Biomedicines. 2023 Jan 9;11(1):163. doi: 10.3390/biomedicines11010163.

ABSTRACT

Idiopathic pulmonary fibrosis is a chronic interstitial lung disease whose pathogenesis involves a complex interaction of cell types and signaling pathways. Lung epithelial cells responding to repeated injury experience persistent inflammation and sustained epithelial-mesenchymal transition (EMT). The persistence of EMT-induced signals generates extracellular matrix accumulation, thereby causing fibrosis. Ferroptosis is a newly characterized iron-dependent non-apoptotic regulated cell death. Increased iron accumulation can increase iron-induced oxidant damage in alveolar epithelial cells. Studies have demonstrated that iron steady states and oxidation steady states play an important role in the iron death regulation of EMT. This review summarizes the role of ferroptosis in regulating EMT in pulmonary fibrosis, aiming to provide a new idea for the prevention and treatment of this disease.

PMID:36672671 | DOI:10.3390/biomedicines11010163

Inflamm Res. 2023 Jan 19. doi: 10.1007/s00011-023-01692-5. Online ahead of print.

ABSTRACT

INTRODUCTION: Chronic inflammatory lung diseases are a common cause of suffering and death. Chronic obstructive pulmonary disease (COPD) is the reason for 6% of all deaths worldwide. A total of 262 million people are affected by asthma and 461,000 people died in 2019. Idiopathic pulmonary fibrosis (IPF) is diagnosed in 3 million people worldwide, with an onset over the age of 50 with a mean survival of only 24-30 months. These three diseases have in common that remodeling of the lung tissue takes place, which is responsible for an irreversible decline of lung function. Pathological lung remodeling is mediated by a complex interaction of different, often misguided, repair processes regulated by a variety of mediators. One group of these, as has recently become known, are the Wnt ligands. In addition to their well-characterized role in embryogenesis, this group of glycoproteins is also involved in immunological and structural repair processes. Depending on the combination of the Wnt ligand with its receptors and co-receptors, canonical and noncanonical signaling cascades can be induced. Wnt5A is a mediator that is described mainly in noncanonical Wnt signaling and has been shown to play an important role in different inflammatory diseases and malignancies.

OBJECTIVES: In this review, we summarize the literature available regarding the role of Wnt5A as an immune modulator and its role in the development of asthma, COPD and IPF. We will focus specifically on what is known about Wnt5A concerning its role in the remodeling processes involved in the chronification of the diseases.

CONCLUSION: Wnt5A has been shown to be involved in all three inflammatory lung diseases. Since the ligand affects both structural and immunological processes, it is an interesting target for the treatment of lung diseases whose pathology involves a restructuring of the lung tissue triggered in part by an inflammatory immune response.

PMID:36658268 | DOI:10.1007/s00011-023-01692-5

Am J Chin Med. 2023 Jan 20:1-17. doi: 10.1142/S0192415X23500192. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is identifiable by the excessive increase of mesenchyme paired with the loss of epithelium. Total flavonoids of Astragalus (TFA), the main biologically active ingredient of the traditional Chinese medicine, Astragalus membranaceus (Huangqi), shows outstanding effects on treating pulmonary disorders, including COVID-19-associated pulmonary dysfunctions. This study was designed to evaluate the efficacy of TFA on treating pulmonary fibrosis and the possible mechanisms behind these effects. A549 cells were treated with TGF-[Formula: see text]1 and TFA to observe the potential effects of TFA on regulating alveolar epithelial cell proliferation, TGF-[Formula: see text]1-induced EMT, and the underlying mechanisms in vitro. Then, mouse pulmonary fibrosis was induced with a single intra-tracheal injection of bleomycin, and TFA was administrated by i.p. injection. Lung fibrosis was evaluated through histological and molecular analyses, and the possible mechanisms were explored using immunological methods. The results demonstrated that TFA could promote cell proliferation but inhibit TGF-[Formula: see text]1-induced EMT on A549 cells. TFA attenuated BLM-induced pulmonary fibrosis in mice by modulating inflammatory infiltration and M2 macrophage polarization; it furthermore modulated EMT through regulating the TGF-[Formula: see text]1/Smad pathway. In addition, TFA augmented the expression of the Wnt7b protein, which plays an important role in alveolar epithelium reparation. In conclusion, TFA alleviated bleomycin-induced mouse lung fibrosis by preventing the fibrotic response and increasing epithelium regeneration.

