Front Pharmacol. 2024 Feb 13;15:1348708. doi: 10.3389/fphar.2024.1348708. eCollection 2024.

ABSTRACT

Background: The etiological underpinnings of gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remain elusive, coupled with a scarcity of effective therapeutic interventions for IPF. Angelicae sinensis radix (ASR, also named Danggui) is a Chinese herb with potential anti-fibrotic properties, that holds promise as a therapeutic agent for IPF. Objective: This study seeks to elucidate the causal interplay and potential mechanisms underlying the coexistence of GERD and IPF. Furthermore, it aims to investigate the regulatory effect of ASR on this complex relationship. Methods: A two-sample Mendelian randomization (TSMR) approach was employed to delineate the causal connection between gastroesophageal reflux disease and IPF, with Phennoscanner V2 employed to mitigate confounding factors. Utilizing single nucleotide polymorphism (SNPs) and publicly available microarray data, we analyzed potential targets and mechanisms related to IPF in GERD. Network pharmacology and molecular docking were employed to explore the targets and efficacy of ASR in treating GERD-related IPF. External datasets were subsequently utilized to identify potential diagnostic biomarkers for GERD-related IPF. Results: The IVW analysis demonstrated a positive causal relationship between GERD and IPF (IVW: OR = 1.002, 95%CI: 1.001, 1.003; p < 0.001). Twenty-five shared differentially expressed genes (DEGs) were identified. GO functional analysis revealed enrichment in neural, cellular, and brain development processes, concentrated in chromosomes and plasma membranes, with protein binding and activation involvement. KEGG analysis unveiled enrichment in proteoglycan, ERBB, and neuroactive ligand-receptor interaction pathways in cancer. Protein-protein interaction (PPI) analysis identified seven hub genes. Network pharmacology analysis demonstrated that 104 components of ASR targeted five hub genes (PDE4B, DRD2, ERBB4, ESR1, GRM8), with molecular docking confirming their excellent binding efficiency. GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF (ESR1: AUCGERD = 0.762, AUCIPF = 0.725; GRM8: AUCGERD = 0.717, AUCIPF = 0.908). GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF, validated in external datasets. Conclusion: This study establishes a causal link between GERD and IPF, identifying five key targets and two potential diagnostic biomarkers for GERD-related IPF. ASR exhibits intervention efficacy and favorable binding characteristics, positioning it as a promising candidate for treating GERD-related IPF. The potential regulatory mechanisms may involve cell responses to fibroblast growth factor stimulation and steroidal hormone-mediated signaling pathways.

PMID:38414734 | PMC:PMC10897002 | DOI:10.3389/fphar.2024.1348708

Int J Nanomedicine. 2024 Feb 23;19:1827-1842. doi: 10.2147/IJN.S444470. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease characterized by chronic lung injury leading to macrophage infiltration and fibroblast activation. However, there is no effective therapeutic strategy targeting the crucial crosstalk between macrophages and fibroblasts to halt IPF progression.

METHODS: Studies were conducted in IPF patients and fibrotic mice models to elucidate the role of Bcar3 in the pathogenesis of pulmonary fibrosis. The effect of Bcar3 on macrophage polarization, fibroblast activation, and related signaling pathways were next investigated to unravel the underlying mechanisms.

RESULTS: Our study elucidates a marked increase in Bcar3 expression in lung tissues from IPF patients and fibrotic mice, recording 1.7 and 7.8-fold increases compared to control subjects, respectively. Additionally, Bcar3 was found to significantly enhance macrophage activation and fibroblast differentiation, observable in both in vivo and in vitro settings. Mechanistically, the upregulation of Bcar3 in macrophages was reliant on Stat6, while in fibroblasts, it depended on TGFβR1/Smad3. Furthermore, Bcar3 augmented IL-4/Stat6 pathway in macrophages and TGF-β/Smad3 pathway in fibroblasts, supporting a synergistic activation loop that expedited lung fibrogenesis. Notably, intratracheal injection of liposomes containing Bcar3 siRNA precisely delivered gene therapeutics to lung macrophages and fibroblasts, effectively reducing Bcar3 expression to 59% of baseline levels. Importantly, this intervention protected mice from lung fibrosis induced by either FITC or bleomycin, as well as human precision-cut lung slices against TGF-β1 stimulation.

