ERJ Open Res. 2024 Nov 25;10(6):00550-2024. doi: 10.1183/23120541.00550-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing and progressive interstitial lung disease of unknown aetiology with a pathogenesis still partly unknown. Several microvascular and macrovascular abnormalities have been demonstrated in the pathogenesis of IPF and related pulmonary hypertension (PH), a complication of the disease.

METHODS: We carried out a non-systematic, narrative literature review aimed at describing the role of the vasculature in the natural history of IPF.

RESULTS: The main molecular pathogenetic mechanisms involving vasculature (i.e. endothelial-to-mesenchymal transition, vascular remodelling, endothelial permeability, occult alveolar haemorrhage, vasoconstriction and hypoxia) and the genetic basis of vascular remodelling are described. The prevalence and clinical relevance of associated PH are highlighted with focus on the vasculature as a prognostic marker. The vascular effects of current antifibrotic therapies, the role of pulmonary vasodilators in the treatment of disease, and new pharmacological options with vascular-targeted activity are described.

CONCLUSIONS: The vasculature plays a key role in the natural history of IPF from the early phases of disease until development of PH in a subgroup of patients, a complication related to a worse prognosis. Pulmonary vascular volume has emerged as a novel computed tomography finding and a predictor of mortality, independent of PH. New pharmacological options with concomitant vascular-directed activity might be promising in the treatment of IPF.

PMID:39588083 | PMC:PMC11587140 | DOI:10.1183/23120541.00550-2024

Food Funct. 2024 Nov 26. doi: 10.1039/d4fo01474j. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with a high mortality rate. Kaempferol (KMP), an active ingredient in common plants and foods with anti-inflammatory, antioxidant and immunomodulatory properties, has been shown to be effective against fibrotic diseases. However, the molecular mechanisms underlying the treatment of IPF with KMP remain unclear. Therefore, IPF mice were established by intratracheal instillation of bleomycin (BLM) to explore the efficacy and underlying mechanism of KMP in the treatment of IPF. We found that KMP improved the body weight changes of BLM-induced IPF mice, alleviated inflammatory infiltration and collagen deposition, and decreased the expression levels of hydroxyproline, α-SMA, Col3a1, Mmp2, Timp1, Vim, Fn, TNF-α, TGF-β1, IL-6 and IL-8, while up-regulating the expression E-cadherin in lung tissues. The transcriptomic results showed that KMP may exert therapeutic effects against IPF by regulating the PPARG/TNC signaling pathway to reduce extracellular matrix (ECM) deposition. Interestingly, ROC curve analysis suggested that TNC and PPARG had good diagnostic performance for IPF, and TF prediction revealed that PPARG is an important upstream gene regulating TNC, and the IF experiment confirmed the co-localization of TNC and PPARG. Molecular docking showed that KMP bound well to PPARG and TNC, and IF results revealed that KMP significantly reduced the interaction between PPARG and TNC. Furthermore, RT-PCR, WB, IHC and IF experiments confirmed that KMP elevated the expression of PPARG and inhibited the expression of TNC, thus inhibiting the ECM-receptor interaction pathway and ultimately serving as a therapeutic treatment for IPF mice. These findings revealed that KMP reduced inflammatory infiltration and collagen deposition in the lungs of IPF mice and that the PPARG/TNC signaling pathway may be an important mechanism for the treatment of IPF with KMP, which provides a new perspective for the development of therapeutic approaches for IPF.

PMID:39587935 | DOI:10.1039/d4fo01474j

J Transl Med. 2024 Nov 25;22(1):1058. doi: 10.1186/s12967-024-05895-0.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) stands as a significant contributor to global mortality rates. Presently, there exists a dearth of effective anti-fibrotic treatments for this condition. While itraconazole (ITR) has exhibited potential in mitigating pulmonary fibrosis, its oral administration is hampered by unfavorable pharmacokinetics, which elevate the risk of adverse reactions, thus limiting its clinical utility.

METHODS: An inhalable formulation of ITR were engineered which aimed at enhancing its pulmonary dispersion. First, pharmacokinetics were conducted to investigate the blood concentration and tissue residue of ITR after inhalation administration. In addition, bleomycin induced mouse pulmonary fibrosis model was used to compare the therapeutic effects of ITR administered by inhalation and intragastric administration. Finally, single-cell RNA sequencing (scRNAseq) was used to explore the mechanism of ITR inhalation administration.

