J Clin Med. 2024 May 17;13(10):2956. doi: 10.3390/jcm13102956.

ABSTRACT

Background: High-flow nasal cannula (HFNC) therapy has emerged as a promising treatment modality for interstitial lung disease (ILD)-related respiratory failure. This systematic review aims to evaluate the efficacy and safety of HFNC therapy in patients with ILDs. Methods: A comprehensive literature search was conducted using major electronic databases to identify relevant studies investigating the use of HFNC therapy in ILD patients with respiratory failure. Outcome measures of interest included improvements in oxygenation, dyspnea relief, respiratory rate control, hospital length of stay, and mortality. Results: Twelve studies were analyzed with an overall population of 715 patients included. Idiopathic Pulmonary Fibrosis (IPF) was the most prevalent type of ILD. Evaluated clinical settings were acute (7 studies), chronic (2 studies), and end-stage (3 studies) ILDs. The HFNC as a support for acute respiratory failure seems not inferior to non-invasive ventilation while offering better comfort and patient's perception. Poor data are available about use in chronic/long-term or rehabilitative settings. In end of life/palliative care, an HFNC might improve quality of life. Despite the promising results, further research is warranted to establish optimal HFNC protocols, identify patient subgroups most likely to benefit, and explore long-term outcomes. Conclusions: Overall, the HFNC appears to be a valuable therapeutic option for managing respiratory failure in ILD patients, offering potential improvements in oxygenation and symptom relief.

PMID:38792497 | DOI:10.3390/jcm13102956

J Clin Med. 2024 May 10;13(10):2825. doi: 10.3390/jcm13102825.

ABSTRACT

Background: There are only a few reports on the nutritional status and mortality of patients with idiopathic pulmonary fibrosis (IPF). As such, this study aims to investigate the relationship between controlling nutritional status (CONUT) and the mortality of elderly patients with IPF. Methods: A total of 170 IPF patients aged ≥65 years old who visited the rehabilitation department of our hospital between July 2014 and July 2021 (mean age: 75.7 ± 6.3 years, sex (male/female): 138/32, %FVC: 78.3 ± 18.3%) were retrospectively analyzed. The Kaplan-Meier method and log-rank test were applied. Furthermore, using a Cox proportional hazards model with multivariate analysis, we analyzed the relationship between all-cause mortality and baseline characteristics including CONUT. Results: Based on the CONUT score, the normal group included 101 cases, the mild group included 58 cases, the moderate group included 11 cases, and the severe group had 0 cases. There were 49 cases of all-cause mortality events, suggesting that the mortality of the moderate group was significantly poorer than that of the normal and mild groups (p < 0.05). Furthermore, multivariate analysis identified GAP stage (HR: 5.972, 95%CI: 2.901~12.291, p < 0.0001), mMRC scale (HR: 0.615, 95%CI: 0.389~0.971, p = 0.009), and CONUT (HR: 2.012, 95%CI: 1.192~3.395, p = 0.037) as factors significantly influencing mortality. Conclusions: Severe malnutrition was not observed in elderly patients with IPF. Moderate malnutrition was associated with a significantly higher risk of all-cause mortality, suggesting that CONUT is an important indicator for predicting mortality.

PMID:38792367 | DOI:10.3390/jcm13102825

Biomedicines. 2024 May 16;12(5):1108. doi: 10.3390/biomedicines12051108.

ABSTRACT

Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75-1.51] ng/mL versus 0.81 [0.65-0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80-1.72] ng/mL versus 0.99 [0.66-1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes.

PMID:38791069 | DOI:10.3390/biomedicines12051108

Biomedicines. 2024 May 9;12(5):1047. doi: 10.3390/biomedicines12051047.

