PLoS One. 2024 Dec 3;19(12):e0314876. doi: 10.1371/journal.pone.0314876. eCollection 2024.

ABSTRACT

Fibrotic interstitial lung diseases (ILDs) result from excessive deposition of extracellular matrix (ECM) proteins in the lung, causing irreversible damage to the lung architecture. Clinical management of ILDs differs depending on the diagnosis, but differentiation between subtypes can be difficult and better clinical biomarkers are needed. In this study, we use a 166-gene NanoString assay to investigate whether there are ILD subtype-specific transcripts in whole blood. We identified one transcript, killer cell lectin like receptor 1 (KLRF1), as differentially expressed between idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD), and identified two transcripts (VCAN, LTK) associated with IPF expression against other ILD subtypes. These findings were validated by examining their expression in ILD lung, with KLRF1 expression significantly higher in SSc-ILD compared to IPF and hypersensitivity pneumonitis (HP) samples. Taken together, this pilot study provides support for the use of the peripheral transcriptome in identifying diagnostic biomarkers of ILD with biological relevance.

PMID:39625896 | DOI:10.1371/journal.pone.0314876

Clin Exp Rheumatol. 2024 Dec 3. doi: 10.55563/clinexprheumatol/s73lah. Online ahead of print.

ABSTRACT

OBJECTIVES: Human epididymis protein 4 (HE4) inhibits the degradation of type I collagen, thus promoting fibrosis. We aimed to investigate serum HE4 levels in patients with idiopathic inflammatory myopathies (IIMs), as potential biomarker of interstitial lung disease (ILD).

METHODS: IIMs patients followed in our centre between June 2020 and January 2023 were enrolled. ILD was detected by high-resolution computed tomography (CT) and pulmonary function tests. Serum HE4 levels were measured in patients and controls. Progressive fibrosing (PF-) ILD was evaluated in patients with available 2-year follow-up (INBUILD criteria).

RESILTS: We enrolled 90 consecutive IIMs patients (68% females, mean age 59.5 [52.75- 66.0] years) and 42 healthy, age- and sexmatched controls. ILD was diagnosed in 44 (49%) patients. Serum HE4 levels were higher in IIMs patients than controls: 78.55 [54.6-114.4] vs. 51.05 [41.8-62.8] pmol/L (p=0.001). IIMs-ILD patients had higher levels of HE4 vs. those without ILD (193.7 [78.92-137.42] vs. 58.15 [48.32-79] pmol/L, p<0.0001). Serum HE4 levels correlated inversely with diffusing capacity for carbon monoxide (rho=-0.556, p<0.0001) and total lung capacity (rho=-0.459, p=0.001). Serum HE4 levels were the only variable independently associated with IIMs-ILD in two models of multivariate analysis: OR 1.063 (CI 95% 1.02-1.108), p=0.004, and OR 1.059 (CI 95% 1.020-1.099), p=0.003. PF-ILD was detected in 39.4% of IIMs-ILD patients with available follow-up (33/44), without any significant association with baseline serum HE4 levels.

CONCLUSIONS: HE4 might be a useful biomarker in the identification and assessment of ILD in IIMs patients.

PMID:39625826 | DOI:10.55563/clinexprheumatol/s73lah

Exp Ther Med. 2024 Nov 18;29(1):16. doi: 10.3892/etm.2024.12766. eCollection 2025 Jan.