RESULTS: We found that a large amount of drugs accumulated in the lung tissue for a long time after inhalation administration, thus maximizing the therapeutic effect of drugs. Inhalation of ITR daily at for 21 days significantly attenuated bleomycin-induced lung fibrosis and inflammation in murine models. Additionally, our findings revealed that ITR inhalation diminished the proportion of diseased fibroblasts while promoting reparative fibroblast populations in the murine model. Furthermore, it effectively reversed the proportion of activated phagocytic macrophages. Mechanistically, ITR inhalation exerted its effects by regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts.

CONCLUSIONS: These insights into the molecular mechanisms underlying ITR's therapeutic effects on IPF underscore the favorable pharmacokinetic profile conferred by inhalation, thus presenting a promising formulation poised for clinical translation.

PMID:39587675 | DOI:10.1186/s12967-024-05895-0

Pharmacol Ther. 2024 Nov 23:108757. doi: 10.1016/j.pharmthera.2024.108757. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) remains a challenging disease with no drugs available to change the trajectory. It is a condition associated with excessive and highly progressive scarring of the lungs with remodelling and extracellular matrix deposition. It is a highly "destructive" disease of the lungs. The diagnosis of IPF is challenging due to continuous evolution of the disease, which also makes early interventions very difficult. The role of vascular endothelial cells has not been explored in IPF in great detail. We do not know much about their contribution to arterial or vascular remodelling, extracellular matrix changes and contribution to pulmonary hypertension and lung fibrosis in general. Endothelial to mesenchymal transition appears to be central to such changes in IPF. Similarly, for epithelial changes, the process of epithelial to mesenchymal transition seem to be the key both for airway epithelial cells and type-2 pneumocytes. We focus here on endothelial and epithelial cell changes and its contributions to IPF. In this review we revisit the pathology of IPF, mechanistic signalling pathways, clinical definition, update on diagnosis and new advances made in treatment of this disease. We discuss ongoing clinical trials with mode of action. A multidisciplinary collaborative approach is needed to understand this treacherous disease for new therapeutic targets.

PMID:39586361 | DOI:10.1016/j.pharmthera.2024.108757

Adv Respir Med. 2024 Nov 6;92(6):466-471. doi: 10.3390/arm92060042.

ABSTRACT

Background: Depression and anxiety represent significant comorbidities in idiopathic pulmonary fibrosis (IPF) patients, affecting their quality of life. The COVID-19 pandemic has had an uneven impact on global mental health. The Hospital Anxiety and Depression Scale (HADS) constitutes a validated tool to identify anxiety disorders and depression. The aim of this multicentre study was to evaluate the effect of COVID-19 vaccination on depression and anxiety in IPF patients. Methods: Consecutive IPF patients (median 73.5 years) who are regularly followed-up with were included in the study. Demographics, functional, and clinical were recorded. The HADS score was calculated before and one month after vaccination against COVID-19 in all participants. A Wilcoxon signed ranks test was conducted. Results: A total of 180 IPF patients (median 73.5 years) were included in the study. Among them, 145 patients (81%) received antifibrotic treatment. A significant reduction in HADS, both in anxiety and depression scales, was observed one month after vaccination against SARS-COV-2), independent of age, smoking, lung function impairment, and prior history of depression (p < 0.01). Conclusions: A higher Hospital Anxiety and Depression Scale score was detected before vaccination against COVID-19. It seems that vaccination also offered a beneficial effect on depression and anxiety in IPF patients, independent of age, smoking, lung function impairment, and prior history of depression.

PMID:39584853 | DOI:10.3390/arm92060042

Immun Inflamm Dis. 2024 Nov;12(11):e70042. doi: 10.1002/iid3.70042.

ABSTRACT

RATIONALE: Elevated levels of CD11c+ myeloid cells are observed in various pulmonary disorders, including Idiopathic Pulmonary Fibrosis (IPF). Dendritic cells (DCs) and macrophages (MΦ) are critical antigen-presenting cells (APCs) that direct adaptive immunity. However, the role of CD11c+ myeloid cells in lung extracellular matrix (ECM) accumulation and pulmonary fibrosis is poorly understood.

OBJECTIVE: We aimed to investigate the impact of depleting CD11c+ myeloid cells, including DCs and macrophages, during bleomycin-induced pulmonary fibrosis in mice.

METHODS: We used a diphtheria toxin (DTx) receptor (DTR) transgenic mouse model (CD11c-DTR-Tg) to deplete CD11c+ myeloid cells through two methods: Systemic Depletion (SD) via intraperitoneal injection (i.p.) and local depletion (LD) via intranasal instillation (i.n.). We then assessed the effects of CD11c+ cell depletion during bleomycin-induced lung inflammation and fibrosis.