CONCLUSION: Our study underscores the pivotal role of Bcar3 in orchestrating the macrophage-fibroblast crosstalk during pulmonary fibrosis progression. Targeting Bcar3 emerges as a novel therapeutic avenue to halt IPF progression and enhance patient prognosis.

PMID:38414524 | PMC:PMC10898485 | DOI:10.2147/IJN.S444470

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241232561. doi: 10.1177/17534666241232561.

ABSTRACT

BACKGROUND: Nintedanib and pirfenidone are preferred pharmacological therapies for patients with idiopathic pulmonary fibrosis (IPF). However, evidence favoring antifibrotic therapy in patients with non-IPF fibrosing interstitial lung diseases (ILD) is limited.

OBJECTIVE: To investigate the effects of antifibrotic therapy on disease progression, all-cause mortality, and acute exacerbation (AE) risk in patients with non-IPF fibrosing ILDs.

DESIGN: Meta-analysis.

DATA SOURCES AND METHODS: Electronic databases were searched for articles published before 28 February 2023. Studies that evaluated the efficacy of antifibrotic agents in patients with fibrosing ILDs were selected. The primary outcome was the disease progression risk, and the secondary outcomes included all-cause mortality and AE risk. The GRADE criteria were used for the certainty of evidence assessment.

RESULTS: Nine studies with 1990 participants were included. Antifibrotic therapy reduced the rate of patients with disease progression (five trials with 1741 subjects; relative risk (RR), 0.56; 95% CI, 0.42-0.75; p < 0.0001; I2 = 0; high-certainty evidence). Antifibrotic therapy did not significantly decrease all-cause mortality (nine trials with 1990 subjects; RR, 0.76; 95% CI, 0.55-1.03; p = 0.08; I2 = 0; low-certainty evidence). However, in patients with progressive fibrosing ILDs (PF-ILD), antifibrotic therapy decreased all-cause mortality (four trials with 1100 subjects; RR, 0.69; 95% CI, 0.48-0.98; p = 0.04; I2 = 0; low-certainty evidence).

CONCLUSION: Our study supports the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality.

TRIAL REGISTRATION: This study protocol was registered with PROSPERO (registration number: CRD42023411272).

PMID:38414439 | DOI:10.1177/17534666241232561

BMJ Open Respir Res. 2024 Feb 27;11(1):e001997. doi: 10.1136/bmjresp-2023-001997.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) is a life-threatening condition taking place not only in idiopathic pulmonary fibrosis (IPF) but also in interstitial lung diseases (ILD) other than IPF (non-IPF ILD). This study aims to compare the clinical manifestations between patients hospitalised with AE-IPF and AE-non-IPF ILD, and further analyse the risk factors related to in-hospital mortality.

METHODS: Clinical data of 406 patients hospitalised with AE-IPF (93 cases) and AE-non-IPF ILD (313 cases) were retrospectively collected. Clinical features were compared between the two groups. Risk factors related to in-hospital mortality in patients with overall AE-ILD, AE-IPF and AE-non-IPF ILD were identified by multiple logistic regression analyses, respectively, and assessed by receiver operating characteristic curve.

RESULTS: In addition to having more smokers and males, the AE-IPF group also had more respiratory failure on admission, comorbidities of pulmonary hypertension (PAH) or coronary artery disease/heart failure, a longer history of pre-existing ILD. Comorbidity of coronary heart disease/heart failure, respiratory failure at admission, neutrophil (N)%, serum hydroxybutyrate dehydrogenase (HBDH), lactate dehydrogenase (LDH) and low cholesterol levels were independent risk factors for patients with AE-ILD, while respiratory failure on admission, N%, serum HBDH, urea nitrogen, LDH and low albumin levels were risk factors for the AE-non-IPF ILD group, and fever, N% and PAH were the AE-IPF group's. Among them, HBDH 0.758 (sensitivity 85.5%, specificity 56%, cut-off 237.5 U/L) for patients with AE-ILD; N% 0.838 (sensitivity 62.5%, specificity 91.18%, cut-off 83.55%) for the AE-IPF group and HBDH 0.779 (sensitivity 86.4%, specificity 55.1%, cut-off 243.5 U/L) for the AE-non-IPF ILD group were the risk factors with the highest area under the curve.

CONCLUSIONS: Clinical characteristics differ between patients with AE-IPF and AE-non-IPF ILD. HBDH outperformed LDH in predicting the prognosis for patients with AE-ILD and AE-non-IPF ILD. N% was an independent predictor of death in-hospital in all three groups, especially in the AE-IPF group.