PMID:36655684 | DOI:10.1142/S0192415X23500192

J Vet Intern Med. 2023 Jan 19. doi: 10.1111/jvim.16622. Online ahead of print.

ABSTRACT

BACKGROUND: Salivary bile acids are used to diagnose extraesophageal reflux (EER) and to evaluate the risk of reflux aspiration that is associated with respiratory diseases in dogs.

OBJECTIVES: To study total bile acid (TBA) concentrations in saliva and in bronchoalveolar lavage fluid (BALF) to investigate EER and reflux aspiration in dogs with respiratory diseases and in healthy dogs.

ANIMALS: Thirty-one West Highland White Terriers (WHWTs) with idiopathic pulmonary fibrosis (IPF), 12 dogs with inflammatory airway disease (IAD), 6 dogs with recurrent pneumonia (RP), 26 brachycephalic dogs (BD), 27 healthy WHWTs (HW), 52 healthy dogs (HD). All privately-owned dogs.

METHODS: Saliva and BALF were collected from dogs in each group.

RESULTS: Salivary TBA concentrations were higher in IPF (median 0.1692 μM, interquartile range [IQR] 0.1115-0.2925 μM, Cohen's d 3.4, 95% confidence interval [CI] 2.2-4.0, P < .001) and BD (0.0256 μM, IQR 0.0086-0.0417 μM, d 0.5, CI -0.1 to 1.1, P = .003) compared to HD (0 μM, IQR not quantifiable [n.q.]-0.0131 μM). Bronchoalveolar lavage fluid TBA concentrations were higher in IPF (0.0117 μM, IQR 0.0048-0.0361 μM, d 0.5, CI 0-1.1, P < .001) compared to HD (0 μM, IQR n.q.-0.0074 μM).

CONCLUSION AND CLINICAL IMPORTANCE: Extraesophageal reflux and reflux aspiration occur in healthy dogs and those with respiratory diseases.

PMID:36655626 | DOI:10.1111/jvim.16622

Respir Res. 2023 Jan 18;24(1):19. doi: 10.1186/s12931-023-02317-5.

ABSTRACT

BACKGROUND: The objective of the present study is to describe the characteristics of interstitial pneumonia with autoimmune features (IPAF) patients, to assess the incidence rate of functional respiratory impairment over time and to evaluate the influence of therapeutic alternatives on the prognosis of these patients.

METHODS: A longitudinal observational multicenter study was performed (NEREA registry). It was carried out by a multidisciplinary team in seven Hospitals of Madrid. Patients were included from IPAF diagnosis.

MAIN OUTCOME: poor prognosis as functional respiratory impairment (relative decline in FVC % defined as ≥ 5% every 6 months). Covariates: therapy, sociodemographic, clinical, radiological patterns, laboratory and functional tests.

STATISTICS: Survival techniques were used to estimate IR per 100 patients-semester with their 95% confidence interval [CI]. The influence of covariates in prognosis were analyzed through cox multivariate regression models (hazard ratio (HR) and [CI]).

RESULTS: 79 IPAF were included, with a mean and a maximum follow-up of 3.17 and 12 years respectively. Along the study, 77.2% received treatment (52 glucocorticoids, 25 mycophenolate, 21 azathioprine, 15 rituximab and 11 antifibrotics). IR was 23.9 [19.9-28.8], and 50% of IPAF developed functional respiratory impairment after 16 months from its diagnosis. Multivariate analysis: usual interstitial pneumonia (UIP) had poorer prognosis compared to non-specific interstitial pneumonia (NSIP) (p = 0.001). In NSIP, positive ANA, increased the risk of poor prognosis. In UIP, glucocorticoids (HR: 0.53 [0.34-0.83]), age (HR: 1.04 [1.01-1.07]), and Ro-antibodies (HR: 0.36 [0.19-0.65]) influenced the prognosis.

CONCLUSIONS: IPAF have functional impairment during the first years of disease. Factors predicting deterioration differ between radiographic patterns. Our real-life study suggests the potential benefit of particular therapies in IPAF.

PMID:36653833 | DOI:10.1186/s12931-023-02317-5

J Cell Mol Med. 2023 Jan 18. doi: 10.1111/jcmm.17673. Online ahead of print.