RESULTS: Fourteen days after bleomycin instillation, there was a progressive accumulation of myeloid cells, specifically F4/80-MHCII+CD11c+ DCs and F4/80 + MHCII+CD11c+ MΦ, preceding mortality and pulmonary fibrosis. Systemic depletion of CD11c+ DCs and MΦ via i.p. DTx administration in CD11c-DTR-Tg mice protected against bleomycin-induced mortality and pulmonary fibrosis compared to wild-type (WT) mice. Systemic depletion reduced myeloid cells, airway inflammation (total leukocytes, neutrophils, and CD4+ lymphocytes in bronchoalveolar lavage (BAL), inflammatory and fibrogenic mediators, and fibrosis-related mRNAs (Collagen-1α1 and α-SMA). Increased anti-inflammatory cytokine IL-10 and CXCL9 levels were observed, resulting in lower lung hydroxyproline content and Ashcroft fibrosis score. Conversely, local depletion of CD11c+ cells increased mortality by acute leukocyte influx (predominantly neutrophils, DCs, and MΦ in BAL) correlated to IL-1β, with lung hyper-inflammation and early fibrosis development.

CONCLUSION: Systemic depletion of CD11c+ cells confers protection against inflammation and fibrosis induced by Bleomycin, underscoring the significance of myeloid cells expressing F4/80-MHCII+CD11c+ DCs and F4/80 + MHCII+CD11c+ MΦ orchestrating the inflammatory milieu within the lungs, potentially as a source of cytokines sustaining pulmonary chronic inflammation leading to progressive fibrosis and mortality.

PMID:39582275 | DOI:10.1002/iid3.70042

Cancer Radiother. 2024 Nov 23:S1278-3218(24)00155-0. doi: 10.1016/j.canrad.2024.05.004. Online ahead of print.

ABSTRACT

PURPOSE: Bronchiolitis obliterans with pneumonic organization, or organizing pneumonia (OP), is an inflammatory disorder of the lungs, which can be triggered following pulmonary attacks of infectious or non-infectious origin. The non-infectious origins of OP include various entities including connective tissue diseases, exposure to toxic substances, medications, autoimmune diseases, and thoracic radiotherapy. The objective of this article is to summarize the literature on post-radiotherapy organized pneumonia, its etiologies, its clinical and radiological characteristics, as well as its treatment.

MATERIALS AND METHODS: A systematic review was performed in Medline database using the search engine PubMed. Keywords for the search included cryptogenic organizing pneumonia, bronchiolitis obliterans organizing pneumonia (BOOP), idiopathic organizing pneumonia and radiation, radiotherapy, breast cancer. The selected articles had to study the link between bronchiolitis obliterans with pneumonic organization and radiotherapy.

RESULTS: A total of 96 articles were identified. Of these 96 articles, 49 fulfilled the defined selection criteria. Fourteen epidemiological studies were found in the literature. These epidemiological studies have published incidences of post-radiotherapy organizing pneumonia of less than 2.9% for patients treated for breast cancer. The predictive risk factors for bronchiolitis obliterans with pneumonic organization syndrome were age, smoking and the volume of irradiated lung. In a post-radiation context, bronchiolitis obliterans with pneumonic organization could be diagnosed several months, or even up to a year, after the end of irradiation. Treatment was based on the prescription of long-term corticosteroid therapy. Bronchiolitis obliterans with pneumonic organization should not be confused with post-radiation pulmonary fibrosis, which is inflammatory, dose-dependent, non-immunological, and localized in the irradiation area.

CONCLUSION: Organized pneumonia secondary to radiotherapy is a syndrome affecting approximately 1.4 to 3% of patients treated with radiotherapy for breast cancer. The main risk factors found are age, smoking and the volume of lung irradiated. Post-radiotherapy organized pneumonia needs to be known to all radiotherapists to improve patient care.

PMID:39581827 | DOI:10.1016/j.canrad.2024.05.004

Tissue Cell. 2024 Nov 19;91:102624. doi: 10.1016/j.tice.2024.102624. Online ahead of print.