ABSTRACT

Obstructive sleep apnea (OSA) and idiopathic pulmonary fibrosis (IPF) frequently coexist. Elevated levels of Krebs von den Lungen-6 (KL-6), endothelin-1 (ET-1) and S100 calcium-binding protein A9 (S100A9) have been observed in patients with IPF, suggesting their potential role as biomarkers for lung fibrosis. The aim of the present study was to measure the levels of KL-6, ET-1 and S100A9 in patients with IPF-OSA and to test the potential of these biomarkers as a characteristic OSA signature with diagnostic and prognostic potential for IPF. A total of 55 subjects with newly-diagnosed IPF participated in the present cross-sectional study. In addition to performing overnight attended polysomnography and pulmonary function tests, serum and bronchoalveolar lavage (BAL) levels of KL-6, along with serum levels of ET-1 and S100A9, were also assessed. A total of 15 patients with IPF and 40 patients with IPF-OSA were included. Age, sex, comorbidities and pulmonary function tests did not differ between the groups. Although there was no significant difference between groups in the levels of KL-6, ET-1 and S100A9 (P>0.05), the serum ET-1 levels tended to be elevated in patients with OSA-IPF compared with patients with IPF (1.78 vs. 1.07 pg/ml; P=0.06). Additionally, a significant association was observed between serum KL-6 levels and the severity of IPF, and also between BAL KL-6 levels and nocturnal mean SaO2 levels, even after taking into account factors such as obesity and smoking. S100A9 levels were associated with the oxygen desaturation index, even after adjustments for obesity, smoking and the gender-age-physiology index, only in the IPF-OSA group. Conclusively, the present findings suggested significant associations between serum ET-1, S100A9 and BAL KL-6 levels and specific OSA severity parameters in the IPF-OSA group. This evidence suggested that these molecules could serve as biomarkers for the identification of patients with IPF-OSA, offering a distinct OSA signature that has diagnostic and potential treatment value. Larger studies are crucial to substantiate the present findings and reinforce this hypothesis.

PMID:39624594 | PMC:PMC11609610 | DOI:10.3892/etm.2024.12766

ERJ Open Res. 2024 Dec 2;10(6):00403-2024. doi: 10.1183/23120541.00403-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Acute exacerbations of fibrosing interstitial lung diseases (ILDs) are associated with high mortality. We used prospective data from the INBUILD trial to investigate risk factors for acute exacerbations and the impact of these events in patients with progressive pulmonary fibrosis.

METHODS: Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF) were randomised to receive nintedanib or placebo. Associations between baseline characteristics and time to first acute exacerbation were assessed using pooled data from both treatment groups using Cox proportional hazard models, firstly univariable models and then a multivariable model using forward stepwise selection. The risk of death was estimated based on the Kaplan-Meier method.

RESULTS: Over a median follow-up of approximately 19 months, acute exacerbations were reported in 58 (8.7%) of 663 patients. In the risk factor analysis, the final model included diffusing capacity of the lung for carbon monoxide (D LCO) % predicted, treatment and age. Lower D LCO % predicted was associated with an increased risk of acute exacerbation with a hazard ratio (HR) of 1.56 (95% CI 1.21-2.02) per 10 units lower (p<0.001). Age ≥65 years was associated with a numerically increased risk (HR 1.55, 95% CI 0.87-2.77; p=0.14). Treatment with nintedanib conferred a numerically reduced risk versus placebo (HR 0.60, 95% CI 0.35-1.02; p=0.06). The estimated risks of death ≤30 days and ≤90 days after an acute exacerbation were 19.0% (95% CI 8.9-29.2) and 32.0% (95% CI 19.7-44.2).

CONCLUSIONS: Acute exacerbations of progressive pulmonary fibrosis may have similar risk factors and prognostic impact as acute exacerbations of IPF.

PMID:39624387 | PMC:PMC11610068 | DOI:10.1183/23120541.00403-2024

ERJ Open Res. 2024 Dec 2;10(6):00570-2024. doi: 10.1183/23120541.00570-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) there is a need to identify biomarkers that 1) are associated with increased risk of adverse outcome and 2) can be used to monitor treatment response or identify disease progression over time.

METHODS: Two consecutive cohorts of patients with IPF were accessed from the Open Source Imaging Consortium database. Automated computed tomography (CT) biomarkers of disease severity incorporating fibrotic and pulmonary vascular features (the reticulovascular score and weighted reticulovascular score (WRVS)) were studied. Relationships between imaging biomarkers, lung function and survival were analysed.

RESULTS: In separate test and validation cohorts, 168 and 176 patients with IPF respectively (median survival 2.6 years) were studied. A threshold of WRVS ≥15% at baseline CT was most strongly associated with transplant-free survival (HR 3.00, 95% CI 1.47-6.10, p=0.002) when adjusted for baseline forced vital capacity (FVC) and age. In patients with 12-month follow-up CT and lung function tests (n=89) an increase in 3% of WRVS (the minimal clinically important difference) was also significantly associated with reduced survival independent of FVC, and outperformed visual evaluation of progressive fibrosis.