ABSTRACT

Different factors, not limited to the lung, influence the progression of ILDs. A "treatable trait" strategy was recently proposed for ILD patients as a precision model of care to improve outcomes. However, no data have been published so far on the prevalence of TTs in ILD. A prospective, observational, cohort study was conducted within the ILD Program at the IRCCS Humanitas Research Hospital (Milan, Italy) between November 2021 and November 2023. TTs were selected according to recent literature and assigned during multidisciplinary discussion (MDD) to one of the following categories: pulmonary, etiological, comorbidities, and lifestyle. Patients were further divided into four groups according to their post-MDD diagnosis: idiopathic ILD, sarcoidosis, connective tissue disease-ILD, and other ILD. The primary study outcome was the prevalence of each TT in the study population. A total of 116 patients with ILD [63.9% male; median (IQR) age: 69 (54-78) years] were included in the study. All the TTs identified in the literature were found in our cohort, except for intractable chronic cough. We also recognized differences in TTs across the ILD groups, with less TTs in patients with sarcoidosis. This analysis provides the first ancillary characterization of TTs in ILD patients in a real setting to date.

PMID:38791009 | DOI:10.3390/biomedicines12051047

Sci Rep. 2024 May 24;14(1):11921. doi: 10.1038/s41598-024-62572-4.

ABSTRACT

Association between body mass index (BMI) and prognosis in patients with idiopathic pulmonary fibrosis (IPF) remains uncertain. We investigated the association between BMI and clinical outcomes in patients with IPF using national health claims data. The study included 11,826 patients with IPF and rare incurable disease exemption codes (mean age: 68.9 years, male: 73.8%) and available BMI data who visited medical institutions between January 2002 and December 2018. Multivariable Cox proportional hazard models were used to evaluate the association of BMI with all-cause mortality and hospitalization. Based on BMI, 3.1%, 32.8%, 27.8%, and 36.4% were classified as underweight, normal, overweight, and obese, respectively. Multivariable analysis showed independent associations of overweight (hazard ratio [HR] 0.856, 95% confidence interval [CI] 0.801-0.916) and underweight (HR 1.538, 95% CI 1.347-1.757) with mortality in patients with IPF. Similarly, overweight (HR 0.887, 95% CI 0.834-0.943) and underweight (HR 1.265, 95% CI 1.104-1.449) were also associated with hospitalization in patients with IPF in the multivariable analysis. Spline HR curve analysis adjusted for all covariates revealed a non-linear relationship between BMI and mortality in patients with IPF. Our data suggest that BMI is associated with clinical outcomes in patients with IPF.

PMID:38789476 | DOI:10.1038/s41598-024-62572-4

Eur J Intern Med. 2024 May 23:S0953-6205(24)00229-2. doi: 10.1016/j.ejim.2024.05.024. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease; most patients die in hospitals because palliative care (PC) is not wildly and early available. We aimed to determine the impact of an early PC program in IPF patients on place of death, emergency department (ED) admission, unplanned medical visits and survival before and after its implementation at our clinic.

METHODS: IPF patients from our ILD clinic who died between January 1st, 2018 and December 31th, 2023 were included in the analysis. Primary outcomes were location of death, number of ED access and unplanned medical visits; secondary outcomes was survival from diagnosis.

RESULTS: A total of 46 decedents between 2018 and 2023 were analysed: (median age 71,5 ± 5,5 years, 89 % male): 26 died before the implementation of the early PC program and 20 after. Through χ2 test, location of death resulted significantly different in the two groups, showing the capacity of early PC to favor at home or in hospice death (p = 0,02); similarly, the number of unplanned visits was significantly lower (p = 0,03). Finally, survival was significantly lower in patients not receiving the early PC program (p = 0,01).

CONCLUSION: The availability of an early PC program since the diagnosis significantly reduced both the death rate in hospital settings, favoring dying in hospice or at home, and the number of unplanned medical visits. Furthermore, IPF patients receiving early PC showed a longer survival than those who did not.