ABSTRACT

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population within the tumor that have recently come into the spotlight. By extracellular matrix (ECM) remodeling and robust cross-talk with cancer cells via different secretions such as cytokines, chemokines, and growth factors, CAFs contribute to cancer progression and poorer prognoses in patients. Novel candidates have been developed to inhibit CAFs; however, due to safety and efficacy issues, none have successfully passed clinical trials. Despite these shortcomings, one concept embraced by many researchers is to repurpose non-oncology drugs with potential anti-cancer properties for cancer treatment. One such example is pirfenidone (PFD), an oral anti-fibrotic medication, primarily administered for idiopathic pulmonary fibrosis. Emerging evidence suggests that PFD has promising anti-cancer effects, mainly manifesting through targeting CAFs. With inhibitory effects on CAFs, PFD restricts cancer proliferation, metastasis, immunosuppression, drug resistance, and tumor stiffness. To improve efficacy and minimize adverse effects, several innovative approaches have been proposed for targeting CAFs via PFD. Interestingly, combination therapy comprising PFD and chemotherapeutics e.g. doxorubicin has shown synergistic anti-cancer effects while protecting normal tissue. Furthermore, novel drug delivery systems, e.g. biomimetic liposomes and multilayer core-shell nanoparticles, have enhanced the pharmacokinetic properties of PFD and further increased its intratumoral delivery. Single-cell RNA sequencing (scRNA-seq) has also been suggested to characterize different subpopulations of CAFs and design precise PFD-based therapeutic strategies. Herein, we discuss the promising anti-cancer effects of PFD via inhibition of CAFs. We then provide findings on novel PFD-based approaches to target CAFs using combination therapy, nanocarrier-based drug delivery, and scRNA-seq.

PMID:39581071 | DOI:10.1016/j.tice.2024.102624

Phytomedicine. 2024 Nov 17;136:156266. doi: 10.1016/j.phymed.2024.156266. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Our previous research has shown that the Jinshui Huanxian formula (JHF) is effective in treating IPF. However, the biomechanical mechanisms of its refined components, known as the effective-component compatibility of JHF II (ECC-JHF II), are not well understood.

PURPOSE: This study aims to explore how bioactive components from traditional Chinese medicine (TCM) impact the biomechanical progression of pulmonary fibrosis.

STUDY DESIGN AND METHODS: A mouse model of pulmonary fibrosis was established by a single intratracheal instillation of bleomycin (Bleomycin). Pulmonary function, pathological changes, collagen deposition, lung tissue stiffness, and EMT markers were evaluated at the end of the study. Polyethylene glycol hydrogels with adjustable stiffness were used to mimic both normal and pathological lung conditions. The effects of ECC-JHF II on matrix stiffness-mediated EMT were assessed by quantitative real-time PCR, western blot, and immunofluorescence. The biomechanical mechanisms underlying ECC-JHF II on EMT and pulmonary fibrosis were verified both in vivo and in vitro.

RESULTS: ECC-JHF II significantly improved bleomycin (Bleomycin)-induced pulmonary fibrosis in mice, manifested as increased tidal volume and 50 % tidal volume expiratory flow, reduced lung tissue stiffness, and decreased EMT markers. Histopathological analysis showed reduced inflammation, alveolar damage, and collagen deposition. In vitro, ECC-JHF II reversed the EMT phenotypic transition induced by substrate stiffness, demonstrated by the upregulation of E-cadherin, occludin, and zonula occluden-1, and the downregulation of N-cadherin, vimentin, caldesmon 1 and tropomyosin 1. Moreover, ECC-JHF II could inhibit integrin/ROCK/MRTF signaling in vitro and in vivo. Silencing integrin β1 or activating it with pyrintegrin further confirmed the role of integrin β1 in the mechanotransduction pathway and the efficacy of ECC-JHF II.

CONCLUSION: Taken together, the findings of this study indicate that ECC-JHF II exerts a therapeutic effect on pulmonary fibrosis through the attenuation of lung tissue stiffness and inhibition of EMT, potentially via the integrin/ROCK/MRTF signaling pathway.

PMID:39580995 | DOI:10.1016/j.phymed.2024.156266

J Pharm Pharmacol. 2024 Nov 23:rgae143. doi: 10.1093/jpp/rgae143. Online ahead of print.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic interstitial lung disease. The two drugs indicated for IPF have limited efficacy and there is an urgent need to develop new drugs. Thymosin β4 (Tβ4) is a natural endogenous repair factor whose antifibrotic effects have been reported. This study aimed to evaluate the effect of exogenous recombinant human thymosin beta 4 (rhTβ4) on pulmonary fibrosis.

METHODS: Pulmonary fibrosis was induced in mice with bleomycin, and rhTβ4 was administrated by nebulization following three strategies: early dosing, mid-term dosing, and late dosing. The rhTβ4 efficacy was assessed by hydroxyproline, lung function, and lung histopathology. In vitro, the effects of rhTβ4 on fibroblast and lung epithelial cell phenotypes, as well as the TGF-β1 pathway, were evaluated.

