Endogenous Long Pentraxin 3 Exerts a Protective Role in a Murine Model of Pulmonary Fibrosis

Abstract

Pulmonary fibrosis is a progressive scarring disease of the lungs, characterized by inflammation, fibroblast activation, and deposition of extracellular matrix. The long pentraxin 3 (PTX3) is a member of the pentraxin family with non-redundant functions in innate immune responses, tissue repair, and haemostasis. The role played in the lungs by PTX3 during the fibrotic process has not been elucidated. In this study, the impact of PTX3 expression on lung fibrosis was assessed in an intratracheal bleomycin (BLM)-induced murine model of the disease applied to wild type animals, transgenic mice characterized by endothelial overexpression and stromal accumulation of PTX3 (Tie2-PTX3 mice), and genetically deficient Ptx3−/− animals. Our data demonstrate that PTX3 is produced during BLM-induced fibrosis in wild type mice, and that PTX3 accumulation in the stroma compartment of Tie2-PTX3 mice limits the formation of fibrotic tissue in the lungs, with reduced fibroblast activation and collagen deposition, and a decrease in the recruitment of the immune infiltrate. Conversely, Ptx3-null mice showed an exacerbated fibrotic response and decreased survival in response to BLM treatment. These results underline the protective role of endogenous PTX3 during lung fibrosis and pave the way for the study of novel PTX3-derived therapeutic approaches to the disease.

PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis

“…In the same model, Ptx3 -/mice showed reduced survival (Figure 1C) and accentuated weight loss (Figure 1C). Corroborating the results by Maccarinelli et al (29), lungs from Ptx3 -/mice showed hemorrhagic areas (day-14)(Figure 1C) and increased fibrosis, as assessed by total collagen content (day-22) (Figure 1D). In Ptx3 -/mice lung homogenates (Figure 1E), fibrosis was not associated with differences in IL-4, IL-10, IL-6, and CCL2, thus indicating the independence of PTX3 in the regulation of inflammation (1, 2, 31), while we found increased TGF-b1 in Ptx3 -/mice (Figure 1E)(day-14).…”

“…Data reported by Maccarinelli et al (29) and our results suggest that IPF may be related to a low expression of PTX3 in lung tissue. Therefore, we could consider restoring PTX3 levels exogenously (as summarized in Figure 1G) as a possible therapeutic approach for IPF.…”

“…Bleomycin (BLM) is vastly used to investigate the mechanisms involved in lung fibrosis in mice, and also in the selection of therapeutic drugs for IPF, including Pirfenidone and Nintedanib (25,26). Several studies have addressed the relevance of PTX3 in different models of pulmonary fibrosis (27)(28)(29). Despite the observation that BLM induces PTX3 expression in murine models of lung fibrosis (27,29), a paucity of information exists on the functional role of the protein in this model.…”

“…Several studies have addressed the relevance of PTX3 in different models of pulmonary fibrosis (27)(28)(29). Despite the observation that BLM induces PTX3 expression in murine models of lung fibrosis (27,29), a paucity of information exists on the functional role of the protein in this model. It has been shown that PTX3 promotes murine fibrocyte differentiation dependent on FcgRI in vitro (28).…”

“…It has been shown that PTX3 promotes murine fibrocyte differentiation dependent on FcgRI in vitro (28). In vivo, PTX3 is localized in fibrotic areas, and its distribution is associated with collagen deposition in lung parenchyma (28) and with macrophage infiltration at sites of fibrogenesis (29), revealing an interplay with macrophages during BLM-induced tissue fibrogenesis. Taking advantage of transgenic mice overexpressing PTX3 (Tie2-PTX3), it was recently shown that the protein could limit lung fibrosis, reducing collagen deposition and fibroblast activation and decreasing leukocyte recruitment (29).…”