PMID:38413119 | DOI:10.1136/bmjresp-2023-001997

Exp Mol Med. 2024 Feb 28. doi: 10.1038/s12276-024-01170-w. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-β1 (TGF)-β1 activity and TGF-β1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-β1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

PMID:38413821 | DOI:10.1038/s12276-024-01170-w

J Thorac Dis. 2024 Jan 30;16(1):688-695. doi: 10.21037/jtd-23-1183. Epub 2023 Dec 22.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible condition characterized by the deposition of extracellular matrix resulting from repetitive damage to the alveolar epithelium. These injuries, along with dysregulated wound repair and fibroblast dysfunction, lead to continuous tissue remodeling and fibrosis, eventually resulting in end-stage pulmonary fibrosis. Currently, there is no specific pharmacological treatment available for IPF. The role of inflammation in the development of IPF is still a topic of debate, and it is sometimes considered incidental to fibrosis. Over the past decade, macrophages have emerged as significant contributors to the pathogenesis of fibrosis. M1 macrophages are responsible for wound healing following alveolar epithelial injury, while M2 macrophages are involved in resolving wound repair and terminating the inflammatory response in the lungs. Various studies provide evidence that M2-like macrophages contribute to the abnormal fibrogenesis. In recent years, there has been growing interest in understanding macrophage polarization and its role in the development of pulmonary fibrosis. Histone deacetylase 6 (HDAC6), a member of the HDAC family with two functional deacetylase structural domains and a ubiquitin-binding zinc finger structural domain (ZnF-BUZ), plays a crucial role in pulmonary fibrosis. This article explores the role of HDAC6 in pulmonary fibrosis and evaluates its potential as a treatment approach for IPF.

METHODS: PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, China Biomedical Literature Service System (CBMdisc) and Web of Science were searched to obtain researches, published in English and Chinese, until July 2023. The search was performed using specific keywords such as Histone deacetylase 6, HDAC6, Idiopathic pulmonary fibrosis, IPF, fibrosis.

KEY CONTENT AND FINDINGS: HDAC6 has diverse effects on physiological processes, including the NLRP3 inflammasome, epithelial-mesenchymal transition, the TGFβ-PI3K-AKT pathway, macrophage polarization and TGF-β-Smad signaling pathway, due to its unique structure. HDAC6 has been found to enhance the inflammatory response and fibrosis of lung tissues, contributing to the development of IPF.

CONCLUSIONS: In the future, HDAC6 inhibitors are expected to play a crucial role in the treatment of fibrotic disorders and should be studied further deserves to pursue in future research.

PMID:38410580 | PMC:PMC10894383 | DOI:10.21037/jtd-23-1183

Respir Med. 2024 Feb 24:107577. doi: 10.1016/j.rmed.2024.107577. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF.

METHODS: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated.

RESULTS: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002).

CONCLUSIONS: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF.

PMID:38408707 | DOI:10.1016/j.rmed.2024.107577

MedComm (2020). 2024 Feb 23;5(2):e494. doi: 10.1002/mco2.494. eCollection 2024 Feb.

ABSTRACT

Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

PMID:38405059 | PMC:PMC10885188 | DOI:10.1002/mco2.494

Respir Res. 2024 Feb 26;25(1):101. doi: 10.1186/s12931-024-02721-5.

ABSTRACT

BACKGROUND: Although some studies have indicated that Psoriasis could contribute to the risk of idiopathic pulmonary fibrosis (IPF), no study has reported a clear causal association between them. Our aim was to explore the potential relationship between Psoriasis and IPF using Mendelian randomization (MR) design.

METHODS: To explore a causal association between Psoriasis and IPF, we used genetic instruments from the largest available genome-wide association study (GWAS) of European ancestry, including psoriasis (5314 cases, 457,619 controls) and IPF (1028 cases, 196,986 controls). Our main analyses were conducted by inverse-variance weighted (IVW) method with random-effects model, with the other complementary four analyses: weighted median method, weighted mode, multivariable MR and MR-Egger approach.

RESULTS: The results of IVW methods demonstrated that genetically predicted psoriasis was significantly associated with higher odds of IPF, with an odds ratio (OR) of 1.09 (95%CI, 1.01-1.18; P = 0.02). Weighted median method, weighted mode and multivariable MR also demonstrated directionally similar results (P < 0.05), while the MR-Egger regression did not reveal the impact of psoriasis on IPF (OR = 1.09, 95%CI, 0.98-1.21; P = 0.11). In addition, both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between psoriasis and IPF.