KEY FINDINGS: Aerosol administration of rhTβ4 could alleviate bleomycin-induced pulmonary fibrosis in mice at different stages of fibrosis. Studies conducted in vitro suggested that rhTβ4 could suppress lung fibroblasts from proliferating, migrating, and activation via regulating the TGF-β1 signalling pathway. In vitro, rhTβ4 also inhibited the epithelial-mesenchymal transition-like process of pulmonary epithelial cells.

CONCLUSIONS: This study suggests that nebulized rhTβ4 is a potential treatment for IPF.

PMID:39579076 | DOI:10.1093/jpp/rgae143

Orphanet J Rare Dis. 2024 Nov 22;19(1):432. doi: 10.1186/s13023-024-03410-8.

ABSTRACT

BACKGROUND: Genetic polymorphisms in Toll-interacting protein (TOLLIP) have been documented in relation to clinical manifestations of interstitial lung disease (ILD). Nevertheless, the findings across studies present inconsistencies. The present meta-analysis endeavors to elucidate the nexus between genetic variations in TOLLIP and the onset and prognosis of interstitial lung disease (ILD), with the overarching aim of providing insight into the pathophysiological underpinnings of ILD.

METHOD: This systematic review was registered in PROSPERO. The OVID MEDLINE, OVID EMBASE, and Web of Science electronic databases were searched.

RESULTS: Fourteen studies with a total of 4821 cases and 9765 controls were examined. The final TOLLIP variants to be included in this meta-analysis were rs5743890, rs111521887, and rs3750920. There were significantly fewer TOLLIP rs5743890 minor allele C carriers among individuals with interstitial lung disease (ILD) than among those without this condition (11.42% vs. 18.92%). Conversely, patients with ILD exhibited higher frequencies of rs111521887 minor allele G carriers (28.92% vs. 22.44%) and rs3750920 minor allele T carriers (40.06% vs. 34.00%). A potential association between rs5743890_C and a reduced incidence of ILD was plausible (p = 0.04, OR = 0.72, 95% CI = 0.53-0.99). Furthermore, a stratified analysis revealed that rs5743890_C was significantly associated with a decreased risk of IPF (p = 0.004, OR = 0.62, 95% CI = 0.44-0.86). There was a significant correlation between susceptibility to ILD and rs111521887 G (p < 0.00001, OR = 1.48, 95% CI = 1.33-1.65) and rs3750920 T (p < 0.00001, OR = 1.34, 95% CI = 1.26-1.44). The survival of IPF patients was correlated with the TOLLIP rs5743890 SNP, and patients with the rs5743890_C genotype had worse survival (p = 0.02, HR = 1.59, 95% CI = 1.07-2.36).

CONCLUSION: This study showed that rs5743890_C was associated with a lower incidence of ILD and a worse survival rate in patients with IPF. Rs111521887_G and rs3750920_T were found to be associated with an elevated risk of ILD incidence, while no significant association was observed with ILD prognosis. Furthermore, studies are warranted to validate our results and assess the effects of TOLLIP genetic variants on ILD.

PMID:39578840 | DOI:10.1186/s13023-024-03410-8

Mol Med. 2024 Nov 22;30(1):225. doi: 10.1186/s10020-024-00961-1.

ABSTRACT

Smad5 (small mothers against decapentaplegic 5) protein is a receptor-regulated member of the Smad family proteins, mainly participating in the bone morphogenetic protein (BMP) signaling pathway in its phosphorylated form. This article will provide a detailed review of Smad5, focusing on its gene characteristics, protein structure, and subcellular localization properties. We will also explore the related signaling pathways and the mechanisms of Smad5 in respiratory diseases, including chronic obstructive pulmonary disease (COPD), bronchial asthma, pulmonary arterial hypertension(PAH), lung cancer, and idiopathic pulmonary fibrosis (IPF). Additionally, the review will cover aspects such as proliferation, differentiation, apoptosis, anti-fibrosis, and mitochondrial function metabolism. In addition, the review will cover aspects of proliferation, differentiation, apoptosis, anti-fibrosis and functional mitochondrial metabolism related to the above topics. Numerous studies suggest that Smad5 may play a unique and important role in the pathogenesis of respiratory system diseases. However, in previous research, Smad5 was mainly used to broadly determine the activation of the BMP signaling pathway, and its own function has not been given much attention. It is worth noting that Smad5 has distinct nuclear-cytoplasmic distribution characteristics different from Smad1 and Smad8. It can undergo significant nuclear-cytoplasmic shuttling when intracellular pH (pHi) changes, playing important roles in both the classical BMP signaling pathway and non-BMP signaling pathways. Given that Smad5 can move intracellularly in response to changes in physicochemical properties, its cellular localization may play a crucial role in the development of respiratory diseases. This article will explore the possibility that its distribution characteristics may be an important factor that is easily overlooked and not adequately considered in disease research.

