Tuberc Respir Dis (Seoul). 2023 Dec 19. doi: 10.4046/trd.2023.0093. Online ahead of print.

ABSTRACT

BACKGROUND: The mechanisms leading to lung fibrosis are still under investigation. This study aimed to demonstrate whether antacids could prevent the development of interstitial lung disease (ILD).

STUDY DESIGN AND METHODS: This population-based longitudinal cohort study was conducted between January 2006 and December 2010 in South Korea. Eligible subjects were ≥40 years of age, exposed to proton pump inhibitors (PPI) +/- histamine-2 receptor antagonists (H-2 blockers) or H-2 blockers only, and had no history of ILD between 2004 and 2005. Exposure to antacids was defined as the administration of either PPI or H-2 receptor antagonists for > 14 days, whereas underexposure was defined as antacid treatment administered for less than 14 days. Newly developed ILDs, including idiopathic pulmonary fibrosis (IPF), were counted during the 5-year observation period. The association between antacid exposure and ILD development was evaluated using adjusted Cox regression models with variables, such as age, sex, smoking history, and comorbidities.

RESULTS: The incidence rates of ILD with /without antacid use were 43.2 and 33.8/100,000 person-years, respectively and those of IPF were 14.9 and 22.9/100,000 person-years, respectively. In multivariable analysis, exposure to antacid before the diagnosis of ILD was independently associated with a reduced development of ILD (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.45 to 0.71; P <0.001), while antacid exposure was not associated with development of IPF (HR, 0.88; 95% CI, 0.72 to 1.09; P =0.06).

CONCLUSION: Antacid exposure may be independently associated with a decreased risk of ILD development.

PMID:38111098 | DOI:10.4046/trd.2023.0093

Tuberc Respir Dis (Seoul). 2023 Dec 19. doi: 10.4046/trd.2023.0117. Online ahead of print.

ABSTRACT

Interstitial lung abnormalities (ILAs) are radiologic abnormalities found incidentally on chest CT that can be show a wide range of diseases, from subclinical lung fibrosis to early pulmonary fibrosis including definitive usual interstitial pneumonia. To clear up confusion about ILA, the Fleischner society published a position paper on the definition, clinical symptoms, increased mortality, radiologic progression, and management of ILAs based on several Western cohorts and articles. Recently, studies on long-term outcome, risk factors, and quantification of ILA to address the confusion have been published in Asia. The incidence of ILA was 7-10% for Westerners, while the prevalence of ILA was about 4% for Asians. ILA is closely related to various respiratory symptoms or increased rate of treatment-related complication in lung cancer. There is little difference between Westerners and Asians regarding the clinical importance of ILA. Although the role of quantitative CT as a screening tool for ILA requires further validation and standardized imaging protocols, using a threshold of 5% in at least one zone demonstrated 67.6% sensitivity, 93.3% specificity, and 90.5% accuracy, and a 1.8% area threshold showed 100% sensitivity and 99% specificity in South Korea. Based on the position paper released by the Fleischner society, I would like to report how much ILA occurs in the Asian population, what the prognosis is, and review what management strategies should be pursued in the future.

PMID:38111097 | DOI:10.4046/trd.2023.0117

Respir Res. 2023 Dec 18;24(1):320. doi: 10.1186/s12931-023-02622-z.

ABSTRACT

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease (ILD) associated with smoking, whose definitive diagnosis requires the exclusion of other forms of ILD and a compatible surgical lung biopsy. Bronchoalveolar lavage (BAL) is commonly proposed for the diagnosis of ILD, including PLCH, but the diagnostic value of this technique is limited. Here, we have analyzed the levels of a panel of cytokines and chemokines in BAL from PLCH patients, in order to identify a distinct immune profile to discriminate PLCH from other smoking related-ILD (SR-ILD), and comparing the results with idiopathic pulmonary fibrosis (IPF) as another disease in which smoking is considered a risk factor.

METHODS: BAL samples were collected from thirty-six patients with different ILD, including seven patients with PLCH, sixteen with SR-ILD and thirteen with IPF. Inflammatory profiles were analyzed using the Human Cytokine Membrane Antibody Array. Principal component analysis (PCA) was performed to reduce dimensionality and protein-protein interaction (PPI) network analysis using STRING 11.5 database were conducted. Finally, Random forest (RF) method was used to build a prediction model.