CONCLUSIONS: Our study provided potential evidence between genetically predicted psoriasis and IPF, which suggests that understanding the mutual risk factors between psoriasis and IPF can facilitate the clinical management of both diseases.

PMID:38403646 | DOI:10.1186/s12931-024-02721-5

Biomed Pharmacother. 2024 Feb 22;173:116282. doi: 10.1016/j.biopha.2024.116282. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is a chronic and progressive lung disease characterized by the accumulation of scar tissue in the lungs, which leads to impaired lung function and reduced quality of life. The prognosis for idiopathic pulmonary fibrosis (IPF), which is the most common form of pulmonary fibrosis, is generally poor. The median survival for patients with IPF is estimated to be around 3-5 years from the time of diagnosis. Currently, there are two approved drugs (Pirfenidone and Nintedanib) for the treatment of IPF. However, Pirfenidone and Nintedanib are not able to reverse or cure pulmonary fibrosis. There is a need for new pharmacological interventions that can slow or halt disease progression and cure pulmonary fibrosis. This review aims to provide an updated overview of current and future drug interventions for idiopathic pulmonary fibrosis, and to summarize possible targets of potential anti-pulmonary fibrosis drugs, providing theoretical support for further clinical combination therapy or the development of new drugs.

PMID:38401514 | DOI:10.1016/j.biopha.2024.116282

Microorganisms. 2024 Jan 29;12(2):287. doi: 10.3390/microorganisms12020287.

ABSTRACT

The importance of lung microbiome changes in developing chronic lung allograft dysfunction (CLAD) after lung transplantation is poorly understood. The lung microbiome-immune interaction may be critical in developing CLAD. In this context, examining alterations in the microbiome and immune cells of the lungs following CLAD, in comparison to the lung condition immediately after transplantation, can offer valuable insights. Four adult patients who underwent lung retransplantation between January 2019 and June 2020 were included in this study. Lung tissues were collected from the same four individuals at two different time points: at the time of the first transplant and at the time of the explantation of CLAD lungs at retransplantation due to CLAD. We analyzed whole-genome sequencing using the Kraken2 algorithm and quantified the cell fractionation from the bulk tissue gene expression profile for each lung tissue. Finally, we compared the differences in lung microbiome and immune cells between the lung tissues of these two time points. The median age of the recipients was 57 years, and most (75%) had undergone lung transplants for idiopathic pulmonary fibrosis. All patients were administered basiliximab for induction therapy and were maintained on three immunosuppressants. The median CLAD-free survival term was 693.5 days, and the median time to redo the lung transplant was 843.5 days. Bacterial diversity was significantly lower in the CLAD lungs than at transplantation. Bacterial diversity tended to decrease according to the severity of the CLAD. Aerococcus, Caldiericum, Croceibacter, Leptolyngbya, and Pulveribacter genera were uniquely identified in CLAD, whereas no taxa were identified in lungs at transplantation. In particular, six taxa, including Croceibacter atlanticus, Caldiserium exile, Dolichospermum compactum, Stappia sp. ES.058, Kinetoplastibacterium sorsogonicusi, and Pulveribacter suum were uniquely detected in CLAD. Among immune cells, CD8+ T cells were significantly increased, while neutrophils were decreased in the CLAD lung. In conclusion, unique changes in lung microbiome and immune cell composition were confirmed in lung tissue after CLAD compared to at transplantation.

PMID:38399691 | DOI:10.3390/microorganisms12020287

Life (Basel). 2024 Feb 6;14(2):229. doi: 10.3390/life14020229.

ABSTRACT

Interstitial lung diseases comprise a heterogenous range of diffuse lung disorders, potentially resulting in pulmonary fibrosis. While idiopathic pulmonary fibrosis has been recognized as the paradigm of a progressive fibrosing interstitial lung disease, other conditions with a progressive fibrosing phenotype characterized by a significant deterioration of the lung function may lead to a burden of significant symptoms, a reduced quality of life, and increased mortality, despite treatment. There is now evidence indicating that some common underlying biological mechanisms can be shared among different chronic fibrosing disorders; therefore, different biomarkers for disease-activity monitoring and prognostic assessment are under evaluation. Thus, understanding the common pathways that induce the progression of pulmonary fibrosis, comprehending the diversity of these diseases, and identifying new molecular markers and potential therapeutic targets remain highly crucial assignments. The purpose of this review is to examine the main pathological mechanisms regulating the progression of fibrosis in interstitial lung diseases and to provide an overview of potential biomarker and therapeutic options for patients with progressive pulmonary fibrosis.

