American Journal of Respiratory Cell and Molecular Biology最新文献

Lipid metabolism disorder is increasingly recognized as hallmarks of Pulmonary hypertension (PH). Fatty acid-binding proteins (FABPs), particularly FABP4 and FABP5, which regulate lipid transport and metabolism of fatty acid, are thought to contribute to the development of PH. However, it remains unclear whether FABP4 and FABP5 serve as therapeutic targets for the treatment of PH. In the present study, the levels of FABP4/5 were elevated in the plasma and lung tissues of IPAH patients, as well as in the lung tissues of the PH rat model compared with control. The circulating levels of FABP4 of IPAH patients were correlated with mean pulmonary arterial pressure (mPAP). To determine the preventive or therapeutic effect of FABP4 and FABP5 inhibition, FABP4 and FABP5 inhibitors alone or combination were administered at early (days 2 following monocrotaline (MCT) injection) and late (day 12 following MCT injection) stage of PH rat model, respectively. Combined treatment with FABP4/5 inhibitors in the early stage of the MCT-PH rat model effectively reduced right ventricular systolic pressure (RVSP) and improved right ventricular function, accompanied by reductions in pulmonary vascular and right ventricular fibrosis, as well as blood lipid levels, lipid peroxidation, and inflammation. Combined treatment with FABP4/5 inhibitors at the late stage of MCT-PH improved right ventricular function, suppressed pulmonary vascular and right ventricular fibrosis, and lowered blood lipid levels, but did not affect RVSP. In conclusion, our study indicates that combined inhibition of FABP4 and FABP5 can prevent the pathogenesis of PH, representing a potential therapeutic strategy for PH.

As a 5-methylcytosine (m5C) methyltransferase, increased NOP2/Sun RNA methyltransferase 2 (NSUN2) has been revealed to promote the progression of non-small cell lung cancer (NSCLC) through m5C modification. Herein, this study aimed to investigate the potential molecular mechanisms underlying the high NSUN2 expression in NSCLC, and the potential downstream m5C mRNAs of NSUN2 in promoting NSCLC progression. Functional analyses were conducted using in vitro MTT, EdU, transwell, wound healing, sphere and tube formation assays, and in vivo murine model. m5C modification was determined by MeRIP assay. RIP assay determined the binding between NSUN2 and SLC7A5 mRNA. The upstream molecular mechanism of the upregulation of NSUN2 expression was explored using ChIP, Co-immunoprecipitation (Co-IP), and luciferase reporter assays. NSUN2 was highly expressed in NSCLC and predicted poor outcomes in NSCLC patients. Functionally, NSUN2 silencing suppressed cancer cell proliferation, migration, stemness properties, angiogenic ability and glutamine metabolism. Mechanistically, NSUN2 induced m5C methylation modification of SLC7A5, and stabilized SLC7A5 mRNA via a YBX1-dependent mechanism. Accordingly, SLC7A5 overexpression reversed the anticancer effects of NSUN2 on above oncogenic phenotypes. Further upstream molecular mechanism analysis showed that P300 could bind to and cooperate with transcription factor SP1 to increase NSUN2 expression by Histone H3 Lysine 27 acetylation (H3K27ac). Further in vivo analyses suggested that NSUN2 silencing suppressed ESCC growth and metastasis in vivo by regulating SLC7A5 expression. In conclusion, increased NSUN2 derived by P300/SP1 complex-mediated histone acetylation promoted the growth, metastasis and glutamine metabolism of NSCLC by stabilizing SLC7A5 mRNA via m5C modification.

