Yunjuan Nie

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited treatment options. Macrophages, as the primary immune cells in the lungs, play a key role in the progression of pulmonary fibrosis. Salvinorin A (SA), a naturally occurring non-nitrogenous diterpenoid, exhibits anti-inflammatory and anti-neuropathic pain effects in various models. However, whether SA alleviates bleomycin-induced pulmonary fibrosis by modulating macrophage function remains unclear. This study aimed to investigate the therapeutic effects and mechanisms of SA on bleomycin-induced pulmonary fibrosis in mice. A bleomycin-induced pulmonary fibrosis mouse model was established, and SA was administered via intraperitoneal injection starting from day 7 post-modeling. The study further explored the effects of SA on M2 macrophage polarization and macrophage-to-myofibroblast transition (MMT) both in vivo and in vitro. SA treatment significantly alleviated the degree of pulmonary fibrosis and inflammatory response, improved lung tissue pathological structure, and reduced extracellular matrix deposition and the release of related inflammatory cytokines. Mechanistic studies revealed that SA effectively inhibited M2 macrophage polarization both in vivo and in vitro, as evidenced by the downregulation of marker molecules such as CD206, Arg1, Fizz1, and YM1. Additionally, SA also inhibited MMT, specifically manifested as a significant decrease in the proportion of α-SMA^⁺CD68^⁺ double-positive cells. This study reveals that SA can effectively alleviate the progression of pulmonary fibrosis by dually inhibiting M2 macrophage polarization and the MMT process, providing important experimental evidence for SA as a potential therapeutic agent against pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease where macrophages drive fibrogenesis, yet Hdac11's role is unclear. We first identify pronounced Hdac11 upregulation in IPF lungs, which is associated with an enrichment in alveolar macrophages (AMs). Genetic ablation of Hdac11 or adoptive transfer of Hdac11-deficient macrophages markedly attenuates fibrosis. Specifically, Hdac11 deficiency significantly reduces M2 macrophage polarization in vivo and vitro and is associated with reduced macrophage-myofibroblast transition (MMT) like phenotypic reprogramming, thereby decreasing myofibroblast accumulation and profibrotic gene expression. Mechanistically, impaired mitophagy mediates Hdac11-mediated M2 macrophage polarization and is associated with MMT-like changes. Hdac11 regulates mitochondrial quality control by deacetylating Parkin at lysine 76, promoting its ubiquitination and degradation, which impairs mitophagy and drives profibrotic macrophage activation. Pharmacological Hdac11 inhibition effectively reverses bleomycin-induced fibrosis. Taken together, our work identifies Hdac11 as a target of Parkin-mediated mitophagy in macrophages, establishing Hdac11-Parkin axis disruption as an important mechanism in IPF and highlighting Hdac11 inhibition as a potential therapeutic strategy.

Introduction: This article examines the teaching method of experimental design in the context of Chinese universities, specifically focusing on the exploration of the disease development process. Cultivating innovative and research-oriented medical skills is a crucial objective within medical education, and the design of high-quality experimental courses is a significant aspect of optimizing and reforming medical education. Methods: Innovative experimental teaching design serves as a novel approach to integrating scientific research into undergraduate instruction. Centered on the exploration of the disease development process and combining the characteristics of clinical diseases, this method integrates experimental techniques from diverse disciplines such as anatomy, pathology, and molecular biology. It achieves a seamless fusion of theoretical knowledge and experimental operations. In this teaching initiative, students are fully immersed in the entire journey, from establishing disease-model mice to collecting and identifying samples at various time points during disease progression. Through hands-on engagement, students not only enhance their experimental skills but also gain a vivid and profound understanding of the dynamic evolution of diseases. Results: From the perspective of experimental exploration, students’ theoretical understanding is reinforced, and they grasp the occurrence and progression of diseases. This approach provides technical support for scientific research and offers a new line of thinking for the treatment of clinical diseases. Conclusion: Experimental teaching focused on exploring the disease development process can foster students’ scientific thinking, enhance their practical capabilities, and cultivate research-oriented medical professionals while they learn experimental techniques.

