Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory responses and structural alterations of the airways, lung parenchyma and pulmonary vasculature. Since Pentraxin-3 (PTX3) is a tuner of inflammatory responses and is produced by endothelial and inflammatory cells upon stimuli such as interleukin-1β (IL-1β), we hypothesized that PTX3 is involved in COPD pathogenesis.Methods and ResultsWe evaluated whether cigarette smoke (CS) triggers pulmonary and systemic PTX3 expression in vivo in a murine model of COPD. Using immunohistochemical (IHC) staining, we observed PTX3 expression in endothelial cells of lung venules and veins but not in lung arteries, airways and parenchyma. Moreover, ELISA on lung homogenates and semi-quantitative scoring of IHC-stained sections revealed a significant upregulation of PTX3 upon subacute and chronic CS exposure. Interestingly, PTX3 expression was not enhanced upon subacute CS exposure in IL-1RI KO mice, suggesting that the IL-1 pathway is implicated in CS-induced expression of vascular PTX3. Serum PTX3 levels increased rapidly but transiently after acute CS exposure.To elucidate the functional role of PTX3 in CS-induced responses, we examined pulmonary inflammation, protease/antiprotease balance, emphysema and body weight changes in WT and Ptx3 KO mice. CS-induced pulmonary inflammation, peribronchial lymphoid aggregates, increase in MMP-12/TIMP-1 mRNA ratio, emphysema and failure to gain weight were not significantly different in Ptx3 KO mice compared to WT mice. In addition, Ptx3 deficiency did not affect the CS-induced alterations in the pulmonary (mRNA and protein) expression of VEGF-A and FGF-2, which are crucial regulators of angiogenesis.ConclusionsCS increases pulmonary PTX3 expression in an IL-1 dependent manner. However, our results suggest that either PTX3 is not critical in CS-induced pulmonary inflammation, emphysema and body weight changes, or that its role can be fulfilled by other mediators with overlapping activities.
Highlights
Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory responses and structural alterations of the airways, lung parenchyma and pulmonary vasculature
Our results suggest that either PTX3 is not critical in cigarette smoke (CS)-induced pulmonary inflammation, emphysema and body weight changes, or that its role can be fulfilled by other mediators with overlapping activities
It is produced in response to the pro-inflammatory cytokines IL-1b and tumor necrosis factor-a (TNF-a) and microbial components such as LPS, a component of gram-negative bacteria, which is present in CS [10,11,12]
Summary
Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory responses and structural alterations of the airways, lung parenchyma and pulmonary vasculature. Since Pentraxin-3 (PTX3) is a tuner of inflammatory responses and is produced by endothelial and inflammatory cells upon stimuli such as interleukin-1b (IL-1b), we hypothesized that PTX3 is involved in COPD pathogenesis. COPD is characterized by progressive and largely irreversible airflow limitation caused by obstructive bronchiolitis and emphysema which are associated with an abnormal inflammatory response of the lungs to molecular mechanisms whereby CS triggers abnormal pulmonary and systemic manifestations remain unclear. PTX3 is, in contrast with the hepatically derived short pentraxins, mainly produced by inflammatory cells [9] and endothelial cells [10,11], which allows it to act locally at sites of infection and inflammation. It is produced in response to the pro-inflammatory cytokines IL-1b and tumor necrosis factor-a (TNF-a) and microbial components such as LPS, a component of gram-negative bacteria, which is present in CS [10,11,12]
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