PMID:38789287 | DOI:10.1016/j.ejim.2024.05.024

Int Immunopharmacol. 2024 May 23;135:112322. doi: 10.1016/j.intimp.2024.112322. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive respiratory disorder characterized by poor prognosis, often presenting with acute exacerbation. The primary cause of death associated with IPF is acute exacerbation of IPF (AE-IPF). However, the pathophysiology of acute exacerbation has not been clearly elucidated yet. This study aims to investigate the underlying pathophysiological molecular mechanism in a mouse AE-PF model. C57BL/6J mice were intratracheally administered bleomycin (BLM, 5 mg/kg) to induce pulmonary fibrosis. After 14 days, lipopolysaccharide (LPS, 2 mg/kg) was injected via the trachea route. Histological assessments, including H&E and Masson staining, as well as inflammatory indicators, were included to evaluate the induction of AE-PF by BLM and LPS in mice. Transcriptomic profiling of pulmonary tissues identified CSF3 as one of the top 10 upregulated DEGs in AE-PF mice. Indeed, administration of exogenous CSF3 protein exacerbated AE-PF in mice. Mechanistically, CSF3 disrupted alveolar epithelial barrier integrity and permeability by regulating specialized cell adhesion complexes such as tight junctions (TJs) and adherens junctions (AJs) via PI3K/p-Akt/Snail pathway, contributing to the aggravation of AE-PF in mice. Moreover, the discovery of elevated sera CSF3 indicated a notable increase in IPF patients during the exacerbation of the disease. Pearson correlation analysis in IPF patients revealed significant positive associations between CSF3 levels and KL-6 levels, LDH levels, CRP levels, respectively. These results provide mechanistic insights into the role of CSF3 in exacerbating of lung fibrotic disease and indicate monitoring CSF3 levels may aid in early clinical decisions for alternative therapy in the management of rapidly progressing IPF.

PMID:38788452 | DOI:10.1016/j.intimp.2024.112322

Chron Respir Dis. 2024 Jan-Dec;21:14799731241258216. doi: 10.1177/14799731241258216.

ABSTRACT

OBJECTIVES: Pulmonary Rehabilitation (PR) is a high-impact intervention for individuals with idiopathic pulmonary fibrosis (IPF) but access is limited in India. PR barriers include distance to travel, lack of service provision and lack of healthcare professionals to deliver PR, thus it is disproportionate to the immense burden of IPF in India. We explored the lived experiences of people living with IPF, family caregivers (CGs) and healthcare workers (HCWs) as well as their views towards home-based PR (HBPR) in Delhi, India.

METHODS: A qualitative study using semi-structured interviews with individuals with IPF (n = 20), CGs (n = 10) and HCWs (n = 10) was conducted. Data were analysed using codebook thematic analysis.

RESULTS: Three major themes were generated: (i) Health impact, which included pathophysiological changes, range of symptoms experienced, disease consequences and impact of comorbidities; (ii) Disease management, which described strategies to control the progression and overall management of IPF, such as medications and exercises; (iii) Mode of Pulmonary Rehabilitation, which described perceptions regarding HBPR, comparisons with centre-based programmes, and how HBPR may fit as part of a menu of PR delivery options.

CONCLUSION: People living with IPF, family caregivers and healthcare workers were positive about the potential implementation of HBPR and suggested the development of a paper-based manual to facilitate HBPR over digital/online approaches. The content of HBPR should be sensitive to the additional impact of non-IPF health issues and challenges of reduced interactions with healthcare professionals.

PMID:38787595 | DOI:10.1177/14799731241258216

Front Med (Lausanne). 2024 May 9;11:1363643. doi: 10.3389/fmed.2024.1363643. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown etiology with a poor prognosis, characterized by a lack of effective diagnostic and therapeutic interventions. The role of immunity in the pathogenesis of IPF is significant, yet remains inadequately understood. This study aimed to identify potential key genes in IPF and their relationship with immune cells by integrated bioinformatics analysis and verify by in vivo and in vitro experiments.