Asthma is a prevalent respiratory disorder with limited treatment strategy. Neuropeptide S (NPS) is a highly conserved peptide via binding to its receptor NPSR, a susceptibility gene for asthma from genomics studies. However, little is known about the role of NPS-NPSR in the pathogenesis of asthma. This study was performed to determine the effect and underlying mechanism of NPS-NPSR on asthma. NPSR knockdown was verified to affect asthma through autophagy by transcriptome sequencing and molecular biology experiments in animal models. Silencing of transcription factor EB in a bronchial epithelial cell line and validation of NPS-NPSR activation of autophagy dependent on transcription factor EB. Our results showed that NPSR expression was markedly increased in asthmatic humans and mice, mainly localized in bronchial epithelial cells. Using ovalbumin (OVA) and papain-induced asthma mouse models, NPSR-deficient mice exhibited significantly alleviated asthma, with reduced small airway lesions and inflammatory infiltration compared with wild-type mice. OVA and papain promoted TFEB-mediated autophagy with increased ATG5 and LC3 II expression, and NPS effectively regulated the activation of TFEB and autophagy. In turn, specific TFEB knockdown could restore the effect of exogenous NPS and its receptor antagonist on the autophagy and cytokines secretion in bronchial epithelial cells. Furthermore, Prkcg may be the key upstream targeting of the TFEB-autophagy pathway involved in asthma. NPS-NPSR exacerbated asthma by regulating the TFEB-autophagy axis in airway epithelial injury, which may be a potential target for asthma therapy.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disease with a limited therapeutic strategy. Mitochondrial oxidative stress in macrophages is directly linked to IPF. Elamipretide(SS-31) is a mitochondrion-targeted peptide that has been shown to be safe and beneficial for multiple diseases. However, whether SS-31 alleviates IPF is unclear. In the present study, we used a bleomycin (BLM)-induced mouse model followed by SS-31 injection every other day to investigate its role in IPF and explore the possible mechanism. Our results showed that SS-31 treatment significantly suppressed BLM-induced pulmonary fibrosis and inflammation, with improved histological change, and decreased extracellular matrix deposition and inflammatory cytokines release. Impressively, the expression percentage of IL-1β and IL-18 was downregulated to lower than half with SS-31 treatment. Mechanistically, SS-31 inhibited IL-33- or lipopolysaccharide(LPS)/IL-4-induced production of IL-1β and IL-18 in macrophages by suppressing NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome activation. Nuclear factor erythroid 2-related factor 2(Nrf2) was dramatically upregulated along with improved mitochondrial function after SS-31 treatment in activated macrophages and BLM-induced mice. Conversely, there was no significant change after SS-31 treatment in Nrf2−/− mice and macrophages. These findings indicated that SS-31 protected against pulmonary fibrosis and inflammation by inhibiting the Nrf2-mediated NLRP3 inflammasome in macrophages. Our data provide initial evidence for the therapeutic efficacy of SS-31 in IPF.

Introduction Idiopathic pulmonary fibrosis (IPF) is a debilitating lung condition with few available treatments. The early driver of wound repair that contributes to IPF has been extensively identified as repetitive alveolar epithelial damage. According to recent reports, IPF is linked to ferroptosis, a unique type of cell death characterized by a fatal buildup of iron and lipid peroxidation. Objective and method There is little information on epithelial cells that induce pulmonary fibrosis by going through ferroptosis. In this study, we used bleomycin (BLM) to examine the impact of ferroptosis on IPF in mouse lung epithelial cells (MLE-12). Results We discovered that BLM increases ferroptosis in MLE-12. Additionally, we found that NCOA4 is overexpressed and plays a key role in the ferroptosis of epithelial cells throughout the IPF process. Using Molecular docking, we found that Fraxetin, a natural component extracted from Fraxinus rhynchophylla, formed a stable binding to NCOA4. In vitro investigations showed that Fraxetin administration greatly decreased ferroptosis and NCOA4 expression, which in turn lowered the release of inflammatory cytokines. Conclusion Fraxetin treatment significantly alleviated BLM-induced lung inflammation and fibrosis. Our findings imply that fraxetin possesses inhibitory roles in ferroptosis and can be a potential drug against IPF.

Objectives Pulmonary fibrosis (PF) is a chronic and refractory interstitial lung disease with limited therapeutic options. 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, has been shown to have anti-oxidative and anti-inflammatory properties. However, the effect and the underlying mechanism of 4-OI on PF are still unknown. Methods WT or Nrf2 knockout (Nrf2^−/−) mice were intratracheally injected with bleomycin (BLM) to establish PF model and then treated with 4-OI. The mechanism study was performed by using RAW264.7 cells, primary macrophages, and conditional medium-cultured MLE-12 cells. Results 4-OI significantly alleviated BLM-induced PF and EMT process. Mechanism studies have found that 4-OI can not only directly inhibit EMT process, but also can reduce the production of TGF-β1 by restraining macrophage M2 polarization, which in turn inhibits EMT process. Moreover, the effect of 4-OI on PF and EMT depends on Nrf2. Conclusion 4-OI ameliorates BLM-induced PF in an Nrf2-dependent manner, and its role in alleviating PF is partly due to the direct inhibition on EMT, and partly through indirect inhibition of M2-mediated EMT. These findings suggested that 4-OI has great clinical potential to develop as a new anti-fibrotic agent for PF therapy.