CONCLUSIONS: WRVS is an automated CT biomarker which can identify patients with IPF at increased risk of progression and is able to reliably capture disease progression over time.

PMID:39624378 | PMC:PMC11610042 | DOI:10.1183/23120541.00570-2024

J Scleroderma Relat Disord. 2024 Nov 27:23971983241296721. doi: 10.1177/23971983241296721. Online ahead of print.

ABSTRACT

Advances in pulmonary arterial hypertension therapies have led to improvements in the quality of life and survival for patients with idiopathic pulmonary arterial hypertension, but these trends have not uniformly translated to patients with systemic sclerosis-associated pulmonary arterial hypertension. In order to better understand the heterogeneity in treatment response and survival, we aimed to examine the histological and immunophenotypic differences between the systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension pulmonary vasculopathies. We performed a semi-quantitative lung morphometry-based analysis comparing sections obtained from systemic sclerosis-associated pulmonary arterial hypertension (n = 24), idiopathic pulmonary arterial hypertension (n = 9), and control (n = 13) bio-banked lung tissue specimens. H&E (Hematoxylin and Eosin) and VVG (Verhoeff-Van Gieson)-stained lung sections were analyzed for interstitial and vascular pathology. Immunohistochemistry was used to stain for an array of inflammatory and fibrosis mediators. Baseline demographic and hemodynamic data for each patient were collected via chart review at the time of lung explantation. Plexiform lesions were present in 5/9 (55%) of idiopathic pulmonary arterial hypertension samples, but absent in all systemic sclerosis-associated pulmonary arterial hypertension samples (0/24). Systemic sclerosis-associated pulmonary arterial hypertension lungs demonstrated significantly worse interstitial fibrosis (p = 0.0001) and interstitial cellularity (p = 0.0002) compared to idiopathic pulmonary arterial hypertension lungs. The degree of smooth muscle hypertrophy and pulmonary artery intimal proliferation were not different between systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension lungs. Immunohistochemistry analysis revealed that systemic sclerosis-associated pulmonary arterial hypertension lungs exhibited increased interstitial infiltration of CD3 T-cells (p = 0.009), CD20 B-cells (p = 0.01), and CD163 macrophages (p = 0.048) when compared to idiopathic pulmonary arterial hypertension and control lungs. Systemic sclerosis-associated pulmonary arterial hypertension lungs display a distinct pulmonary vascular pathology as well as significant interstitial fibrosis when compared to idiopathic pulmonary arterial hypertension lungs.

PMID:39619640 | PMC:PMC11603424 | DOI:10.1177/23971983241296721

Int J Nanomedicine. 2024 Nov 25;19:12593-12614. doi: 10.2147/IJN.S491335. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease caused by aberrant deposition of extracellular matrix in the lungs with significant morbidity and mortality. The therapeutic choices for IPF remain limited. Extracellular vesicles (EVs), as messengers for intercellular communication, are cell-secreted lipid bilayer nanoscale particles found in body fluids, and regulate the epithelial phenotype and profibrotic signaling pathways by transporting bioactive cargo to recipients in the pathogenesis of IPF. Furthermore, an increasing number of studies suggests that EVs derived from stem cells can be employed as a cell-free therapeutic approach for IPF, given their intrinsic tissue-homing capabilities and regeneration characteristics. This review highlights new sights of EVs in the pathogenesis of IPF, their potential as diagnostic and prognostic biomarkers, and prospects as novel drug delivery systems and next-generation therapeutics against IPF. Notably, bringing engineering strategies to EVs holds great promise for enhancing the therapeutic effect of anti-pulmonary fibrosis and promoting clinical transformation.

PMID:39619058 | PMC:PMC11606342 | DOI:10.2147/IJN.S491335

Lab Invest. 2024 Nov 29:102204. doi: 10.1016/j.labinv.2024.102204. Online ahead of print.