RESULTS: We have found significant differences (p < 0.05) on thirty-two cytokines/chemokines when comparing BAL from PLCH patients with at least one of the other ILD. Four main groups of similarly regulated cytokines were established, identifying distinct sets of markers for each cluster. Exploratory analysis using PCA (principal component analysis) showed clustering and separation of patients, with the two first components capturing 69.69% of the total variance. Levels of TARC/CCL17, leptin, oncostatin M (OSM) and IP-10/CXCL10 were associated with lung function parameters, showing positive correlation with FVC. Finally, random forest (RF) algorithm demonstrates that PLCH patients can be differentiated from the other ILDs based solely on inflammatory profile (accuracy 96.25%).

CONCLUSIONS: Our results show that patients with PLCH exhibit a distinct BAL immune profile to SR-ILD and IPF. PCA analysis and RF model identify a specific immune profile useful for discriminating PLCH.

PMID:38111019 | DOI:10.1186/s12931-023-02622-z

Chron Respir Dis. 2023 Jan-Dec;20:14799731231221818. doi: 10.1177/14799731231221818.

ABSTRACT

BACKGROUND AND OBJECTIVE: Reference values of physical activity to interpret longitudinal changes are not available in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to define the minimal clinical important difference (MCID) of longitudinal changes in physical activity in patients with IPF.

METHODS: Using accelerometry, physical activity (steps per day) was measured and compared at baseline and 6-months follow-up in patients with IPF. We calculated MCID of daily step count using multiple anchor-based and distribution-based methods. Forced vital capacity and 6-minute walk distance were applied as anchors in anchor-based methods. Effect size and standard error of measurement were used to calculate MCID in distribution-based methods.

RESULTS: One-hundred and five patients were enrolled in the study (mean age: 68.5 ± 7.5 years). Step count significantly decreased from baseline to 6-months follow-up (-461 ± 2402, p = .031). MCID calculated by anchor-based and distribution-based methods ranged from 570-1358 steps.

CONCLUSION: Daily step count significantly declined over 6-months in patients with IPF. MCID calculated by multiple anchor-based and distribution-based methods was 570 to 1358 steps/day. These findings contribute to interpretation of the longitudinal changes of physical activity that will assist its use as a clinical and research outcome in patients with IPF.

PMID:38108832 | DOI:10.1177/14799731231221818

Front Med (Lausanne). 2023 Dec 1;10:1282757. doi: 10.3389/fmed.2023.1282757. eCollection 2023.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis interstitial lung disease (IPF-ILD) is a progressive lung disease characterized by excessive collagen deposition and fibrotic changes in the lungs. Identifying reliable serum markers that correlate with disease progression is crucial for diagnosis and prognosis.

OBJECTIVE: This study aimed to explore the association between serum markers KL-6 and VEGF and IPF-ILD. Specifically, it assessed their correlation with PaO2, a measure of pulmonary gas function, to provide diagnostic and prognostic indicators.

METHODS: Patients with IPF-ILD were included, and their serum levels of KL-6 and VEGF were measured. Correlations with fibrotic damage and PaO2 were analyzed using statistical methods.

RESULTS: The analysis confirmed a positive correlation between the serum marker KL-6 and the degree of fibrotic damage in IPF-ILD. On the other hand, the serum marker VEGF was found to promote disease progression. In terms of correlation with PaO2, both KL-6 and VEGF demonstrated high sensitivity and specificity. Specifically, the correlation between KL-6 and PaO2 suggests that it can be used as a reliable indicator to assess the status of pulmonary oxygenation function in patients with ILD. The correlation between VEGF and PaO2 helps to understand its role in the progression of IPF-ILD and provides an important basis for predicting patient prognosis.

CONCLUSION: This study confirmed the correlation between KL-6 and VEGF with IPF-ILD and their association with PaO2. KL-6 and VEGF demonstrated high specificity and sensitivity in diagnosing, monitoring, and predicting prognosis in IPF-ILD. These findings contribute to our understanding of the disease and have clinical implications for diagnosis and prognostication.

PMID:38105892 | PMC:PMC10722179 | DOI:10.3389/fmed.2023.1282757

Clin Transl Sci. 2023 Dec 17. doi: 10.1111/cts.13701. Online ahead of print.

