Machine learning analysis of the bleomycin-mouse model reveals the compartmental and temporal inflammatory pulmonary fingerprint

Abstract

30The bleomycin mouse model is the most extensively used animal model to study pulmonary fibrosis. 31 Despite this, the inflammatory cell kinetics and cell compartmentalisation is still incompletely 32 understood. Here we simultaneously analysed 16 inflammatory cell populations in 303 samples and 33 applied advanced data modelling to conclusively detail these kinetics. 34 Three days post-bleomycin, the inflammatory profile was typified by acute innate inflammation, 35 pronounced neutrophilia and loss of alveolar macrophages. After 14 days, rapid responders were 36 increasingly replaced by the adaptive immune system and monocyte-derived alveolar macrophages, 37 which progressed till 21 days. Multi-colour imaging revealed the spatial-temporal cell distribution and 38 the close association of T-cells with fibrotic lung tissue at later time-points. 39

CDK4/6 inhibition enhances pulmonary inflammatory infiltration in bleomycin-induced lung fibrosis

“…Furthermore, palbociclib treated mice showed a greater loss of bodyweight compared to mice treated with bleomycin only, suggesting more deleterious effects. This difference was most evident during the acute inflammatory phase of bleomycin treatment around day 7-9 [7], and less pronounced thereafter ( Fig. 1e).…”

“…Bleomycin-treated mice were co-treated with palbociclib (PD 0332991, 150 mg/kg/day) in a preventive fashion (Fig. 1a), as described previously [6][7][8].…”

Nuclear respiratory factor-1 negatively regulates TGF-β1 and attenuates pulmonary fibrosis

“…Fibrosis requires a second phase of pro-fibrotic mediator elaboration, which includes TGFb1 (Chaudhary et al, 2006), a potent inducer of extracellular matrix deposition. Owing to the upregulation of anti-inflammatory factors, acute inflammation resolves by day 14; thereafter many alveoli become nearly obliterated with plugs of connective tissue, and evolution of the inflammatory response after BLM indicates a persistent, adaptive immune presence at 21 days (Bordag et al, 2020). Compared to other models of BLM induced lung injury, subcutaneous injections used in our study induced moderate but diffuse inflammatory infiltrates and lung fibrosis.…”

“…Pulmonary fibrosis (PF) is a life-threatening pulmonary disease featuring heterogeneous denudation of alveolar epithelium, fibroblast proliferation (Wynn, 2011), excessive collagen, and matrix deposition in the lung. Current therapy is based on empirical anti-fibrotic agents, which have limited benefits and significant side effects (Borgeson et al, 2011). Though the mechanisms of PF are not fully understood, mitochondrial damage and dysfunction has emerged as a key pathogenic factor in the disease (Rangarajan et al, 2017).…”

Low-Dose Lung Radiation Therapy for COVID-19 Lung Disease: A Preclinical Efficacy Study in a Bleomycin Model of Pneumonitis

“…To address this need, we undertook preclinical studies using a mouse model of bleomycin-induced pneumonitis. Many pathophysiological changes of COVID-19 lung disease (epithelial cytopathy, endotheliitis, inflammatory infiltrates, surfactant loss) are reproduced in the pneumonitis induced by inhaled bleomycin (20,21). Indeed, single cell sequencing studies of mouse bleomycin (22) and COVID-19 (23,24) pneumonitis have shown pathogenic SPP1 pos macrophage orthologues expressing key inflammatory mediators to be prominent in both conditions, along with profoundly reduced expression of anticoagulant and anti-apoptotic protein S in alveolar macrophages.…”