Airway Transplantation of Adipose Stem Cells Protects against Bleomycin-Induced Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis. Adipose-derived stem cells (ADSC) have demonstrated regenerative properties in several tissues. The hypothesis of this study was that airway transplantation of ADSC could protect against bleomycin (BLM)-induced pulmonary fibrosis (PF). Fifty-eight lungs from 29 male Sprague-Dawley rats were analyzed. Animals were randomly divided into five groups: a) control (n=3); b) sham (n=6); c) BLM (n=6); d) BLM+ADSC-2d (n=6); and e) BLM+ADSC-14d (n=8). Animals received 500 µL saline (sham), 2.5 UI/kg BLM in 500 µL saline (BLM), and 2×10 ADSC in 100 µL saline intratracheally at 2 (BLM+ADSC-2d) and 14 days (BLM+ADSC-14d) after BLM. Animals were sacrificed at 28 days. Blinded Ashcroft score was used to determine pulmonary fibrosis extent on histology. Hsp27, Vegf, Nfkβ, IL-1, IL-6, Col4, and Tgfβ1 mRNA gene expression were determined using real-time quantitative-PCR. Ashcroft index was: control=0; sham=0.37±0.07; BLM=6.55±0.34 vs sham (P=0.006). BLM vs BLM+ADSC-2d=4.63±0.38 (P=0.005) and BLM+ADSC-14d=3.77±0.46 (P=0.005). BLM vs sham significantly increased Hsp27 (P=0.018), Nfkβ (P=0.009), Col4 (P=0.004), Tgfβ1 (P=0.006) and decreased IL-1 (P=0.006). BLM+ADSC-2d vs BLM significantly decreased Hsp27 (P=0.009) and increased Vegf (P=0.006), Nfkβ (P=0.009). BLM+ADSC-14d vs BLM significantly decreased Hsp27 (P=0.028), IL-6 (P=0.013), Col4 (P=0.002), and increased Nfkβ (P=0.040) and Tgfβ1 (P=0.002). Airway transplantation of ADSC significantly decreased the fibrosis rate in both early and established pulmonary fibrosis, modulating the expression of Hsp27, Vegfa, Nfkβ, IL-6, Col4, and Tgfβ1. From a translational perspective, this technique could become a new adjuvant treatment for patients with IPF.

Adipose Stromal Cell-Secretome Counteracts Profibrotic Signals From IPF Lung Matrices

“…Adipose tissue-derived stromal cells (ASCs) have been tested experimentally for the treatment of various conditions, including IPF ( Barczyk et al, 2015 ). A variety of studies showed attenuated, but not resolved, fibrosis after ASC treatment in bleomycin-induced lung fibrosis in mice and rats ( Lee et al, 2014 ; Jiang et al, 2015 ; Tashiro et al, 2015 ; Rathinasabapathy et al, 2016 ; Reddy et al, 2016 ; Llontop et al, 2018 ; Felix et al, 2020 ). Similar results were achieved in other rat models of pulmonary fibrosis ( Fikry et al, 2015 ; Chen et al, 2018 ; Zhang et al, 2019 ; Radwan et al, 2020 ).…”

Effectivity of mesenchymal stem cells for bleomycin-induced pulmonary fibrosis: a systematic review and implication for clinical application

“…Grading was scored on a scale from 0 to 8, using the average of microscope field scores [ 44 ]. Seventeen of them showed that the Ashcroft scoring were significantly lower in the MSCs treatment group than that in the BLM group (all p < 0.05) [ 11 – 15 , 18 – 21 , 23 , 29 , 30 , 32 , 33 , 41 – 43 ]. Three studies found no significant difference in the Ashcroft score between the MSCs and the BLM groups [ 22 , 28 , 35 ].…”

“…Both the early and delayed treatment groups showed significant reductions in lung inflammation, collagen deposition, and Ashcroft score. Although lung function in the delayed treatment group was not complete restored [ 11 , 15 , 29 ]. Four studies found that the early treatment group (day 0 or 1) had significantly reduced PF score and collagen content, while the delayed treatment group (day 7 or 9) had no significant difference in the degree of PF compared with the BLM group [ 18 , 31 , 38 , 40 ].…”

Single-Cell RNA Sequencing Reveals the Interaction of Injected ADSCs with Lung-Originated Cells in Mouse Pulmonary Fibrosis

“…Groups ii and iii mice were anesthetized with 2.5% tribromoethanol (0.8% NaCl, 1 mM Tris (pH 7.4), 0.25 mM EDTA (pH 7.4)) and administered 3.5 mg/kg bleomycin solution (Sigma B5507-15un) in 50 μ L of phosphate-buffered saline (PBS) intratracheally on day 0 using a 1 mL syringe with a 25G needle. Control animals were treated with PBS instead of BLM [ 23 , 24 ].…”