ABSTRACT

Among breast cancer patients, metastases are the leading cause of death. Despite decades of effort, little progress has been made to improve the treatment of breast cancer metastases, especially triple-negative breast cancer (TNBC). The extracellular matrix plays an important role in tumour growth and metastasis by causing its deposition, remodelling, and signalling. As we know, the process of fibrosis results in excessive amounts of extracellular matrix being deposited within the cells. So, it will be interesting to study if the use of anti-fibrotic drugs in combination with conventional chemotherapy drugs can produce synergistic antitumor effects. In this study, we assessed the efficacy of Pirfenidone (PFD), an FDA-approved medication for the treatment of idiopathic pulmonary fibrosis, on TNBC cells as well as its anti-tumour effects in xenograft tumour model. PFD inhibited in a dose-dependent manner breast cancer cell proliferation, migration, and invasion, while promoted their apoptosis in vitro. PFD also suppressed TGF-β-induced activation of Smad signalling pathway and expression level of EMT-inducing transcription factors (e.g. SNAI2, TWIST1, ZEB1) as well as the mesenchymal genes such as VIMENTIN and N-Cadherin. On the contrary, the expression level of epithelial marker gene E-Cadherin was up-regulated in the presence of PFD. In vivo, PFD alone exerted a milder but significant anti-tumour effect than the chemotherapy drug nanoparticle albumin-bound paclitaxel (nab-PTX) did in the breast cancer xenograft mouse model. Interestingly, PFD synergistically boosted the cancer-killing effect of nab-PTX. Furthermore, Our data suggest that PFD suppressed breast cancer metastasis by inhibiting the activity of the TGFβ/SMAD pathway.

PMID:36651490 | DOI:10.1111/jcmm.17673

J Cell Mol Med. 2023 Jan 18. doi: 10.1111/jcmm.17665. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K-δ and PI3K-γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose-dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.

PMID:36651446 | DOI:10.1111/jcmm.17665

Am J Physiol Lung Cell Mol Physiol. 2023 Jan 17. doi: 10.1152/ajplung.00119.2022. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis is increasingly associated with nerve-driven processes and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lung's adrenergic nerve supply drives αSMA-expressing fibroblast accumulation via mechanisms involving α1 adrenoreceptors and mtDNA. Using the bleomycin model, we compared ablation of the lung's adrenergic nerve supply to surgical adrenal resection and found that NA derived from local but not adrenal sources drives experimentally induced lung fibrosis and the emergence of an αSMA+ fibroblast population expressing adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed extracellular mtDNA accumulation. Cultured normal human lung fibroblasts displayed α1 adrenoreceptors and in response to co-stimulation with TGFβ1 and NA adopted ACTA2 expression and extracellular mtDNA release. These findings were opposed by terazosin. IPF patients prescribed α1 adrenoreceptor antagonists for non-pulmonary indications demonstrated improved survival and reduced plasma mtDNA. Our observations link nerve-derived NA, α1 adrenoreceptors, extracellular mtDNA, and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuroinnate connection may yield new avenues for investigation in the clinical and basic science realms.

PMID:36648147 | DOI:10.1152/ajplung.00119.2022

J Thorac Dis. 2022 Dec;14(12):4713-4724. doi: 10.21037/jtd-22-906.

ABSTRACT

BACKGROUND: Understanding health-related quality of life (HRQL) in patients with interstitial lung disease (ILD) provides insight into disease burden and treatment effects on patients' well-being. We examined HRQL in a multiracial Asian ILD cohort using the King's brief ILD (K-BILD) and EuroQol 5-dimension-3-level (EQ5D-3L) questionnaires and their associations with several clinical variables.

METHODS: This was a single-centre cross-sectional study of ILD patients in a university-affiliated tertiary public hospital in Singapore. All patients completed two self-administered HRQL questionnaires upon study entry, and their clinical information was retrieved from electronic medical records.