PMID:39578779 | DOI:10.1186/s10020-024-00961-1

Mol Med. 2024 Nov 23;30(1):227. doi: 10.1186/s10020-024-00990-w.

ABSTRACT

Impaired interaction of fibroblasts with pneumocytes contributes to the progression of chronic lung disease such as idiopathic pulmonary fibrosis (IPF). Mucin 5B (MUC5B) is associated with IPF. Here we analyzed the interaction of primary fibroblasts and alveolar type 2 (AT2) pneumocytes in the organoid model. Single-cell analysis, histology, and qRT-PCR revealed that fibroblasts expressing high levels of fibrosis markers regulate STAT3 signaling in AT2 cells, which is accompanied by cystic organoid growth and MUC5B expression. Cystic growth and MUC5B expression were also caused by the cytokine IL-6. The PI3K-Akt signaling pathway was activated in fibroblasts. The drug dasatinib prevented the formation of MUC5B-expressing cystic organoids. MUC5B associated with AT2 cells in samples obtained from IPF patients. Our model shows that fibrotic primary fibroblasts induce impaired differentiation of AT2 cells via STAT3 signaling pathways, as observed in IPF patients. It can be used for mechanistic studies and drug development.

PMID:39578767 | DOI:10.1186/s10020-024-00990-w

Chemosphere. 2024 Nov 20:143785. doi: 10.1016/j.chemosphere.2024.143785. Online ahead of print.

ABSTRACT

Polyhexamethylene guanidine (PHMG) is widely utilized in personal hygiene products due to its bactericidal, non-volatile, and hydrophilic properties. However, the long-term toxic effects and underlying mechanisms associated with respiratory exposure to the commonly used form, PHMG phosphate (PHMG-p), are still insufficiently understood. This study aims to elucidate the types of pulmonary lesions and the incidence of lung cancer associated with varying concentrations of PHMG-p and observation periods, along with the molecular mechanisms underlying this relationship. To assess these effects, CT scans and pathological analyses were conducted for up to 54 weeks following initial exposure to PHMG-p. Furthermore, to investigate the underlying causes of pulmonary toxicity, TGF-beta-activated kinase 1 was identified as a PHMG-p-binding protein, and its associated signaling pathways, including necroptosis, apoptosis, and MKK7, were explored. Somatic mutational signature, and gene ontology (GO) analyses were performed to investigate the genetic characteristics of PHMG-p-induced lung carcinogenesis. PHMG-p exposure led to somatic mutations in lung cancer-related genes, including TP53, SOS1, KMT2D, MDM2, ERBB2, SETD2, MET, and ARID1A, as well as in genes such as RAB31, WASHC1, and DDX11. The mutated genes were primarily associated with impaired DNA repair mechanisms. GO analysis highlighted the activation of pathways related to cell cycle checkpoints, necroptosis, MAPK, and idiopathic pulmonary fibrosis, while also revealing the suppression of signaling pathways associated with natural killer cells, GADD45, LXR/RXR activation, and IL-15 production. Gain-of-function experiments confirmed the oncogenic roles of PLAU and HMGA2, as well as the tumor-suppressive functions of TBX4 and GPX3. These findings suggest that PHMG-p activates necroptosis and MAPK signaling, increases the frequency of somatic mutations, and inhibits apoptosis, thus fostering an environment conducive to carcinogenesis. This underscores the importance of understanding the potential health risks associated with PHMG-p exposure and provides insights for future research and regulatory considerations regarding the safety of personal hygiene products.

PMID:39577803 | DOI:10.1016/j.chemosphere.2024.143785

bioRxiv [Preprint]. 2024 Nov 6:2024.11.03.621735. doi: 10.1101/2024.11.03.621735.