ABSTRACT

Desmoid-type fibromatosis (DTF) is a benign but locally aggressive neoplasm characterized by the persistent fibroblast activation, unlike reactive fibrosis (RF), where fibroblast activation is transient. Although the Wnt/β-catenin signaling pathway is known to play a role in DTF pathogenesis, the specific genetic drivers contributing to this abnormal fibroblast activation are not fully understood. To identify additional driver genes that underlie the persistent activation of fibroblasts in DTF, we conducted a comparative transcriptome analysis between 29 DTF and 14 RF tissue samples, identifying 4,267 differentially expressed genes (DEGs) specific to DTF. These DTF-specific DEGs were significantly associated with pathways involved in embryonic limb morphogenesis and muscle contraction, whereas RF-specific DEGs were linked to immune response and apoptosis. Using weighted gene co-expression network analysis (WGCNA) to further elucidate the key regulatory circuits associated with the persistent activation of DTF fibroblasts, we identified a highly DTF-specific gene module comprising 120 genes. This module was also significantly enriched in other fibro-proliferative conditions showing the persistent fibroblasts activation, such as keloid disease and idiopathic pulmonary fibrosis. Subsequent analyses identified seven driver transcription factors (ZNF536, IRX5, TWIST2, NKD2, PAX9, SHOX2, and SALL4) within this DTF-specific module that may contribute to the sustained activation of DTF fibroblasts. We further assessed the utility of five key genes from this module (TWIST2, LRRC15, CTHRC1, SHOX2, and SALL4) as potential biomarkers to distinguish DTF from RF using immunohistochemistry. All markers demonstrated excellent diagnostic performance, with TWIST2 showing exceptionally high sensitivity and specificity, surpassing β-catenin, the current standard biomarker for DTF. In conclusion, our study identifies gene modules and driver transcription factors that are highly specific to DTF, offering new insights into the genetic underpinnings of abnormal fibroblast activation in DTF. We also propose novel biomarkers that could improve the diagnostic accuracy and clinical management of DTF.

PMID:39617099 | DOI:10.1016/j.labinv.2024.102204

Mod Pathol. 2024 Nov 28:100675. doi: 10.1016/j.modpat.2024.100675. Online ahead of print.

ABSTRACT

Fibroblastic foci (FF) are considered important findings of usual interstitial pneumonia (UIP); however, they are not specific to UIP but are also observed in various fibrotic interstitial lung diseases (ILDs). Previous studies have reported the significance of FF comparing UIP with nonspecific interstitial pneumonia (NSIP) or with secondary interstitial pneumonia, such as collagen vascular disease-related interstitial lung disease (CVD-ILD) or fibrotic hypersensitivity pneumonitis (FHP). However, only few studies have mentioned its location, and no reports have shown significant results regarding its location. This study aimed to compare the spatial distribution of FF across various forms of ILDs, based on anatomical location. Among patients who underwent lung transplantation at Kyoto University Hospital between April 1, 2008, and March 31, 2023, those diagnosed with idiopathic pulmonary fibrosis (IPF) (n = 24), idiopathic NSIP (n = 11), CVD-ILD (n = 36), and FHP (n = 12) were included, and 744 slides were obtained. FF were classified into four categories: peripheral, such as subpleural/paraseptal (pFF); intralobular, along the alveolar wall (aFF); centrilobular (cFF); and distorted or dense fibrotic lesion (dFF). The number of total and each location's FF/cm2 were counted, and the percentage of each location's FF was calculated. IPF showed more total FF and pFF than NSIP. FHP had more cFF than CVD (p = 0.026) and NSIP (p = 0.018). The dFF was higher in IPF than that in CVD (p = 0.018) and NSIP (p = 0.039). The aFF/total FF was higher in CVD than that in FHP (p = 0.021) and IPF (p < 0.001). A high cFF/total FF was correlated with FHP vs. IPF (p = 0.032). In conclusion, FF with existing peripheral and distorted/dense fibrosis were more closely related to IPF, whereas centrilobular FF were highly correlated with FHP. Moreover, high aFF/total FF was suggestive of CVD.