PMID:38398739 | DOI:10.3390/life14020229

J Clin Med. 2024 Feb 19;13(4):1160. doi: 10.3390/jcm13041160.

ABSTRACT

Background: We have previously reported that endothelial-to-mesenchymal transition (EndMT) is an active process in patients with idiopathic pulmonary fibrosis (IPF) contributing to arterial remodelling. Here, we aim to quantify drivers of EndMT in IPF patients compared to normal controls (NCs). Methods: Lung resections from thirteen IPF patients and eleven NCs were immunohistochemically stained for EndMT drivers, including TGF-β1, pSmad-2/3, Smad-7, and β-catenin. Intima, media, and adventitia were analysed for expression of each EndMT driver in pulmonary arteries. Computer- and microscope-assisted Image ProPlus7.0 image analysis software was used for quantifications. Results: Significant TGF-β1, pSmad-2/3, Smad-7, and β-catenin expression was apparent across all arterial sizes in IPF (p < 0.05). Intimal TGF-β1, pSmad-2/3, Smad-7, and β-catenin were augmented in the arterial range of 100-1000 μm (p < 0.001) compared to NC. Intimal TGF-β1 and β-catenin percentage expression showed a strong correlation with the percentage expression of intimal vimentin (r' = 0.54, p = 0.05 and r' = 0.61, p = 0.02, respectively) and intimal N-cadherin (r' = 0.62, p = 0.03 and r' = 0.70, p = 0.001, respectively). Intimal TGF-β1 and β-catenin expression were significantly correlated with increased intimal thickness as well (r' = 0.52, p = 0.04; r' = 0.052, p = 0.04, respectively). Moreover, intimal TGF-β1 expression was also significantly associated with increased intimal elastin deposition (r' = 0.79, p = 0.002). Furthermore, total TGF-β1 expression significantly impacted the percentage of DLCO (r' = -0.61, p = 0.03). Conclusions: This is the first study to illustrate the involvement of active TGF-β/Smad-2/3-dependent and β-catenin-dependent Wnt signalling pathways in driving EndMT and resultant pulmonary arterial remodelling in patients with IPF. EndMT is a potential therapeutic target for vascular remodelling and fibrosis in general in patients with IPF.

PMID:38398472 | DOI:10.3390/jcm13041160

Biomedicines. 2024 Feb 8;12(2):402. doi: 10.3390/biomedicines12020402.

ABSTRACT

Mucin-1 is a multi-functional glycoprotein expressed by type II alveolocytes and may be detectable in the circulation following pulmonary fibrosis. The prognostic utility of baseline pre-treatment blood levels of mucin-1 in patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotics has not yet been fully established. We retrospectively studied a cohort of patients (from two hospitals) with IPF who were receiving pirfenidone for >12 weeks. Baseline blood mucin-1 levels were measured via sandwich enzyme-linked immunosorbent assays. We investigated the performance of mucin-1 levels in longitudinally predicting the risks of acute exacerbation of IPF (AE-IPF) and severe adverse outcomes (SAO), including lung transplantation and death. Seventy patients were included; 20 developed AE-IPF; and 31 had SAO during the follow-up period. Patients with baseline mucin-1 levels ≥2.5 ng/mL had enhanced risks of AE-IPF (adjusted hazard ratio [aHR], 14.07; 95% confidence interval [CI], 4.26-46.49) and SAO within 2 years (aHR, 7.87; 95% CI, 2.86-21.70) and anytime during the follow-up (aHR, 4.68; 95% CI, 2.11-10.39). The risks increased across subgroups with increasing mucin-1 levels. Patients in the "mucin-1 ≥ 2.5" group also exhibited an accelerated decline in DLCO. This study supports baseline blood mucin-1 levels as a biomarker for IPF that predicts adverse outcomes during pirfenidone treatment.