RESULTS: Ninety-nine patients (56% male, 75% Chinese) were included. The median (interquartile range) age was 63 (54-72) years. The most common ILD diagnosis was connective tissue disease-related ILD (n=51, 52%), followed by idiopathic pulmonary fibrosis (n=27, 27%). The mean (standard deviation) scores for the EQ5D-3L utility value, EQ5D Visual Analogue Scale (VAS) and K-BILD total were 0.806 (0.284), 75.1 (12.8) and 63.9 (14.3), respectively. A moderate correlation was found between the EQ5D-3L and K-BILD total and domain scores. The HRQL scores also correlate moderately with the modified Medical Research Council dyspnoea scale (mMRC) scores. There was a weak-to-moderate correlation between HRQL and forced vital capacity (FVC), carbon monoxide diffusing capacity (DLCO) and Charlson comorbidity index. Multiple linear regression showed a significant association of K-BILD total [beta coefficient 0.244, 95% confidence interval (CI): 0.075-0.414; P=0.005], K-BILD 'breathlessness and activities' (beta coefficient 0.448, 95% CI: 0.192-0.703; P=0.001), and the 'psychological' domain (beta coefficient 0.256, 95% CI: 0.024-0.488; P=0.031) with DLCO %pred after adjustment for age, sex, BMI, race, smoking history, comorbidities, FVC %pred and ILD diagnosis. Non-Chinese race was a predictor of better K-BILD 'psychological' domain (beta coefficient 8.680, 95% CI: 0.656-16.704; P=0.034) after adjustment.

CONCLUSIONS: HRQL is significantly impaired in ILD patients, and low DLCO is a strong predictor of this impairment.

PMID:36647495 | PMC:PMC9840018 | DOI:10.21037/jtd-22-906

Clin Immunol. 2023 Jan 13:109230. doi: 10.1016/j.clim.2023.109230. Online ahead of print.

ABSTRACT

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event resulting from immunotherapy in patients with malignant tumors. However, the pathogenesis of CIP remains poorly understood.

METHODS: We collected bronchoalveolar lavage fluid (BALF) from cohorts of patients with CIP, new-onset lung cancer (LC), and idiopathic pulmonary fibrosis (IPF). Non-targeted metabolomics analysis was conducted to analyze metabolic signatures. Flow cytometry was used to evaluate immune cell subsets.

RESULTS: Lymphocytes were predominant in the BALF of patients with CIP. A total of 903 metabolites were identified, among which lipid compounds were the most abundant. In a comparison between patients with CIP and LC, enrichment analysis of the altered metabolites showed suppressed amino sugar metabolism, and spermidine and spermine biosynthesis in the CIP group. Metabolism of alpha linolenic acid, linoleic acid, and their fatty acid derivatives was enriched in the CIP group relative to the IPF group. The twelve metabolites found to be enriched in the CIP group were positively correlated with the proportion of CD8+ T cells. One cluster of BALF metabolites, 57.14% of which were lipid molecules, was inversely correlated with the proportion of natural killer cells.

CONCLUSIONS: In this study, the metabolomic landscape of BALF in patients with CIP was determined. We elucidated suppressed tumor metabolic signatures, enhanced pulmonary inflammatory signaling, and the characteristics of responsible immune cells, which helps to understand the pathogenesis of CIP.

PMID:36646189 | DOI:10.1016/j.clim.2023.109230

Respirology. 2023 Jan 15. doi: 10.1111/resp.14452. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity (FVC) with an adverse event profile characterized mainly by gastrointestinal events. We analysed the effects of nintedanib in the subset of Asian subjects.

METHODS: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis who had shown progression of ILD at any time within the prior 24 months despite management deemed appropriate in clinical practice were randomized to receive nintedanib or placebo. We analysed the rate of decline in FVC (ml/year) over 52 weeks in all Asian subjects and in Asian subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT).

RESULTS: One hundred sixty-four subjects in the INBUILD trial were of Asian race. The rate of decline in FVC (ml/year) over 52 weeks in this subgroup was -116.8 in the nintedanib group and -207.9 in the placebo group (difference: 91.0 [95% CI: 8.1, 173.9]; nominal p = 0.03). In Asian subjects with a UIP-like fibrotic pattern on HRCT, the rate of decline in FVC (ml/year) over 52 weeks was -130.1 in the nintedanib group and -224.2 in the placebo group (difference: 94.1 [5.5, 182.7]; nominal p = 0.04). Adverse events led to treatment discontinuation in 19.0% of the nintedanib group and 13.8% of the placebo group.

CONCLUSION: In Asian patients with progressive fibrosing ILDs, nintedanib reduced the rate of decline in FVC with adverse events that were manageable for most patients.