ABSTRACT

Bersiporocin, a potent and selective prolyl-tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open-label, two-part, one-sequence, three-period, three-treatment study was designed to evaluate the effect of drug-drug interactions (DDIs) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated enteric-coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. A 46 participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs suggesting bersiporocin alone or in combination therapy were well-tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there is no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib.

PMID:38105420 | DOI:10.1111/cts.13701

Respir Res. 2023 Dec 17;24(1):318. doi: 10.1186/s12931-023-02633-w.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive.

METHODS: To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis.

RESULTS: Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pY256N-WASP). Furthermore, TUFT1 promoted transforming growth factor-β1 (TGF-β1) induced fibroblast activation by increasing nuclear translocation of pY256N-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes.

CONCLUSIONS: Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.

PMID:38105232 | DOI:10.1186/s12931-023-02633-w

Pharmacol Ther. 2023 Dec 14:108578. doi: 10.1016/j.pharmthera.2023.108578. Online ahead of print.

ABSTRACT

The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-β. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach.

PMID:38103794 | DOI:10.1016/j.pharmthera.2023.108578

Front Pharmacol. 2023 Nov 30;14:1303646. doi: 10.3389/fphar.2023.1303646. eCollection 2023.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, age-related interstitial lung disease (ILD) with limited therapeutic options. Despite the wide variety of different in vivo models for IPF, these preclinical models have shown limitations that may significantly impair their translational potential. Among the most relevant limitations are the methodologies used to assess the efficacy of anti-fibrotic treatments, that are not the ones used in humans. In this scenario, the goal of the work presented in this paper is to provide translational relevance to the bleomycin (BLM)-induced pulmonary fibrosis mouse model, introducing and validating novel readouts to evaluate the efficacy of treatments for IPF. Methods: The BLM model was optimized by introducing the use of functional assessments such as the Forced Vital Capacity (FVC) and the Diffusion Factor for Carbon Monoxide (DFCO), that are respectively the primary and secondary endpoints in clinical trials for IPF, comparing them to more common readouts such as lung histology, improved by the application of Artificial Intelligence (AI) to detect and quantify fibrotic tissue deposition, and metalloproitenase-7 (MMP-7), a clinical prognostic biomarker. Results: Lung function measurement and DFCO changes well correlated with Ashcroft score, the current gold-standard for the assessment of pulmonary fibrosis in mice. The relevance and robustness of these novel readouts in the BLM model was confirmed by the results obtained testing Nintedanib and Pirfenidone, the only drugs approved for the treatment of IPF patients: in fact, both drugs administered therapeutically, significantly affected the changes in these parameters induced by BLM treatment, with results that closely reflected the efficacy observed in the clinic. Changes in biomarkers such as MMP-7 were also evaluated, and well correlated with the modifications of FVC and DFCO. Conclusion: Novel functional readouts such as FVC and DFCO can be efficiently used to assess pathology progression in the BLM-induced pulmonary fibrosis mouse model as well as compound efficacy, substantially improving its translational and predictivity potential.

PMID:38099140 | PMC:PMC10719847 | DOI:10.3389/fphar.2023.1303646

Nat Commun. 2023 Dec 14;14(1):8120. doi: 10.1038/s41467-023-43336-6.

ABSTRACT

Pulmonary fibrosis (PF), a condition characterized by inflammation and collagen deposition in the alveolar interstitium, causes dyspnea and fatal outcomes. Although the bleomycin-induced PF mouse model has improved our understanding of exogenous factor-induced fibrosis, the mechanism governing endogenous factor-induced fibrosis remains unknown. Here, we find that Ifngr1-/-Rag2-/- mice, which lack the critical suppression factor for group 2 innate lymphoid cells (ILC2), develop PF spontaneously. The onset phase of fibrosis includes ILC2 subpopulations with a high Il1rl1 (IL-33 receptor) expression, and fibrosis does not develop in ILC-deficient or IL-33-deficient mice. Although ILC2s are normally localized near bronchioles and blood vessels, ILC2s are increased in fibrotic areas along with IL-33 positive fibroblasts during fibrosis. Co-culture analysis shows that activated-ILC2s directly induce collagen production from fibroblasts. Furthermore, increased IL1RL1 and decreased IFNGR1 expressions are confirmed in ILC2s from individuals with idiopathic PF, highlighting the applicability of Ifngr1-/-Rag2-/- mice as a mouse model for fibrosis research.

