The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function

Abstract

Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postnatal stages leads to severe defects in alveologenesis, specifically in the generation of the elastin network, and animals display bronchopulmonary dysplasia (BPD) or BPD-like phenotype. Here we show the surprising results that mesenchyme-specific loss of Hox5 function at adult stages leads to rapid disruption of the mature elastin matrix, alveolar enlargement, and an emphysema-like phenotype. As the elastin matrix of the lung is considered highly stable, adult disruption of the matrix was not predicted. Just 2 weeks after deletion, adult Hox5 mutant animals show significant increases in alveolar space and changes in pulmonary function, including reduced elastance and increased compliance. Examination of the extracellular matrix (ECM) of adult Tbx4rtTA; TetOCre; Hox5afafbbcc lungs demonstrates a disruption of the elastin network although the underlying fibronectin, interstitial collagen and basement membrane appear unaffected. An influx of macrophages and increased matrix metalloproteinase 12 (MMP12) are observed in the distal lung 3 days after Hox5 deletion. In culture, fibroblasts from Hox5 mutant lungs exhibit reduced adhesion. These findings establish a novel role for Hox5 transcription factors as critical regulators of lung fibroblasts at adult homeostasis.

The correlation between a Th1/Th2 cytokines imbalance and vitamin D level in patients with early chronic obstructive pulmonary disease (COPD), based on screening results

“…IFN-γ suppressed not only the function of Th2 cells but also activated neutrophils and stimulated macrophages to participate in the airway inflammation of COPD (Egli et al, 2018). In addition, IFN-γ also promotes the expression of interferon by promoting expression of interferon-inducible protein 10 and monocyte factor, thereby promoting lung macrophages to secrete matrix metallo-proteinase-12 (MMP-12), which further causes lung tissue destruction and advancing emphysema formation (Li et al, 2021). Both Th2 cells and IL-4 increase in patients with early COPD.…”

Characterization of a novel Hoxa5eGFP mouse line

“…Lung fibroblasts in Figure 6A‐C were isolated and cultured as previously described, 41 imaged and processed using the Incucyte S3 Live‐Cell Analysis System (Essen BioScience). For flow cytometry data in Figure 6D, Hoxa5 eGFP /+ adult lung fibroblasts were cultured to passage 8 and analyzed on a Sony MA900 Multi‐Application Cell Sorter at the University of Wisconsin Carbone Cancer Center Flow Cytometry Laboratory.…”

“…Most Hoxa5 null ( Hoxa5 −/− ) animals die perinatally, likely by tracheal collapse and diaphragm defects 35‐39 . Lung‐specific deletion of Hoxa5 during postnatal or adult stages leads to distal airways expansion, abnormal pulmonary function, and disruptions of the lung elastin network, phenotypes that are exacerbated in the background of Hoxb5/Hoxc5 nulls 40,41 . In the gut tube, loss of Hoxa5 function results in the thinning of the gastric epithelium and delayed development of adult digestive functions 24,42 …”

“…[35][36][37][38][39] Lung-specific deletion of Hoxa5 during postnatal or adult stages leads to distal airways expansion, abnormal pulmonary function, and disruptions of the lung elastin network, phenotypes that are exacerbated in the background of Hoxb5/Hoxc5 nulls. 40,41 In the gut tube, loss of Hoxa5 function results in the thinning of the gastric epithelium and delayed development of adult digestive functions. 24,42 There are some critical outstanding questions in Hox5 biology that cannot be addressed with the genetic tools currently available.…”