PMID:36642509 | DOI:10.1111/resp.14452

Eur J Pharm Sci. 2023 Jan 12:106370. doi: 10.1016/j.ejps.2023.106370. Online ahead of print.

ABSTRACT

mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics. eGFP mRNA LNP transfection in human primary cells proved dose- and time-dependent in vitro. In a bleomycin mouse model of lung fibrosis, luciferase mRNA LNPs administered intratracheally led to site-specific lung accumulation. Importantly, bioluminescence signal was detected in lungs as early as 2 h after delivery, with signal still evident at 48 h. Of note, LNPs were found associated with AEC2 and fibroblasts in vivo. Findings highlight the potential for pulmonary delivery of mRNA in IPF, opening therapeutic avenues aimed at halting and potentially reversing disease progression.

PMID:36642345 | DOI:10.1016/j.ejps.2023.106370

J Control Release. 2023 Jan 12:S0168-3659(23)00006-8. doi: 10.1016/j.jconrel.2023.01.010. Online ahead of print.

NO ABSTRACT

PMID:36642251 | DOI:10.1016/j.jconrel.2023.01.010

Proteomics. 2023 Jan 15:e2100414. doi: 10.1002/pmic.202100414. Online ahead of print.

ABSTRACT

Epithelial injury is one of the major drivers of acute pulmonary diseases. Recurring injury followed by aberrant repair is considered as the primary cause of chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF). Preclinical in vivo models allow studying early disease-driving mechanisms like the recently established AAV-DTR mouse model of acute epithelial lung injury, which utilizes adeno-associated virus (AAV) mediated expression of the human diphtheria toxin receptor (DTR). We performed quantitative proteomics of homogenized lung samples from this model and compared the results to spatially resolved proteomics data of epithelial cell regions from the same animals. In whole lung tissue proteins involved in cGAS-STING and interferon pathways, proliferation, DNA replication and the composition of the provisional extracellular matrix were upregulated upon injury. Besides epithelial cell markers SP-A, SP-C and Scgb1a1, proteins involved in cilium assembly, lipid metabolism and redox pathways were among downregulated proteins. Comparison of the bulk to spatially resolved proteomics data revealed a large overlap of protein changes and striking differences. Together our study underpins the broad usability of bulk proteomics and pinpoints to the benefit of sophisticated proteomic analyses of specific tissue regions or single cell types. This article is protected by copyright. All rights reserved.

PMID:36641648 | DOI:10.1002/pmic.202100414

Lancet Respir Med. 2023 Jan 11:S2213-2600(22)00475-1. doi: 10.1016/S2213-2600(22)00475-1. Online ahead of print.

ABSTRACT

Usual interstitial pneumonia (UIP) is characterised by a distinctive morphological and radiological appearance that was considered the pathognomonic hallmark of idiopathic pulmonary fibrosis (IPF). However, this peculiar lung remodelling pattern is also seen in other fibrotic interstitial lung diseases, including hypersensitivity pneumonitis, and connective tissue diseases. In this Personal View, we advocate the designation of a UIP pattern as a single, discrete diagnostic entity, amalgamating its primary form and secondary processes in disorders such as hypersensitivity pneumonitis (hypersensitivity pneumonitis with UIP), rheumatoid arthritis (rheumatoid arthritis with UIP), and others. The current separation between primary and secondary UIP is in keeping with the view that every individual interstitial lung disease must be viewed as a separate entity but does not reflect striking similarities between primary and secondary UIP in the morphological or radiological appearance, clinical behaviour, pathogenic pathways, and the efficacy of anti-fibrotic therapy. We believe that the unification of UIP as a single diagnostic entity has undeniable advantages.