PMID:38097562 | DOI:10.1038/s41467-023-43336-6

Ann Am Thorac Soc. 2023 Dec 14. doi: 10.1513/AnnalsATS.202305-495RL. Online ahead of print.

NO ABSTRACT

PMID:38096447 | DOI:10.1513/AnnalsATS.202305-495RL

Ann Am Thorac Soc. 2023 Dec 14. doi: 10.1513/AnnalsATS.202305-402OC. Online ahead of print.

ABSTRACT

Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic pulmonary disorder of unknown etiology, characterized by a usual interstitial pneumonia (UIP) pattern. Previous meta-analyses have reported associations between occupational exposures and IPF, but higher-quality studies have been published in recent years, doubling the number of studied patients. Objective To provide a contemporary and comprehensive assessment of the relationship between occupational exposures and IPF. Study Design and Methods We searched Pubmed, Embase, and Web of Science through July 2023 to identify all publications on occupational exposure and IPF. We conducted a meta-analysis of the occupational burden, odds ratio (OR), and population attributable fraction (PAF) of exposures. Five exposure categories were analyzed: VGDF (vapors, gas, dust, and fumes), metal dust, wood dust, silica dust, and agricultural dust. A comprehensive bias assessment was performed. The study protocol was registered to the International Prospective Register of Systematic Reviews (ID: CRD42021267808). Results Our search identified 23,942 publications. Sixteen publications contained relative risks needed to calculate pooled ORs and PAFs, and 12 additional publications reported an occupational burden within a case series. The proportion of cases with occupational exposures to VGDF was 44% [95% confidence interval (CI), 36-53], with a range of 8-17% within more specific exposure categories. The pooled OR was elevated for VGDF at 1.8 (CI, 1.3-2.4), with a pooled PAF of 21% (CI, 15-28). The OR and PAF were respectively found to be 1.6 and 7% (metal dust), 1.6 and 3% (wood dust), 1.8 and 14% (agricultural dust), and 1.8 and 4% (silica dust). The pooled OR and PAF within specific exposure categories ranged from 1.6-1.8 and 4-14%, respectively. We identified some publication bias, though it was not sufficient to diminish the association between occupational exposures and IPF based on sensitivity analysis and bias assessment. Conclusions Our findings indicate that 21% (or approximately 1 in 5) IPF cases could be prevented by removal of occupational exposure (alongside a pooled OR of 1.8). Additionally, 44% of patients with IPF report occupational exposure to VGDF. This meta-analysis suggests that a considerable number of cases of IPF are attributable to inhaled occupational exposures and warrant increased consideration in the clinical care of patients and future prevention efforts. Clinical Trials Registration International Prospective Register of Systematic Reviews (ID: CRD42021267808).

PMID:38096107 | DOI:10.1513/AnnalsATS.202305-402OC

Front Immunol. 2023 Nov 29;14:1290585. doi: 10.3389/fimmu.2023.1290585. eCollection 2023.

ABSTRACT

INTRODUCTION: MZB1 is an endoplasmic reticulum residential protein preferentially expressed in plasma cells, marginal zone and B1 B cells. Recent studies on murine B cells show that it interacts with the tail piece of IgM and IgA heavy chain and promotes the secretion of these two classes of immunoglobulin. However, its role in primary human B cells has yet to be determined and how its function is regulated is still unknown. The conversion of peptidylarginine to peptidylcitrulline, also known as citrullination, by peptidylarginine deiminases (PADs) can critically influence the function of proteins in immune cells, such as neutrophils and T cells; however, the role of PADs in B cells remains to be elucidated.

METHOD: An unbiased analysis of human lung citrullinome was conducted to identify citrullinated proteins that are enriched in several chronic lung diseases, including rheumatoid arthritis-associated interstitial lung disease (RA-ILD), chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis, compared to healthy controls. Mass spectrometry, site-specific mutagenesis, and western blotting were used to confirm the citrullination of candidate proteins. Their citrullination was suppressed by pharmacological inhibition or genetic ablation of PAD2 and the impact of their citrullination on the function and differentiation of human B cells was examined with enzyme-linked immunosorbent assay, flow cytometry, and co-immunoprecipitation.