PMID:38398004 | DOI:10.3390/biomedicines12020402

Biomed Pharmacother. 2024 Feb 22;173:116298. doi: 10.1016/j.biopha.2024.116298. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease; its cause is unknown, and it leads to notable health problems. Currently, only two drugs are recommended for IPF treatment. Although these drugs can mitigate lung function decline, neither can improve nor stabilize IPF or the symptoms perceived by patients. Therefore, the development of novel treatment options for pulmonary fibrosis is required. The present study investigated the effects of a novel compound, caffeic acid ethanolamide (CAEA), on human pulmonary fibroblasts and evaluated its potential to mitigate bleomycin-induced pulmonary fibrosis in mice. CAEA inhibited TGF-β-induced α-SMA and collagen expression in human pulmonary fibroblasts, indicating that CAEA prevents fibroblasts from differentiating into myofibroblasts following TGF-β exposure. In animal studies, CAEA treatment efficiently suppressed immune cell infiltration and the elevation of TNF-α and IL-6 in bronchoalveolar lavage fluid in mice with bleomycin-induced pulmonary fibrosis. Additionally, CAEA exerted antioxidant effects by recovering the enzymatic activities of oxidant scavengers. CAEA directly inhibited activation of TGF-β receptors and protected against bleomycin-induced pulmonary fibrosis through inhibition of the TGF-β/SMAD/CTGF signaling pathway. The protective effect of CAEA was comparable to that of pirfenidone, a clinically available drug. Our findings support the potential of CAEA as a viable method for preventing the progression of pulmonary fibrosis.

PMID:38394850 | DOI:10.1016/j.biopha.2024.116298

Stem Cells Int. 2024 Feb 15;2024:3429565. doi: 10.1155/2024/3429565. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related lung interstitial disease that occurs predominantly in people over 65 years of age and for which there is a lack of effective therapeutic agents. It has demonstrated that mesenchymal stem cells (MSCs) including alveolar epithelial cells (AECs) can perform repair functions. However, MSCs lose their repair functions due to their distinctive aging characteristics, eventually leading to the progression of IPF. Recent breakthroughs have revealed that the degree of autophagic activity influences the renewal and aging of MSCs and determines the prognosis of IPF. Autophagy is a lysosome-dependent pathway that mediates the degradation and recycling of intracellular material and is an efficient way to renew the nonnuclear (cytoplasmic) part of eukaryotic cells, which is essential for maintaining cellular homeostasis and is a potential target for regulating MSCs function. Therefore, this review focuses on the changes in autophagic activity of MSCs, clarifies the relationship between autophagy and health status of MSCs and the effect of autophagic activity on MSCs senescence and IPF, providing a theoretical basis for promoting the clinical application of MSCs.

PMID:38390035 | PMC:PMC10883747 | DOI:10.1155/2024/3429565

Cureus. 2024 Jan 23;16(1):e52793. doi: 10.7759/cureus.52793. eCollection 2024 Jan.

ABSTRACT

This comprehensive review examines the diagnostic potential of bronchoalveolar lavage (BAL) in interstitial lung disease (ILD), emphasizing its accuracy and significance in various ILDs, including idiopathic pulmonary fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis, and connective tissue disease-associated ILD. The analysis underscores the importance of abnormalities in both cellular and non-cellular components of BAL fluid for precise ILD diagnosis. Recommendations advocate for the integration of BAL into clinical guidelines, a multidisciplinary diagnostic approach, and further standardization of procedures. Looking toward the future, ongoing research highlights technological advancements, biomarker discovery, and the integration of artificial intelligence in BAL interpretation. These developments not only promise to enhance ILD diagnosis but also offer prospects for a more personalized approach to patient management based on insightful patient stratification guided by BAL findings. This abstract encapsulates the key findings, recommendations, and future prospects identified in the review, providing a concise overview of the diagnostic potential of BAL in ILD.

PMID:38389607 | PMC:PMC10882258 | DOI:10.7759/cureus.52793

Respirol Case Rep. 2024 Feb 21;12(2):e01301. doi: 10.1002/rcr2.1301. eCollection 2024 Feb.

ABSTRACT

Forced vital capacity has been utilized as a parameter of disease progression in idiopathic pulmonary fibrosis (IPF); however, its measurement is difficult when patients do not understand or cooperate. Dynamic digital radiography (DDR) enables sequential chest X-ray imaging during breathing, with lower radiation doses compared to conventional fluoroscopy or computed tomography. There is accumulating evidence showing that parameters obtained from DDR, particularly those related to diaphragmatic dynamics, are correlated with pulmonary function parameters, and are useful for pathophysiological evaluation. We herein present two cases that suggest parameters obtained from DDR during supine normal tidal breathing may predict disease progression of IPF.