ABSTRACT

In single-cell studies, cells can be characterized with multiple sources of heterogeneity such as cell type, developmental stage, cell cycle phase, activation state, and so on. In some studies, many nuisance sources of heterogeneity (SOH) are of no interest, but may confound the identification of the SOH of interest, and thus affect the accurate annotate the corresponding cell subpopulations. In this paper, we develop B-Lightning, a novel and robust method designed to identify marker genes and cell subpopulations correponding to a SOH (e.g., cell activation status), isolating it from other sources of heterogeneity (e.g., cell type, cell cycle phase). B-Lightning uses an iterative approach to enrich a small set of trustworthy marker genes to more reliable marker genes and boost the signals of the SOH of interest. Multiple numerical and experimental studies showed that B-Lightning outperforms existing methods in terms of sensitivity and robustness in identifying marker genes. Moreover, it increases the power to differentiate cell subpopulations of interest from other heterogeneous cohorts. B-Lightning successfully identified new senescence markers in ciliated cells from human idiopathic pulmonary fibrosis (IPF) lung tissues, new T cell memory and effector markers in the context of SARS-COV-2 infections, and their synchronized patterns which were previously neglected. This paper highlights B-Lightning's potential as a powerful tool for single-cell data analysis, particularly in complex data sets where sources of heterogeneity of interest are entangled with numerous nuisance factors.

PMID:39574750 | PMC:PMC11580937 | DOI:10.1101/2024.11.03.621735

J Transl Med. 2024 Nov 21;22(1):1051. doi: 10.1186/s12967-024-05894-1.

ABSTRACT

BACKGROUND: Ficolins were originally identified as proteins that bind to transforming growth factor-β1 (TGF-β1). They are capable of activating the complement system through lectin pathway for immune system protection. Ficolin-2 and 3 have been identified in patients with interstitial lung diseases (ILD) and their function in these diseases is currently being explored. In contrast, the functional role of ficolin-1 in pulmonary fibrosis is still elusive and remains to be elucidated.

METHODS: The expression of ficolin-1 in the plasma of idiopathic pulmonary fibrosis (IPF) and connective tissue disease (CTD)-ILD patients was first determined. As the orthologue of human ficolin-1, ficolin-B knockout and ficolin-B overexpression were used to establish bleomycin (BLM)-induced pulmonary fibrosis mouse model. Co-immunoprecipitation, immunofluorescence and RNA sequencing were utilized to explore and expound on the expression and the functional mechanism of ficolin-1 in pulmonary fibrosis.

RESULTS: Compared with healthy controls, plasma ficolin-1 was significantly decreased in patients with IPF and CTD-ILD. In the bleomycin (BLM)-induced mice model, ficolin-B deficiency aggravated lung injury and fibrosis. There was also observed increase in TGF-β1 levels and enhanced downstream signaling. However, the overexpression of ficolin-B showed preventative and therapeutic efficacy against lung fibrosis. Furthermore, coimmunoprecipitation studies revealed the direct interaction between ficolin-1 and TGF-β1 in human plasma, which was further confirmed by the colocalization of ficolin-1 and TGF-β1 in lung tissues.

CONCLUSIONS: Ficolin-1 inhibits pulmonary fibrosis by directly binding to the key profibrogenic factor TGF-β1, marking it as a potential target for therapy in the treatment of fibrotic lung diseases.

PMID:39574172 | DOI:10.1186/s12967-024-05894-1

Respir Med. 2024 Nov 19:107862. doi: 10.1016/j.rmed.2024.107862. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrosing lung disease. A decreased 6-minute walk distance (6MWD) and exercise-induced oxygen desaturation measured during the 6-minute walk test (6MWT), are known predictors of mortality in patients with IPF. However, the use of antifibrotic drugs showed a survival benefit in IPF. Therefore, this study aimed to evaluate to what extend 6MWT-derived attributes are associated with two-year survival when antifibrotic drugs were introduced as part of standard IPF-care.

METHODS: This real-world data-study included patients with IPF with a 6MWT between 2015-2020, and used composite outcome: mortality or lung transplantation within 2 years of follow-up. Data were collected systematically, including demographics, pulmonary function tests, comorbidities, medications and 6MWT-derived attributes. The prediction attributes of 6MWT were studied with a Cox Proportional-Hazards model and Kaplan-Meier survival curves. The best discriminating attribute to predict mortality was added to the prediction model Gender-Age-Physiology (GAP).

RESULTS: In 216 patients, 2-year transplant-free survival cut-off points were identified for the 6MWD (≥413 m), 6MWD %predicted (≥83%), SpO2-nadir (≥86%) and distance-saturation-product (≥374 m%), with the best discriminative value for SpO2-nadir (area under the curve: 0.761). 2-Year survival percentage of patients with SpO2-nadir below or above threshold (86%) was 37.1% and 80.0%, respectively. Exercise-induced oxygen desaturation added to the GAP model showed an improvement in its predictive power.