RESULTS: Citrullinated MZB1 was preferentially enriched in RA-ILD but not in other chronic lung diseases. MZB1 was a substrate of PAD2 and was citrullinated during the differentiation of human plasmablasts. Ablation or pharmacological inhibition of PAD2 in primary human B cells attenuated the secretion of IgM and IgA but not IgG or the differentiation of IgM or IgA-expressing plasmablasts, recapitulating the effect of ablating MZB1. Furthermore, the physical interaction between endogenous MZB1 and IgM/IgA was attenuated by pharmacological inhibition of PAD2.

DISCUSSION: Our data confirm the function of MZB1 in primary human plasmablasts and suggest that PAD2 promotes IgM/IgA secretion by citrullinating MZB1, thereby contributing to the pathogenesis of rheumatoid arthritis and RA-ILD.

PMID:38094295 | PMC:PMC10716219 | DOI:10.3389/fimmu.2023.1290585

J Thorac Dis. 2023 Nov 30;15(11):5913-5921. doi: 10.21037/jtd-23-946. Epub 2023 Oct 25.

ABSTRACT

BACKGROUND: The role of combination treatments with two antifibrotic agents, pirfenidone and nintedanib, has been not established in idiopathic pulmonary fibrosis (IPF). This study was performed to investigate the safety and tolerability of combination antifibrotic treatment in patients with IPF.

METHODS: We conducted a proportional meta-analysis and searched PubMed, EMBASE, and the Cochrane Central Register for relevant clinical trials. The primary outcome was the proportion of discontinuation of combination treatment over the treatment period. We also examined the pooled proportions of serious and any adverse drug reactions (ADRs).

RESULTS: Four clinical trials involving 191 patients were analyzed. In pooled estimates, 29% of patients discontinued treatment during the study period [95% confidence interval (CI): 17-41%, I2=65.42%]. The pooled proportions of serious and any ADRs were 10% (95% CI: 1-19%; I2=79.13%) and 82% (95% CI: 75-90%; I2=39.20%), respectively. During the follow-up period, gastrointestinal symptoms were the most frequent ADR. Acute exacerbation (AE) of IPF was reported in 7.0% of patients.

CONCLUSIONS: Our findings showed relatively frequent incidence of discontinuation and ADRs for combination therapy in IPF. Further large-scale, randomized, controlled trials are needed to support our results because of the methodological limitations of the included trials and a scarcity of trials for analysis.

PMID:38090320 | PMC:PMC10713318 | DOI:10.21037/jtd-23-946

J Thorac Dis. 2023 Nov 30;15(11):6160-6177. doi: 10.21037/jtd-23-815. Epub 2023 Nov 27.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging.

METHODS: Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed.

RESULTS: The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α.

CONCLUSIONS: These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

PMID:38090292 | PMC:PMC10713321 | DOI:10.21037/jtd-23-815

Front Pharmacol. 2023 Nov 27;14:1324586. doi: 10.3389/fphar.2023.1324586. eCollection 2023.

NO ABSTRACT

PMID:38089050 | PMC:PMC10711599 | DOI:10.3389/fphar.2023.1324586

Respirology. 2023 Dec 12. doi: 10.1111/resp.14643. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Corticosteroids are commonly used for the treatment of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF); however, the optimal initial dose of corticosteroids remains uncertain due to a lack of sufficient evidence. We evaluated whether the administration of a pulse dose of corticosteroids resulted in improved survival outcomes compared with conventional non-pulse dose of corticosteroids.

METHODS: We retrospectively analysed 238 patients with AE-IPF treated with corticosteroids at a tertiary referral hospital between January 2013 and December 2021. Based on whether a pulse dose of corticosteroids (methylprednisolone of ≥250 mg/day or equivalent) was administered within 7 days of hospitalization for AE-IPF, the patients were divided into the pulse and non-pulse regimen groups. The survival outcomes were compared between the two groups using multivariable regression and propensity score-matched analyses.

RESULTS: Among the 238 patients, 59 patients received pulse dose of corticosteroids, whereas 179 patients received conventional non-pulse dose of corticosteroids. After adjusting for the confounding factors related to the baseline clinical and radiographic severity, compared with the conventional non-pulse regimen, the pulse regimen of corticosteroids did not reduce the risk of mortality at the 3-month (aHR 0.84, 95% CI 0.45-1.38) or 12-month (aHR 0.96, 95% CI 0.60-1.25) follow-ups. Propensity score-matched analysis revealed similar results.