PMID:38384743 | PMC:PMC10880408 | DOI:10.1002/rcr2.1301

Front Med (Lausanne). 2024 Feb 7;11:1335758. doi: 10.3389/fmed.2024.1335758. eCollection 2024.

ABSTRACT

OBJECTIVE: This study aimed to identify clinical characteristics associated with the prevalence of progressive pulmonary fibrosis (PPF) in interstitial lung disease (ILD) and to develop a prognostic nomogram model for clinical use.

METHODS: In this single-centered, retrospective study, we enrolled ILD patients with relatively comprehensive clinical data and assessed the incidence of PPF within a year using collected demographics, laboratory data, high-resolution computed tomography (HRCT), and pulmonary function test (PFT) results. We used a training cohort of ILD patients to identify early predictors of PPF and then validated them in an internal validation cohort and subsets of ILD patients using a multivariable logistic regression analysis. A prognostic nomogram was formulated based on these predictors, and the accuracy and efficiency were evaluated using the area under the receiver operating characteristic curve (AUC), calibration plot, and decision curve analysis (DCA).

RESULTS: Among the enrolled patients, 120 (39.09%) cases had connective tissue disease-associated interstitial lung disease (CTD-ILD), 115 (37.46%) had non-idiopathic pulmonary fibrosis idiopathic interstitial pneumonia (non-IPF IIP), and 35 (11.4%) had hypersensitivity pneumonitis (HP). Overall, 118 (38.4%) cases experienced pulmonary fibrosis progression. We found that baseline DLco% pred (OR 0.92; 95% CI, 8.93-0.95) was a protective factor for ILD progression, whereas combined pneumonia (OR 4.57; 95% CI, 1.24-18.43), modified Medical Research Council dyspnea score (mMRC) (OR 4.9; 95% CI, 2.8-9.5), and high-resolution computed tomography (HRCT) score (OR 1.22; 95% CI, 1.07-1.42) were independent risk factors for PPF. The AUC of the proposed nomogram in the development cohort was 0.96 (95% CI, 0.94, 0.98), and the calibration plot showed good agreement between the predicted and observed incidence of PPF (Hosmer-Lemeshow test: P = 0.86).

CONCLUSION: ILD patients with combined pneumonia, low baseline DLco% pred, high mMRC marks, and high HRCT scores were at higher risk of progression. This nomogram demonstrated good discrimination and calibration, indicating its potential utility for clinical practice.

PMID:38384414 | PMC:PMC10879408 | DOI:10.3389/fmed.2024.1335758

Front Pharmacol. 2024 Feb 7;15:1309712. doi: 10.3389/fphar.2024.1309712. eCollection 2024.

ABSTRACT

Background: A growing population of individuals diagnosed with idiopathic pulmonary fibrosis (IPF) are receiving treatment with nintedanib and pirfenidone. The aim of our study was to assess the incidence of drug-induced liver injury (DILI) associated with the use of pirfenidone and nintedanib in patients with IPF in Taiwan. Methods: We collected a cohort of adult patients diagnosed with IPF between 2017 and 2020. The research outcomes involved assessing the incidence of DILI in patients treated with nintedanib or pirfenidone. Poisson regression analysis was employed to estimate incidence rates, with and without adjustments for covariates, to calculate and present both unadjusted and adjusted incidence rate ratios (IRRs). Results: The risk of DILI was greater in patients who received nintedanib than in those who received pirfenidone during the 1-year follow-up. Patients treated with nintedanib exhibited a heightened risk of DILI based on inpatient diagnoses using specific codes after adjusting for variables such as gender, age group, comorbidities and concomitant medications, with an adjusted incidence rate ratio (aIRR) of 3.62 (95% confidence interval (CI) 1.11-11.78). Similarly, the risk of DILI was elevated in patients treated with nintedanib according to a per-protocol Poisson regression analysis of outcomes identified from inpatient diagnoses using specific codes. This was observed after adjusting for variables including gender, age group, comorbidities, and concomitant medications, with an aIRR of 3.60 (95% CI 1.11-11.72). Conclusion: Data from postmarketing surveillance in Taiwan indicate that patients who received nintedanib have a greater risk of DILI than do those who received pirfenidone.

PMID:38384288 | PMC:PMC10879927 | DOI:10.3389/fphar.2024.1309712