Inhibition of antiapoptotic BCL-2 proteins with Lipo-NPs induces fibroblast apoptosis, alleviating pulmonary fibrosis in VILI mice
Year: 2025
Type: article
Abstract: BACKGROUND: Mechanical ventilation in critically ill patients can potentially result in ventilator-induced lung injury (VILI). Additionally, mechanical stretching might activate the pro-fibrotic signaling pathways, which could contribute to programmed cell death and the peripheral distribution of fibrosis observed in idiopathic pulmonary fibrosis (IPF). Based on our previous findings, we further explored whether lipoaspirate nanoparticles (Lipo-NPs) could offer protective effects against pulmonary fibrosis associated with VILI. METHODS: The 8-week-old male SPF C57BL/6 mice were selected for endotracheal intubation after abdominal anesthesia, mechanical ventilation of the mice for 4 h, and tidal volume was set at 30 ml/kg. Lipo-NPs were extracted and identified using a tangential flow filtration (TFF) system. All the mice were divided into three groups: control, VILI, and VILI + Lipo-NPs. The Lipo-NPs were administered into the mice through the tail vein for 7 consecutive days, and an equivalent volume of PBS was administered into the VILI groups. Mice were sacrificed 7 days after mechanical ventilation. RESULTS: Our results suggested that Lipo-NPs could reduce lung tissue damage, pulmonary inflammation, and fibrosis of the VILI mice, accompanied by a reduction in the secretion of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), as well as a decrease in transforming growth factor-β (TGF-β) levels. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed to explore downstream of Lipo-NPs and identified idiopathic pulmonary fibrosis (IPF) as the potential pathway. By the combined analysis of microRNAs (miRNAs) enriched by Lipo-NPs, we hypothesized that B cell lymphoma 2 (BCL-2) is a target that mediates the inhibitory effect of mmu-miR-143-3p on VILI-induced IPF. Analysis of lung tissue from mice experiencing VILI revealed elevated levels of antiapoptotic BCL-2 family proteins within α-smooth muscle actin-expressing (α-SMA+) fibroblasts. Treatment with Lipo-NPs induced fibroblast apoptosis, decreased fibroblast numbers, and reduced histologically evident fibrosis. Blocking Lipo-NPs mmu-miR-143-3p in vivo blunts the beneficial effects of Lipo-NPs. CONCLUSION: Lipo-NPs intervention can partially ameliorate pulmonary fibrosis induced by VILI. This effect is likely due to the enrichment of miR-143 in Lipo-NPs, which promotes fibroblast apoptosis by targeting the anti-apoptotic protein BCL-2.
Source: Respiratory Research
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,490
OpenAlex ID: W4416089041