METHODS: Gene microarray data were obtained from the Gene Expression Omnibus (GEO) for differential expression analysis. The differentially expressed genes (DEGs) were identified and subjected to functional enrichment analysis. By utilizing a combination of three machine learning algorithms, specific genes associated with idiopathic pulmonary fibrosis (IPF) were pinpointed. Then their diagnostic significance and potential co-regulators were elucidated. We further analyzed the correlation between key genes and immune infiltrating cells via single-sample gene set enrichment analysis (ssGSEA). Subsequently, a single-cell RNA sequencing data (scRNA-seq) was used to explore which cell types expressed key genes in IPF samples. Finally, a series of in vivo and in vitro experiments were conducted to validate the expression of candidate genes by western blot (WB), quantitative real-time PCR (qRT-PCR), and immunohistochemistry (IHC) analysis.

RESULTS: A total of 647 DEGs of IPF were identified based on two datasets, including 225 downregulated genes and 422 upregulated genes. They are closely related to biological functions such as cell migration, structural organization, immune cell chemotaxis, and extracellular matrix. CFH and FHL2 were identified as key genes with diagnostic accuracy for IPF by three machine learning algorithms. Analysis using ssGSEA revealed a significant association of both CFH and FHL2 with diverse immune cells, such as B cells and NK cells. Further scRNA-seq analysis indicated CFH and FHL2 were specifically upregulated in human IPF tissues, which was confirmed by in vitro and in vivo experiments.

CONCLUSION: In this study, CFH and FHL2 have been identified as novel potential biomarkers for IPF, with potential diagnostic utility in future clinical applications. Subsequent investigations into the functions of these genes in IPF and their interactions with immune cells may enhance comprehension of the disease's pathogenesis and facilitate the identification of therapeutic targets.

PMID:38784225 | PMC:PMC11111937 | DOI:10.3389/fmed.2024.1363643

BMC Pulm Med. 2024 May 23;24(1):254. doi: 10.1186/s12890-024-03021-w.

ABSTRACT

BACKGROUND: Mortality prediction in interstitial lung disease (ILD) poses a significant challenge to clinicians due to heterogeneity across disease subtypes. Currently, forced vital capacity (FVC) and Gender, Age, and Physiology (GAP) score are the two most utilized metrics in prognostication. Recently, a machine learning classifier system, Fibresolve, designed to identify a variety of computed tomography (CT) patterns associated with idiopathic pulmonary fibrosis (IPF), was demonstrated to have a significant association with mortality across multiple subtypes of ILD. The purpose of this follow-up study was to retrospectively validate these findings in a large, external cohort of patients with ILD.

METHODS: In this multi-center validation study, Fibresolve was applied to chest CT scans of patients with confirmed ILD that had available follow-up data. Fibresolve scores categorized by tertile were analyzed using Cox regression analysis adjusted for tobacco use and modified GAP (mGAP) score.

RESULTS: Of 643 patients included, 446 (69.3%) died over a median follow-up time of 144 [1-821] weeks. The median [range] mGAP score was 5 [3-7]. In multivariable analysis, Fibresolve score categorized by tertile was significantly associated with mortality (Tertile 2 HR 1.47, 95% CI 0.82-2.37, p = 0.11; Tertile 3 HR 3.12, 95% CI 1.98-4.90, p < 0.001). Subgroup analyses revealed significant associations amongst those with non-IPF ILDs (Tertile 2 HR 1.95, 95% CI 1.28-2.97, Tertile 3 HR 4.66, 95% CI 2.94-7.38) and severe disease, defined by a FVC ≤ 75% (Tertile 2 HR 2.29, 95% CI 1.43-3.67, Tertile 3 HR 4.80, 95% CI 2.93-7.86).

CONCLUSIONS: Fibresolve is independently associated with mortality in ILD, particularly amongst patients with non-IPF ILDs and in those with severe disease.

