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Title: Relation between chronic airway inflammation, systemic activation of coagulation pathway and the cardiovascular risk in asthma


INTRODUCTION: Asthma is a chronic and heterogeneous airway disease characterized by variable respiratory symptoms, including shortness of breath, wheeze, cough, and chest tightness. These clinical features result from reversible airflow limitation related to chronic airway inflammation, bronchial hyperresponsiveness and remodeling. There is growing evidence of increased venous thromboembolism risk in asthma patients. Furthermore, it has been shown that asthma is related to the unfavorably altered thrombin generation profile and extended clot lysis time, indicating a hypercoagulable state of circulating blood in those patients. In addition, there is evidence of a local prothrombotic state in the bronchoalveolar space. Accelerated development of atherosclerosis has been demonstrated in several chronic inflammatory diseases. For example, in asthma research, abnormal brachial artery flowmediated dilatation (FMD) and elevated pulse wave velocity (PWV) suggest endothelial dysfunction while increased intima-media thickness of the common carotid artery (CIMT) likely points to a higher cardiovascular risk. In addition, most studies on cardiovascular disease epidemiology indicate an enhanced risk of coronary artery disease or stroke in asthma. However, understanding of mechanisms linking asthma pathology with increased thromboembolic and cardiovascular risk is limited. ; Cellular fibronectin (cFn) is a glycoprotein released in the event of endothelium damage. It may be involved in the regulation of vascular remodeling response. In addition, available evidence indicates its prothrombotic potential in vivo. Moreover, cFn may also participate in airway remodeling. Therefore, we hypothesized that cFn might be associated with the prothrombotic state in stable asthma (article I). Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is involved in the pathophysiology of atherosclerosis. One of the Lp-PLA2 functions is degrading plateletactivating factor (PAF), a prothrombotic and proinflammatory mediator entangled in asthma pathology. In addition, Lp-PLA2 has also an antioxidant role. We hypothesized that Lp-PLA2 might be associated with prothrombotic blood alterations in asthma (article II). 2 Citrullinated histone 3 (H3cit) is a specific marker of neutrophil extracellular traps (NETs) formation. There is extensive evidence that NETs are involved in prothrombotic mechanisms. In asthma, extracellular traps (ETs) may also contribute to persistent airway inflammation. Therefore, we adopted the hypothesis that serum H3cit may be increased in stable asthma (article III). MATERIALS AND METHODS: We performed an observational, cross-sectional study at the Department of Allergy and Immunology and the Department of Pulmonology, Jagielloni ; an University Medical College in Kraków. We enrolled adult patients with clinically stable asthma, defined as no disease exacerbation during six months preceding inclusion into the study. In subsequent publications, we analyzed plasma cFn concentration, plasma Lp-PLA2 activity and serum H3cit concentration in relation to asthma severity, pulmonary function tests, biomarkers of systemic inflammation, and for the first two publications also plasma activation of coagulation. In the first part of the studies, 164 patients with asthma were enrolled (articles I and II). 72 subjects were included in the control group. The next part included 60 asthmatics who underwent bronchoscopy, enabling cellularity and cytokine analysis of bronchoalveolar lavage fluid (BALF) (article III). 50 subjects were included in the control group (not undergoing endoscopy). Control groups were matched according to sex, age, body mass index, and comorbidities. SUMMARY OF RESULTS: ARTICLE I In asthma, plasma cFn was significantly increased compared to the control group (4.11 [3.30-4.95] vs. 2.06 [1.46-2.59] µg/ml; p<0.001). Furthermore, in patients it was positively associated with inflammatory markers, i.e. high-sensitivity C-reactive protein (hsCRP) (β= 0.24 [95%CI: 0.16–0.32]) and interleukin-6 (β= 0.23 [95%CI: 0.15–0.30]), while the relationship between cFn and FEV1/VC was negative (β= –0 ; .15 [95%CI: - 0.23 to -0.07]). The multiple regression model showed that cFn in asthma is the strongest predictor for endogenous thrombin potential (ETP) and for clot lysis time (CLT) among the variables assessed in the study. ARTICLE II Plasma Lp-PLA2 activity in severe asthma was lower than in non-severe asthma (203 [181-229] vs. 224 [191-261] nmol/min/ml, p=0.006 after adjustment for potential 3 confounders). In asthma, an inverse relationship was found between plasma Lp-PLA2 and markers of systemic inflammation, in particular, tumor necrosis factor α (β= -0.27 [95%CI: - 0.35 to -0.20]) and hsCRP (β= -0.1 [95%CI: -0.19 to -0.02]), and between circulating Lp-PLA2 and parameters describing plasma thrombin generation profile (for ETP: β= -0.14 [95%CI: -0.21 to -0.06]). ARTICLE III Asthma was characterized by elevated circulating H3cit (17.49 [11.25–22.58] vs. 13.66 [8.66–18.87] ng/ml, p=0.03). H3cit was increased in asthma patients receiving systemic steroids (21.07 [15.9–32.0] vs. 16.21 [10.52–20.27] ng/ml, p=0.02). In asthmatics, a positive association between serum H3cit and total lung capacity (TLC) was demonstrated (β= 0.37 [95%CI 0.24–0.50]). CONCLUSIONS: ARTICLE I For the first time, elevated plasma cFn in asthma and its positive correlation with disease severity, coagulation activation and markers of inflammation have been demonstrated. These new ; observations suggest a possible role for cFn as a coagulation modulator in asthma. ARTICLE II The lower activity of plasma Lp-PLA2 in severe asthma compared to mild or moderate disease may be related to differences in the pathology of severe asthma phenotypes. The inverse relationship between Lp-PLA2 and markers of inflammation as well as thrombin generation parameters suggest that Lp-PLA2 may not be an adequate marker for assessing cardiovascular risk in patients with asthma. In severe asthma, the decrease in circulating Lp-PLA2 activity may adversely affect the oxidative stress. ARTICLE III For the first time, increased concentration of circulating H3cit in asthma has been shown. The positive relationship between serum H3cit and TLC may suggest that circulating H3cit is related to the ongoing airway inflammation. Further research is needed to determine the relation between ETs and the increased thromboembolic risk in asthma.

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Level of degree:

2 - studia doktoranckie

Degree grantor:

Rada Dyscypliny Nauki medyczne


Bazan-Socha, Stanisława

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pol; eng

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tylko w bibliotece

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Apr 8, 2024

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Apr 8, 2024

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UJCM22802ec9f9844fc59b0c8a9184fa76a6 Apr 8, 2024


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