Pulmonary fibrosis is increasingly understood to involve dysfunction within and across multiple cellular compartments, with recent attention highlighting the involvement of pulmonary vascular dysfunction in failed repair and progression of fibrosis. Formulation and delivery of lung-targeting lipid nanoparticles may provide a means to selectively target the lung but not systemic vasculature. However, the feasibility and efficacy of such approaches in the fibrotic lung are unknown. We sought to test whether intravenously administered lung-targeting lipid nanoparticles can safely deliver mRNA to the healthy and fibrotic lung vasculature in young and aged mice and whether delivery of mRNA encoding a matricellular protein could promote fibrosis resolution. We used a Selective Organ Targeting (SORT) LNP formulation and characterized cell-specificity of delivery after bleomycin-induced lung fibrosis. We then delivered Ccn3 mRNA (encoding cellular communication network factor 3) to aged mice in the setting of established lung fibrosis and evaluated fibrotic regression and vascular repair. The matricellular protein encoded by Ccn3 was previously identified by our group as an important regulator of lung endothelial function. We found that LNP delivery was lung specific and predominantly endothelial targeting in the setting of lung fibrosis. Delivery of Ccn3 mRNA to aged mice via LNPs modestly reduced fibrosis and improved microvascular density in the lungs. Our results support the concept that cell-specific and repair-promoting cargos delivered via lung targeting LNPs may have utility for treatment of established fibrosis.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are heterogeneous and potentially fatal consequences of serious conditions such as trauma and sepsis, an exacerbated inflammatory response to infection. There are no effective treatments for ALI/ARDS, partly due to an incomplete understanding of its pathogenesis across different patient sub-populations, contributing to mortality rates of 25-40%. ALI/ARDS is characterized by lung hypoxia, inflammatory cell infiltration, edema, and endothelial cell injury and death. Lung endothelial viability is essential for gas exchange, nutrient delivery, and immune cell migration, as well as the prevention of proteinaceous fluid accumulation. Given that lung endothelial death is a predominant feature of ALI/ARDS, its inhibition could represent a novel therapeutic strategy. In this article, we review studies examining pulmonary endothelium death during sepsis-induced ALI/ARDS, including studies of lung endothelium apoptosis, pyroptosis, necroptosis, and ferroptosis. We also highlight gaps in current knowledge that, if addressed, could facilitate the development of effective treatments for sepsis-induced ALI/ARDS. Future studies of the mechanisms regulating lung endothelial death may uncover novel therapeutic targets for ALI/ARDS. These targets could be leveraged in precision medicine approaches to treat patient sub-populations most likely to benefit from inhibiting specific forms of lung endothelial death.

Lung injury caused by influenza is a leading cause of respiratory infection-related morbidity and mortality worldwide. In its severe form, influenza can cause acute respiratory distress syndrome (ARDS), which manifests as severe hypoxemic respiratory failure. Survivors of the acute stage of ARDS may develop lung fibrosis. The mechanisms underlying fibrotic responses in this context are unknown. In this study, we investigate fibroblast responses to influenza challenge using single cell gene expression (scGEX) and two-dimensional liquid chromatography coupled with tandem/mass spectrometry (TMT-LC/LC-MS/MS) on lung tissue collected longitudinally in a murine model of influenza A virus (IAV) infection. By TMT-LC/LC-MS/MS, we identified profound changes in the composition of the lung matrisome, which were most evident 10 days after infection. In this context, we identified transcriptional heterogeneity amongst proximal/adventitial fibroblasts expressing Pi16 and Col15a1 as well as a myofibroblast activation state characterized by expression of Tnc, Spp1, Grem1, and Cthrc1. This activation state was transcriptionally similar to those previously described in other contexts. Together, these data suggest compartmentalization and conservation of pulmonary fibroblast responses to lung injury of different primary etiologies.

Cisplatin resistance remains a major barrier to effective lung cancer treatment. In this study, we identified that SART3 is upregulated in cisplatin-resistant non-small cell lung cancer (NSCLC) cells and promotes DNA damage repair. SART3 deletion sensitized cells to cisplatin, whereas re-expression restored resistance. Mechanistically, SART3 enhanced DNA repair mainly through the PARP pathway rather than ATM or DNA-PK, and its deletion increased gH2AX levels and reduced BrdU incorporation. Metabolic analysis revealed that SART3-driven resistance relied on elevated fatty acid (FA) β-oxidation rather than glycolysis. SART3 promoted FA uptake by upregulating CD36, resulting in increased oxidative phosphorylation, ATP production, and enhanced DNA repair. Targeting FA metabolism with CPT1A inhibitors or CD36 antagonists, or blocking PARP activity, significantly reversed SART3-mediated resistance. Further, SART3 recruited FOXM1 to activate CD36 transcription by modulating H2b deubiquitination. In vivo, inhibition of the SART3-CD36-PARP axis effectively suppressed tumor growth and restored cisplatin sensitivity. Collectively, our findings reveal that SART3-driven metabolic reprogramming and DNA repair underpin cisplatin resistance, providing potential therapeutic strategies to overcome drug resistance in NSCLC.