PMID:38783245 | DOI:10.1186/s12890-024-03021-w

Respir Res. 2024 May 23;25(1):217. doi: 10.1186/s12931-024-02848-5.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic interstitial lung disease characterized by progressive dyspnea and decreased lung function, yet its exact etiology remains unclear. It is of great significance to discover new drug targets for IPF.

METHODS: We obtained the cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium as exposure and the genome wide association study (GWAS) of IPF from the International IPF Genetics Consortium as outcomes to simulate the effects of drugs on IPF by employing mendelian randomization analysis. Then colocalization analysis was performed to calculate the probability of both cis-eQTL of druggable genes and IPF sharing a causal variant. For further validation, we conducted protein quantitative trait locus (pQTL) analysis to reaffirm our findings.

RESULTS: The expression of 45 druggable genes was significantly associated with IPF susceptibility at FDR < 0.05. The expression of 23 and 15 druggable genes was significantly associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLco) in IPF patients, respectively. IPF susceptibility and two significant genes (IL-7 and ABCB2) were likely to share a causal variant. The results of the pQTL analysis demonstrated that high levels of IL-7 in plasma are associated with a reduced risk of IPF (OR = 0.67, 95%CI: 0.47-0.97).

CONCLUSION: IL-7 stands out as the most promising potential drug target to mitigate the risk of IPF. Our study not only sheds light on potential drug targets but also provides a direction for future drug development in IPF.

PMID:38783236 | DOI:10.1186/s12931-024-02848-5

BMC Pulm Med. 2024 May 23;24(1):255. doi: 10.1186/s12890-024-03064-z.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive disease presenting with symptoms like dyspnoea, dry cough, and fatigue, which affect physical function and quality of life. No earlier qualitative studies have investigated physical activity in IPF. This study aims to explore experiences of living with IPF in relation to physical activity.

MATERIALS AND METHODS: Qualitative interviews were conducted with 14 participants living with IPF. The participants were 77 years old (range: 56-86) and diagnosed with IPF between 2 and 9 years ago. The analysis was performed by qualitative content analysis according to Graneheim and Lundman.

RESULTS: The results indicated that life and one's ability to be physically active is affected by IPF. Despite this, it seems possible to navigate past obstacles, which was illustrated by an overall theme: "My life is constrained, but I am hanging on". Two major categories cover topics of IPF being a life changing diagnosis with changes in self-image and changed future plans regarding physical activity, as well as life. Physical activity was perceived to be challenging, yet in many ways used as a strategy, developed to manage life.

CONCLUSIONS: IPF affects physical activity as well as life, from onset onwards. By developing strategies for facilitating physical activity as well as identifying barriers, it seems possible to maintain an active life despite the disease. The healthcare system needs to create support systems that meet different needs during different phases of the disease.

TRIAL REGISTRATION: "FoU in Sweden" Research and Development in Sweden (id: 227081).

PMID:38783207 | DOI:10.1186/s12890-024-03064-z

Int Immunopharmacol. 2024 May 22;135:112269. doi: 10.1016/j.intimp.2024.112269. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) presents a challenging progression characterized by lung tissue scarring and abnormal extracellular matrix deposition. This review examines the influence of immune responses, emphasizing their complex role in initiating and perpetuating fibrosis. It highlights how metabolic pathways modulate immune cell function during IPF. Immune cell modulation holds promise in managing pulmonary fibrosis (PF). Inhibiting neutrophil recruitment and monitoring mast cell levels offer insights into PF progression. Low-dose IL-2 therapy and regulation of fibroblast recruitment present potential therapeutic avenues, while the role of innate lymphoid cells (ILC2s) in allergic lung inflammation sheds light on disease mechanisms. The review focuses on metabolic reprogramming's role in shaping immune cell function during IPF progression. While some immune cells use glycolysis for pro-inflammatory responses, others favor fatty acid oxidation for regulatory functions. Targeting specialized pro-resolving lipid mediators (SPMs) presents significant potential for managing fibrotic disorders. Additionally, it highlights the pivotal role of amino acid metabolism in synthesizing serine and glycine as crucial regulators of collagen production and exploring the interconnectedness of lipid metabolism, mitochondrial dysfunction, and adipokines in driving fibrotic processes. Moreover, the review discusses the impact of metabolic disorders such as obesity and diabetes on lung fibrosis. Advocating for a holistic approach, it emphasizes the importance of considering this interplay between immune cell function and metabolic pathways in developing effective and personalized treatments for IPF.