CONCLUSION: The survival outcomes of patients with AE-IPF who received a pulse dose of corticosteroids did not differ from those of patients who received conventional non-pulse dose of corticosteroids. Further prospective studies are required to establish the optimal initial dose of corticosteroids for the treatment of AE-IPF.

PMID:38087838 | DOI:10.1111/resp.14643

Int Immunopharmacol. 2023 Dec 11;127:111330. doi: 10.1016/j.intimp.2023.111330. Online ahead of print.

ABSTRACT

OBJECTIVES: Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls.

METHODS: Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression.

RESULTS: There was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical (CD14++CD16-) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes.

CONCLUSIONS: Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16+ monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.

PMID:38086271 | DOI:10.1016/j.intimp.2023.111330

Rheumatol Int. 2023 Dec 12. doi: 10.1007/s00296-023-05505-0. Online ahead of print.

ABSTRACT

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has a better prognosis compared to idiopathic pulmonary fibrosis (IPF). Recent data suggest that antifibrotics are effective in slowing progression across both groups. Hence, we designed this study to investigate the similarities and differences between these groups of patients. This is a retrospective cohort study examining baseline data, progression and outcomes in patients with RA-ILD and IPF prior to antifibrotic use in the Coventry ILD database. Ethics approval was obtained from the University Hospital Coventry and Warwickshire NHS Trust. Statistical analysis was performed using R software and Cox's proportional hazards technique was used for survival analysis. We identified 131 cases, including 49 patients with IPF, 34 patients with RA-ILD and 48 patients with other forms of idiopathic interstitial pneumonia. At baseline, there were significant differences in the groups with RA-ILD patients being significantly younger (65.7 vs 72.4 years), had preserved lung volumes (FVC 95% vs 84.7%) and higher gas transfer (61.5% vs 48.2%) compared to IPF patients. 5-year survival was better for RA-ILD compared to IPF (87.5% vs 40.4%, p = 0.0042). Univariate analysis revealed gas transfer, FVC, age, sex and phenotype (IPF or RA-ILD) were all significant predictors, but multivariate analysis revealed that gas transfer and age were both significantly associated with prognosis, whereas sex, FVC or phenotype were not significant. This study suggests that the difference between RA-ILD and IPF prognosis may be due to demographics and early diagnosis rather than the diseases behaving differently. This has important management implications.

PMID:38085367 | DOI:10.1007/s00296-023-05505-0

Am J Physiol Lung Cell Mol Physiol. 2023 Dec 12. doi: 10.1152/ajplung.00155.2023. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive scarring of the lungs and resulting in deterioration in lung function. Transforming growth factor-beta (TGF-β) is one of the most established drivers of fibrotic processes. TGF-β promotes transformation of tissue fibroblasts to myofibroblasts, a key finding in the pathogenesis of pulmonary fibrosis. We report here that TGF-β robustly upregulates the expression of the calcium-activated chloride channel Anoctamin-1 (ANO1) in human lung fibroblasts (HLF) at mRNA and protein levels. ANO1 is readily detected in fibrotic areas of IPF lungs in the same area with smooth muscle alpha-actin (SMA)-positive myofibroblasts. TGF-β-induced myofibroblast differentiation (determined by the expression of SMA, collagen-1 and fibronectin) is significantly inhibited by a specific ANO1 inhibitor, T16Ainh-A01, or by siRNA-mediated ANO1 knockdown. T16Ainh-A01 and ANO1 siRNA attenuate pro-fibrotic TGF-β signaling, including activation of RhoA pathway and AKT, without affecting initial Smad2 phosphorylation. Mechanistically, TGF-β treatment of HLF results in a significant increase in intracellular chloride levels, which is prevented by T16Ainh-A01 or by ANO1 knockdown. The downstream mechanism involves the chloride-sensing "with-no-lysine (K)" kinase (WNK1). WNK1 siRNA significantly attenuates TGF-β-induced myofibroblast differentiation and signaling (RhoA pathway and AKT), whereas the WNK1 kinase inhibitor WNK463 is largely ineffective. Together, these data demonstrate that (i) ANO1 is a TGF-β-inducible chloride channel that contributes to increased intracellular chloride concentration in response to TGF-β; and (ii) ANO1 mediates TGF-β-induced myofibroblast differentiation and fibrotic signaling in a manner dependent on WNK1 protein, but independent of WNK1 kinase activity.

PMID:38084409 | DOI:10.1152/ajplung.00155.2023