CONCLUSION: Patients with IPF who have an exercise-induced oxygen desaturation have worse prognosis. Addition of SpO2-nadir to the GAP model seems promising for use in clinical care of IPF patients.

PMID:39571824 | DOI:10.1016/j.rmed.2024.107862

J Med Chem. 2024 Nov 21. doi: 10.1021/acs.jmedchem.4c02090. Online ahead of print.

ABSTRACT

We describe the discovery and preclinical characterization of a potent and selective lysophosphatidic acid receptor 1 (LPAR1) antagonist with a direct-acting antifibrotic mechanism. 18a was initially identified as a potent non-carboxylic acid LPAR1 antagonist in an LPA-induced myocardin-related transcription factor A (MRTF-A) nuclear translocation assay. Modifications to the aromatic elements in the structure allowed for improvements in metabolic stability and the mitigation of GSH adduct formation, but in vitro to in vivo clearance disconnects were observed with several potent sulfonamides (e.g., 27b) across preclinical species. Through modification of the sulfonamide, 42 (GS-2278) emerged as a potent LPAR1 antagonist with a suitable in vitro profile and desirable pharmacokinetic properties for oral QD dosing. GS-2278 dose-dependently blocked LPA-induced histamine release and demonstrated efficacy in an interventional model of bleomycin-induced lung fibrosis. However, CNS-related toxicity was observed in dogs, and based on these findings, the clinical development of GS-2278 for IPF was halted.

PMID:39570661 | DOI:10.1021/acs.jmedchem.4c02090

Sci Rep. 2024 Nov 20;14(1):28743. doi: 10.1038/s41598-024-80023-y.

ABSTRACT

Changes in lung and gut microbial communities have been associated with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate correlations between microbial changes in the lung and gut and host physiological indices in an IPF model, exploring potential mechanisms of the lung-gut axis in IPF pathogenesis. IPF model rats were established via trans-tracheal injection of bleomycin, with assessments of hematological indices, serum cytokines, lung histopathology, and microbiome alterations. Significant differences in microbial structure and composition were observed in the IPF model compared to controls, with 14 lung and 7 gut microbial genera showing significant abundance changes. Further analysis revealed 20 significant correlations between pulmonary and gut genera. Notably, 11 pairs of correlated genera were linked to the same IPF-related physiological indices, such as hydroxyproline, mean corpuscular volume (MCV), and red cell distribution width-standard deviation (RDW-SD). We identified 24 instances where a lung and a gut genus were each associated with the same physiological index, forming "lung genus-index-gut genus" relationships. Mediation analysis showed that indices like hydroxyproline, MCV, and RDW-SD mediated correlations between 10 lung genera (e.g., Cetobacterium, Clostridium XVIII ) and the gut genus Allobaculum. This study first describes gut-lung microbial interactions in pulmonary fibrosis. Mediation analysis suggests pathways underlying "lung genus-host index-gut genus" and "gut genus-host index-lung genus" correlations, thus providing clues to further elucidate the mechanisms of the "gut-lung axis" in IPF pathogenesis.

PMID:39567656 | DOI:10.1038/s41598-024-80023-y

Life Sci Alliance. 2024 Nov 20;8(2):e202402805. doi: 10.26508/lsa.202402805. Print 2025 Feb.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive and lethal interstitial lung disease with an unclear etiology and limited treatment options. Fatty acid synthase (FASN) plays various roles in metabolic-related diseases. This study demonstrates that FASN expression is increased in fibroblasts from the lung tissues of patients with idiopathic pulmonary fibrosis and in bleomycin-treated mice. In MRC-5 cells, the inhibition of FASN using shRNA or the pharmacological inhibitor C75 resulted in the increased mRNA and protein expression of glycogen synthase kinase 3β and Axin1, both negative regulators of the Wnt/β-catenin signaling pathway, and promoted autophagy. This outcome led to a decrease in β-catenin protein and mRNA levels, effectively inhibiting the proliferation, migration, and differentiation of lung fibroblasts into myofibroblasts, while inducing the differentiation of fibroblasts into adipofibroblasts. In vivo experiments showed that C75 alleviated bleomycin-induced lung fibrosis in mice by inhibiting β-catenin. In conclusion, these findings suggest that inhibiting FASN in fibroblasts may diminish the activity of the Wnt/β-catenin signaling pathway, providing a potential therapeutic avenue for pulmonary fibrosis.

PMID:39567194 | DOI:10.26508/lsa.202402805