PMID:38781610 | DOI:10.1016/j.intimp.2024.112269

Br J Radiol. 2024 May 23:tqae108. doi: 10.1093/bjr/tqae108. Online ahead of print.

ABSTRACT

The licensing of antifibrotic therapy for fibrotic lung diseases, including idiopathic pulmonary fibrosis IPF has created an urgent need for reliable biomarkers to predict disease progression and treatment response. Some patients experience stable disease trajectories, while others deteriorate rapidly, making treatment decisions challenging. High-resolution chest CT has become crucial for diagnosis, but visual assessments by radiologists suffer from low reproducibility and high interobserver variability. To address these issues, computer-based image analysis, called quantitative CT, has emerged. However, many quantitative CT methods rely on human input for training, therefore potentially incorporating human error into computer training. Rapid advances in artificial intelligence, specifically deep learning, aim to overcome this limitation by enabling autonomous quantitative analysis. While promising, deep learning also presents challenges including the need to minimize algorithm biases, ensuring explainability, and addressing accessibility and ethical concerns. This review explores the development and application of deep learning in improving the imaging process for fibrotic lung disease.

PMID:38781513 | DOI:10.1093/bjr/tqae108

J Eur Acad Dermatol Venereol. 2024 May 23. doi: 10.1111/jdv.19935. Online ahead of print.

ABSTRACT

The interleukin (IL)-1 superfamily upregulates immune responses and maintains homeostasis between the innate and adaptive immune systems. Within the IL-1 superfamily, IL-36 plays a pivotal role in both innate and adaptive immune responses. Of the four IL-36 isoforms, three have agonist activity (IL-36α, IL-36β, IL-36γ) and the fourth has antagonist activity (IL-36 receptor antagonist [IL-36Ra]). All IL-36 isoforms bind to the IL-36 receptor (IL-36R). Binding of IL-36α/β/γ to the IL-36R recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates downstream signalling pathways mediated by nuclear transcription factor kappa B and mitogen-activated protein kinase signalling pathways. Antagonist binding of IL-36Ra to IL-36R inhibits recruitment of IL-1RAcP, blocking downstream signalling pathways. Changes in the balance within the IL-36 cytokine family can lead to uncontrolled inflammatory responses throughout the body. As such, IL-36 has been implicated in numerous inflammatory diseases, notably a type of pustular psoriasis called generalized pustular psoriasis (GPP), a chronic, rare, potentially life-threatening, multisystemic skin disease characterised by recurrent fever and extensive sterile pustules. In GPP, IL-36 is central to disease pathogenesis, and the prevention of IL-36-mediated signalling can improve clinical outcomes. In this review, we summarize the literature describing the biological functions of the IL-36 pathway. We also consider the evidence for uncontrolled activation of the IL-36 pathway in a wide range of skin (e.g., plaque psoriasis, pustular psoriasis, hidradenitis suppurativa, acne, Netherton syndrome, atopic dermatitis and pyoderma gangrenosum), lung (e.g., idiopathic pulmonary fibrosis), gut (e.g., intestinal fibrosis, inflammatory bowel disease and Hirschsprung's disease), kidney (e.g., renal tubulointerstitial lesions) and infectious diseases caused by a variety of pathogens (e.g., COVID-19; Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pneumoniae infections), as well as in cancer. We also consider how targeting the IL-36 signalling pathway could be used in treating inflammatory disease states.

