Time and phenotype-dependent transcriptome analysis in AAV-TGFβ1 and Bleomycin-induced lung fibrosis models

Abstract

We have previously established a novel mouse model of lung fibrosis based on Adeno-associated virus (AAV)-mediated pulmonary overexpression of TGFβ1. Here, we provide an in-depth characterization of phenotypic and transcriptomic changes (mRNA and miRNA) in a head-to-head comparison with Bleomycin-induced lung injury over a 4-week disease course. The analyses delineate the temporal state of model-specific and commonly altered pathways, thereby providing detailed insights into the processes underlying disease development. They further guide appropriate model selection as well as interventional study design. Overall, Bleomycin-induced fibrosis resembles a biphasic process of acute inflammation and subsequent transition into fibrosis (with partial resolution), whereas the TGFβ1-driven model is characterized by pronounced and persistent fibrosis with concomitant inflammation and an equally complex disease phenotype as observed upon Bleomycin instillation. Finally, based on an integrative approach combining lung function data, mRNA/miRNA profiles, their correlation and miRNA target predictions, we identify putative drug targets and miRNAs to be explored as therapeutic candidates for fibrotic diseases. Taken together, we provide a comprehensive analysis and rich data resource based on RNA-sequencing, along with a strategy for transcriptome-phenotype coupling. The results will be of value for TGFβ research, drug discovery and biomarker identification in progressive fibrosing interstitial lung diseases.

An agent-based modeling approach for lung fibrosis in response to COVID-19

“…Our simulated result showed similar ranges and dynamics of TGF-β concentration compared to the BAL TGF-β1 protein levels in Strobel et al [76] (Fig 6A). In addition, we observed a peak value in the TGF-β concentration around day 5.…”

“…Here, we considered a new case DHMA (DS = 2 × 10 −9 ng min -1 , M S = 2 × 10 −9 ng min -1 , and no apoptosis of M2 macrophages) and simulated it for 28 days to validate our simulated results with experimental observations. Our simulated result showed similar ranges and dynamics of TGF-β concentration compared to the BAL TGF-β1 protein levels in Strobel et al [76] (Fig 6A). In addition, we observed a peak value in the TGF-β concentration around day 5.…”

“…From our in silico experiments, we observed a higher concentration of TGF-β in the earlier phase of infection from the activation of latent TGF-β sources (case D) and [73] and monocytes reported in Strobel et al [76]. The solid curves represent the mean of predictions, and shaded areas represent the predictions between the 5th and 95th percentile of 8 replications of the agent-based model.…”

“…The dynamics of simulated collagen area fractions are also in similar ranges compared to the percentage of affected lung tissue in Sefik et al [73] except on day 2 and day 14 (Fig 6B). In addition, we quantified collagen area fractions using the open-source platform Fiji [78] from the day 21 representative images of NaCl control and AAV-TGF-β1 treated lung tissue section in Strobel et al [76]. We considered the area fraction from NaCl control as an uninfected condition.…”

Changes in lung sialidases in male and female mice after bleomycin aspiration

“…[11][12][13][14][15][16][17]19 In the mouse bleomycin-induced pulmonary fibrosis model, there is an initial inflammation of the lungs lasting from 3 to 10 days, followed by the appearance of fibrosis in the lungs starting at approximately day 10. [20][21][22][23][24] To elucidate possible functions of sialidases, we examined the correlation of sialidase levels and localization in the lungs with the appearance of inflammation and fibrosis in the mouse bleomycin model. We find that NEU1 levels peak at day 14 in male and day 10 in female mice, NEU2 levels peak at day 7 in male and day 10 in female mice, and NEU3 levels appear to have a biphasic response in male mice with peaks at day 7 and then at days 14 and 21, whereas in female mice NEU3 levels increased over 21 days.…”