Collagenase mRNA Overexpression and Decreased Extracellular Matrix Components Are Early Events in the Pathogenesis of Emphysema

Abstract

To describe the progression of parenchymal remodeling and metalloproteinases gene expression in earlier stages of emphysema, mice received porcine pancreatic elastase (PPE) instillation and Control groups received saline solution. After PPE instillation (1, 3, 6 hours, 3 and 21 days) we measured the mean linear intercept, the volume proportion of types I and III collagen, elastin, fibrillin and the MMP-1, -8, -12 and -13 gene expression. We observed an initial decrease in type I (at the 3rd day) and type III collagen (from the 6th hour until the 3rd day), in posterior time points in which we detected increased gene expression for MMP-8 and -13 in PPE groups. After 21 days, the type III collagen fibers increased and the type I collagen values returned to similar values compared to control groups. The MMP-12 gene expression was increased in earlier times (3 and 6 hours) to which we detected a reduced proportion of elastin (3 days) in PPE groups, reinforcing the already established importance of MMP-12 in the breakdown of ECM. Such findings will be useful to better elucidate the alterations in ECM components and the importance of not only metalloelastase but also collagenases in earlier emphysema stages, providing new clues to novel therapeutic targets.

Characterization of a Mouse Model of Emphysema Induced by Multiple Instillations of Low-Dose Elastase

“…Emphysema is characterized by changes in the organization and composition of extracellular matrix (Ito et al, 2005 ; Suki et al, 2012 ; Szabari et al, 2012 ; Takahashi et al, 2014 ; Robertoni et al, 2015 ). In an attempt to repair the damaged lung, new collagen fibers are resynthesized, but are relatively weak, and, because they can rupture, tend to reduce overall tissue stiffness and static lung elastance (Suki et al, 2003 ).…”

Bioactive extracellular matrix fragments in lung health and disease

“…ECM components undergo synthesis (104,105) concurrent with ECM breakdown, and each process is influenced by various factors such as increased mechanical stress (106) and tissue aging (107). Thus, it is challenging to identify matrikines that can exert a specific phenotype in diseases where the ECM undergoes continuous remodeling, as is seen in interstitial lung diseases including idiopathic pulmonary fibrosis, ARDS, and COPD.…”

Animal Models of Chronic Obstructive Pulmonary Disease Exacerbations: A Review of the Current Status

“…A wide variety of studies have highlighted the proteolytic activity of elastase in causing structural changes, such as higher mean linear intercept and alveolar enlargement both in mice [71][72][73][74][75] and in rats [76][77][78][79] (Table 2). Furthermore, several studies reported changes in ECM composition after elastase administration, such as disorganized elastin [80,81], degradation of proteoglycans [82], and abnormal collagen remodeling [83][84][85][86][87][88]. However, as in CS models, these effects are dependent on several factors, including strain; enzyme dose at each instillation; and number of elastase challenges (Figure 2).…”