF). The endothelial repair mechanisms involved remain to be determined. Our aim was to investigate whether there are detectable signs of ongoing angiogenesis in serum of CHF patients and to evaluate the correlation with indexes of haemodynamic and functional impairment. METHODS AND RESULTS: Enzyme-linked immunosorbent assay tests were used to quantify angiogenin, angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, Tie-2, and brain natriuretic peptide in serum of 87 patients with CHF of increasing severity according to New York Heart Association (NYHA; class I, n = 8; II, n = 45; and III, n = 34) and in 14 healthy subjects matched for age and sex. Angiogenin, angiopoietin-2, and Tie-2 were significantly increased in CHF of increasing severity (Kruskal-Wallis: p = 0.0004, p < 0.0001, and p = 0.017, respectively). Angiopoietin-2 was inversely correlated with the 6-min walking test (r = -0.65, p < 0.0001), peak oxygen consumption (VO(2max); r = -0.57, p = 0.0002), and deceleration time (r = -0.61, p < 0.0001). Multiple regression analysis showed that angiopoietin-2 was mainly associated with VO(2max) (p = 0.018). The angiopoietin-2 area under the receiver operating characteristic curve for CHF diagnosis was 0.94 (95% CI 0.88-0.99; p < 0.001). CONCLUSIONS: These data demonstrate that angiopoietin-2 and selected serum markers of angiogenesis progressively increase with haemodynamic and functional decline in CHF.