PMID:36640788 | DOI:10.1016/S2213-2600(22)00475-1

J Colloid Interface Sci. 2023 Jan 6;636:388-400. doi: 10.1016/j.jcis.2023.01.007. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, where M2 macrophages play an irreplaceable role in the anti-inflammatory progress. Targeting M2 macrophages and regulating their polarization may be a potential treatment strategy for IPF. Herein, we designed a magnetic liposome based dual-targeting delivery system for the IPF treatment, constructed by mannose-modified magnetic nanoparticles (MAN-MNPs) loaded on the surface of the liposome (MAN-MNPs@LP). The delivery system is capable of responding to a static magnetic field (SMF) and then recognizing in situ of M2 macrophages through the mannose receptor-dependent internalization. Firstly, a series of physical and chemical assays were used to characterize these nanoparticles. Subsequently, magnetic liposomes accumulation in the damaged lung with/without mannose modification and SMF were compared by in vivo imaging system. Finally, the reduction of M2 macrophages and inhibition of their polarization confirmed that the development of IPF was retarded due to the in situ release of encapsulated dexamethasone (Dex) in lungs under the SMF. Further investigation demonstrated that the expression of α-SMA and collagen deposition was reduced. Altogether, this dual-targeting delivery system can effectively deliver Dex into M2 macrophages in the lung, making it a novel and promising therapeutic system for the IPF treatment.

PMID:36640550 | DOI:10.1016/j.jcis.2023.01.007

J Transl Med. 2023 Jan 13;21(1):24. doi: 10.1186/s12967-022-03837-2.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive, lethal disease in which ectopic lung fibroblast (LF) activation plays a vital part. We have previously shown that alamandine (ALA) exerts anti-fibrosis effects via the MAS-related G-protein coupled receptor D (MrgD). Here, we further investigate how it moderates transforming growth factor β1 (TGF-β1)-induced LF activation by regulating glucose metabolism and mitochondria autophagy (mitophagy).

METHODS: In vitro, we examined glycolysis-related protein hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and lactic acid in cells treated with TGF-β1. The oxygen consumption rate and the extracellular acidification rate were detected using Seahorse assays. Then, mitophagy was evaluated using transmission electron microscopy, mt-Keima, and the co-localization of Parkin and COX IV with LC3 and LAMP1, respectively. The autophagic degradation of HK2 and PFKFB3 was detected by 3MA and bafilomycin A1 and assessed by their co-localization with LC3 and LAMP1, respectively. The effects of ALA on LF activation markers collagen I and α-SMA were detected. The effects of ALA on glucose metabolism, mitophagy, and the activation of LF were also investigated in vivo.

RESULTS: We found that the ALA/MrgD axis improved TGF-β1-mediated LF activation by repressing glycolysis by downregulating HK2 and PFKFB3 expression. Lactic acid sustained positive feedback between glycolysis and LF activation by maintaining the expression of HK2 and PFKFB3. We also showed that glycolysis enhancement resulted from blocking the autophagic degradation of HK2 and PFKFB3 while upregulated mRNA levels by TGF-β1, while all of those improved by ALA adding. Importantly, we determined that moderation of Parkin/LC3-mediated mitophagy by TGF-β1 also promotes glycolysis but is reversed by ALA. Furthermore, we proved that ALA counteracts the effects of bleomycin on HK2, PFKFB3, LC3, Parkin, and LF activation in vivo.

CONCLUSION: In this study, we show that the ALA/MrgD axis prevents TGF-β1-mediated fibroblast activation via regulation of aerobic glycolysis and mitophagy.

PMID:36635651 | DOI:10.1186/s12967-022-03837-2

Occup Environ Med. 2023 Jan 12:oemed-2022-108404. doi: 10.1136/oemed-2022-108404. Online ahead of print.

ABSTRACT

BACKGROUND: Asbestos has been hypothesised as the cause of the recent global increase in the incidence of 'idiopathic' pulmonary fibrosis (IPF). Establishing this has important diagnostic and therapeutic implications. The association between occupational asbestos exposure and IPF, and interaction with a common (minor allele frequency of 9% in European populations) genetic variant associated with IPF, MUC5B rs35705950, is unknown.

METHODS: Multicentre, incident case-control study. Cases (n=494) were men diagnosed with IPF at 21 UK hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was assessed at interview using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs35705950 was investigated using a genetic dominant model.

RESULTS: 327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls had cumulative exposure estimates ≥25 fibre ml⁻¹ years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1 (95% CI 0.8 to 1.4; p=0.6) and there was no gene-environment interaction (p=0.3). Ever smoking was associated with IPF, OR 1.4 (95% CI 1 to 1.9; p=0.04) and interacted with occupational asbestos exposure, OR 1.9 (95% CI 1 to 3.6; p=0.04). In a further non-specified analysis, when stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs35705950.

CONCLUSION: Occupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. Exposure to asbestos and smoking interact to increase IPF risk in carriers of a common genetic variant, the minor allele of MUC5B rs35705950.