PMID:38779986 | DOI:10.1111/jdv.19935

Am J Pathol. 2024 May 20:S0002-9440(24)00176-7. doi: 10.1016/j.ajpath.2024.04.008. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, is characterized by fibroblast activation and aberrant extracellular matrix (ECM) accumulation. Effective therapeutic development is limited due to incomplete understanding of the mechanisms by which fibroblasts become aberrantly activated. Here we show acetaldehyde dehydrogenase 2 (ALDH2) in fibroblasts as a potential therapeutic target for pulmonary fibrosis. A decrease in ALDH2 expression was observed in IPF patients and bleomycin-treated mice. ALDH2 deficiency spontaneously induces collagen accumulation in the lungs of aged mice. Furthermore, Young ALDH2 knockout mice exhibited exacerbated bleomycin-induced pulmonary fibrosis and increased mortality compared with that in control mice. Mechanistic studies revealed that transforming growth factor (TGF)-β1 induction and ALDH2 depletion constitute a positive feedback loop that exacerbates fibroblast activation. TGF-β1 downregulated ALDH2 through a TGF-β receptor 1/Smad3-dependent mechanism. The subsequent deficiency in ALDH2 resulted in fibroblast dysfunction that manifested as impaired mitochondrial autophagy and senescence, leading to fibroblast activation and ECM production. ALDH2 overexpression markedly suppressed fibroblast activation and this effect was abrogated by PTEN-induced putative kinase 1 (PINK1) knockdown, indicating that the pro-fibrotic effects of ALDH2 are PINK1-dependent. Furthermore, Alda-1-induced ALDH2 activation reversed the established pulmonary fibrosis in both young and aged mice. In conclusions, ALDH2 expression inhibits the pathogenesis of pulmonary fibrosis. Strategies to upregulate or activate ALDH2 expression could be potential therapies for pulmonary fibrosis.

PMID:38777148 | DOI:10.1016/j.ajpath.2024.04.008

J Pharm Pharmacol. 2024 May 22:rgae058. doi: 10.1093/jpp/rgae058. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aimed to reveal the anti-fibrotic effects of Botrychium ternatum (Thunb.) Sw. (BT) against idiopathic pulmonary fibrosis (IPF) and to preliminarily analyze its potential mechanism on bleomycin-induced IPF rats.

METHODS: The inhibition of fibrosis progression in vivo was assessed by histopathology combined with biochemical indicators. In addition, the metabolic regulatory mechanism was investigated using 1H-nuclear magnetic resonance-based metabolomics combined with multivariate statistical analysis.

KEY FINDINGS: Firstly, biochemical analysis revealed that BT notably suppressed the expression of hydroxyproline and transforming growth factor-β1 in the pulmonary tissue. Secondly, Masson's trichrome staining and hematoxylin and eosin showed that BT substantially improved the structure of the damaged lung and significantly inhibited the proliferation of collagen fibers and the deposition of extracellular matrix. Finally, serum metabolomic analysis suggested that BT may exert anti-fibrotic effects by synergistically regulating tyrosine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; and synthesis and degradation of ketone bodies.

CONCLUSIONS: Our study not only clarifies the potential anti-fibrotic mechanism of BT against IPF at the metabolic level but also provides a theoretical basis for developing BT as an effective anti-fibrotic agent.