TRIAL REGISTRATION NUMBER: NCT03211507.

PMID:36635100 | DOI:10.1136/oemed-2022-108404

Respir Med Res. 2022 Oct 1;83:100955. doi: 10.1016/j.resmer.2022.100955. Online ahead of print.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease associated with high mortality. The IPF journey affects patients' and caregivers' quality of life, this should be taken into account as an important parameter for a better disease management. An ethnographic study was conducted between December 2019 and January 2020 to explore social disease representations, patients' and cargivers' experiences in the disease journey and consequences in their daily life, to identify the means of actions permitting a quality of life (QoL) improvement.

PATIENTS/CAREGIVERS: Twenty respondents, twelve patients aged 43 to 84 years old and eight caregivers in four French regions were met. Eleven patients were diagnosed with IPF between 2013 and 2017 and one patient in 1988 (at 12 years old). The lung function reported by patients ranged as follows: forced vital capacity from 112% to 40% and diffusing capacity of the lungs for carbon monoxide (DLCO) from 66% to <20%.

RESULTS: The survey included patients diagnosed at least three years ago. Collected data comprised disease representation, patients'/caregivers' experience of the disease, healthcare journey, and consequences for their daily life. The first signs identified by the patient or their caregiver may not have been taken seriously by the primary care physician. The pre-diagnosis period was considered particularly traumatic for most patients. The biopsy performed in 8 cases was experienced as violent by 4/8 patients, some of whom still feel pain. Patients/caregivers knew how to define their disease and spontaneously gave severe representations of the disease such as "Rare, incurable disease", "an organ being destroyed".

DISCUSSION: This study highlighted patients'/caregivers' common needs at each stage of the disease. The lack of disease knowledge from frontline practitioners (general physicians, community pulmonologists) can lead to significant diagnostic error. Patients require psychological support and more information on daily aspects in disease management, such as food good practices and importance of physical activity, along with information about disease progression. The fear caused by these shortages can be reduced through contact with patients' associations.

CONCLUSIONS: Numerous essential data were identified and should be considered for supporting actions that could allow to improve the QoL of patients with IPF.

PMID:36634553 | DOI:10.1016/j.resmer.2022.100955

Int Arch Allergy Immunol. 2023 Jan 11:1-9. doi: 10.1159/000528350. Online ahead of print.

ABSTRACT

INTRODUCTION: Observational studies have reported that allergic rhinitis (AR) was associated with chronic lower respiratory diseases (CLRDs) and lung function; however, their causal effects remain elusive. Therefore, to investigate the causal effects of AR on CLRDs and lung function, we conducted the two-sample Mendelian randomization (MR) study.

METHODS: The data for AR, asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, idiopathic pulmonary fibrosis (IPF), and the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio were obtained from genome-wide association studies, which were large sample studies on people of European ancestry. In this study, single-nucleotide polymorphisms associated with AR were considered instrumental variables. We employed the inverse-variance weighted (IVW) method with random effects to evaluate causal effects, and the weighted median and MR-Egger methods were used for sensitivity analyses. Significant causal associations were attempted for replication and meta-analysis.

RESULTS: In the discovery stage, we found that AR exhibited a significant causal effect on asthma (IVW, odds ratio [OR] = 16.91, 95% CI, 8.03-35.65, p < 0.001) and a suggestive effect on FEV1/FVC ratio (IVW, OR = 0.82, 95% CI, 0.68-0.99, p = 0.039). No causal effect of AR was observed on COPD, bronchiectasis, and IPF. In the replication stage, the causal effect of AR on asthma was replicated (IVW, OR = 11.57, 95% CI, 4.90-27.37, p < 0.001). The meta-analysis demonstrated that the combined OR of AR on asthma was 14.37 (IVW, 95% CI, 8.18-25.24, p < 0.001).

CONCLUSIONS: We demonstrated and measured the causal effects of AR on asthma (OR = 14.37) and FEV1/FVC ratio (OR = 0.82), while there was no evidence to support a causal effect of AR on COPD, bronchiectasis, and IPF. These results suggest that AR tends to have a causal effect on lower airway disease of similar inflammatory types and can provide high-quality causal evidence for clinical practice as well as the pathogenesis and prevention of AR and asthma.

PMID:36630930 | DOI:10.1159/000528350