PMID:38776436 | DOI:10.1093/jpp/rgae058

Phytother Res. 2024 May 22. doi: 10.1002/ptr.8221. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis treatments are limited, often with severe side effects, highlighting the need for novel options. Taraxerone has diverse biomedical properties, but its mechanism remains unclear. This study investigates taraxerone's impact and the mechanisms involved in bleomycin-induced pulmonary fibrosis in mice. After establishing a pulmonary fibrosis mouse model, taraxerone was intraperitoneally injected continuously for 14-28 days. The in vivo antifibrotic and antioxidative stress effects of taraxerone were assessed. In vitro, the influence of taraxerone on transforming growth factor-β1-induced myofibroblast transformation and oxidative stress was investigated. Subsequently, quantitative polymerase chain reaction screened the histone deacetylase and Sirtuin family, and taraxerone's effects on SIRT1 were assessed. After SIRT1 siRNA treatment, changes in myofibroblast transformation and antioxidant capacity in response to taraxerone were observed. Acetylation and phosphorylation levels of Smad3 were evaluated. We also examined the binding levels of SIRT1 with Pho-Smad3 and Smad3, as well as the nuclear localization of Smad2/3. EX527 confirmed SIRT1's in vivo action in response to taraxerone. In vitro experiments suggested that taraxerone inhibited myofibroblast differentiation by activating SIRT1 and reducing oxidative stress. We also observed a new interaction between SIRT1 and the Smad complex. Taraxerone activates SIRT1, enabling it to bind directly to Smad3. This leads to reduced Smad complex phosphorylation and limited nuclear translocation. As a result, the transcription of fibrotic factors is reduced. In vivo validation confirms taraxerone's SIRT1-mediated antifibrotic effectiveness. This suggests that targeting SIRT1-mediated inhibition of myofibroblast differentiation could be a key strategy in taraxerone-based therapy for pulmonary fibrosis.

PMID:38776174 | DOI:10.1002/ptr.8221

Int J Med Sci. 2024 Apr 22;21(6):1079-1090. doi: 10.7150/ijms.93510. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic and progressively worsening lung disease that poses a significant threat to patient prognosis, with a mortality rate exceeding that of some common malignancies. Effective methods for early diagnosis and treatment remain for this condition are elusive. In our study, we used the GEO database to access second-generation sequencing data and associated clinical information from IPF patients. By utilizing bioinformatics techniques, we identified crucial disease-related genes and their biological functions, and characterized their expression patterns. Furthermore, we mapped out the immune landscape of IPF, which revealed potential roles for novel kinase 1 and CD8+T cells in disease progression and outcome. These findings can aid the development of new strategies for the clinical diagnosis and treatment of IPF.

PMID:38774751 | PMC:PMC11103402 | DOI:10.7150/ijms.93510

Arch Rheumatol. 2024 Feb 2;39(1):46-51. doi: 10.46497/ArchRheumatol.2024.10105. eCollection 2024 Mar.

ABSTRACT

OBJECTIVES: The aim of this study was to identify differences and similarities between connective tissue disease (CTD) patients with and without progressive pulmonary fibrosis (PPF) by applying the new guidelines.

PATIENTS AND METHODS: Patient characteristics and disease courses from medical records of 50 CTD-associated Interstitial lung disease (ILD) patients (33 females, 17 males; mean age: 60.1±12.9 years) were longitudinally studied between January 2018 and May 2022. Respiratory involvement in CTD patients was described, and differences in CTD patients who developed PPF compared to those who did not were identified by the 2022 ATS (American Thoracic Society)/ERS (European Respiratory Society)/JRS (Japanese Respiratory Society)/ALAT (Asociación Latinoamericana de Thórax) Guidelines on Idiopathic Pulmonary Fibrosis and Progressive Pulmonary Fibrosis in Adults.

RESULTS: In the majority (74%) of patients, CTD was diagnosed before ILD onset. Nonspecific interstitial pneumonia was the most common high resolution computer tomography pattern, followed by the usual interstitial pneumonia pattern. On pulmonary function test, 38% had a restrictive pattern at baseline. Patients without PPF tended to have worse lung function at baseline and increased macrophage count in bronchoalveolar lavage than patients with PPF.

CONCLUSION: In patients without PPF, disease progression may be missed, resulting in inadequate management. Interdisciplinary management of patients with CTD with the participation of pulmonologists and precise lung function diagnostics is recommended.

PMID:38774704 | PMC:PMC11104760 | DOI:10.46497/ArchRheumatol.2024.10105