PMID:39615840 | DOI:10.1016/j.modpat.2024.100675

Biomater Adv. 2024 Nov 28;168:214123. doi: 10.1016/j.bioadv.2024.214123. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease primarily affecting elderly individuals aged >65 years and has a poor prognosis. No effective treatment is currently available for IPF. The two antipulmonary fibrosis drugs nintedanib and pirfenidone approved by the FDA in the United States have somewhat decelerated IPF progression. However, the side effects of these drugs can lead to poor patient tolerance and compliance with the medications. Researchers have recently developed various methods for IPF treatment, such as gene silencing and pathway inhibitors, which hold great promise in IPF treatment. Nevertheless, the nonselectivity and nonspecificity of drugs often affect their efficacies. Drug delivery systems (DDS) are crucial for delivering drugs to specific target tissues or cells, thereby minimizing potential side effects, enhancing drug bioavailability, and reducing lung deposition. This review comprehensively summarizes the current state of DDS and various delivery strategies for IPF treatment (e.g., nano-delivery, hydrogel delivery, and biological carrier delivery) to completely expound the delivery mechanisms of different drug delivery carriers. Subsequently, the advantages and disadvantages of different DDS are fully discussed. Finally, the challenges and difficulties associated with the use of different DDS are addressed so as to accelerate their rapid clinical translation.

PMID:39615374 | DOI:10.1016/j.bioadv.2024.214123

Exp Mol Pathol. 2024 Nov 29;140:104946. doi: 10.1016/j.yexmp.2024.104946. Online ahead of print.

ABSTRACT

BACKGROUND: During the COVID-19 pandemic, the viral illness caused by SARS-CoV-2 spread through respiratory droplets, resulting in a global pandemic with a range of symptoms from mild to severe. Pathological inflammation posed a critical issue, yet the genetic mechanisms behind the excessive activation of inflammatory responses remained unclear. To uncover the genetic and regulatory basis of the pathogenesis, we first explored possible genetic mechanisms from phenome-wide association studies (PWAS) with different severity levels of COVID-19. PWAS is a genetic research approach that identifies pleiotropic risk variants that contribute to elucidating potential physiological mechanisms from different traits.

METHODS: We used the PWAS approach to link the multiple clinical symptoms to the variants. We discovered a common variant, rs2109069, in dipeptidyl peptidase 9 (DPP9), which relates to the elevated odds ratio of developing severe illness from COVID-19. Interestingly, the proxy of rs2109069 has been identified as the susceptible locus of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). We thus examined the DPP9 expression patterns in selected organs, including the lungs, blood vessels, and skin.

RESULTS: In silico analysis revealed conserved driver activation between COVID-19-induced inflammation and the association with ILD and IPF. Multi-omics analysis further verified the association of DPP9 with abnormal inflammatory responses in COVID-19. Lastly, gene homology analysis inferred a potential regulatory role of DPP9 in inhibiting inflammasome activation, which suggests that DPP9 deficiency may exacerbate inflammation observed in some COVID-19 patients.

CONCLUSIONS: Our in silico findings reveal that severe COVID-19 inflammatory responses and inflammatory lung diseases share the same genetic risk loci, helping to elucidate the underlying physiological mechanisms of severe COVID-19 inflammation. Additionally, the individual differences in immune sensitivity may contribute to the varying multi-organ inflammatory effects among patients. The rs2109069 of DPP9 could be a genetic marker to predict the risk of specific COVID-19 symptoms and severity.

PMID:39615159 | DOI:10.1016/j.yexmp.2024.104946

Thorax. 2024 Nov 29:thorax-2024-221472. doi: 10.1136/thorax-2024-221472. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung scarring. There is a known association between diabetes mellitus (DM) and IPF, but it is unclear whether a causal relationship exists between these traits.

OBJECTIVES: The objectives of this study are to examine causal relationships among DM, diabetes-associated traits and IPF using a Mendelian randomisation approach.

METHODS: Two-sample MR approaches, including bidirectional inverse-variance weighted random effects and routine sensitivity models, used genetic variants identified from genome-wide association studies for type 1 diabetes (T1D), type 2 diabetes (T2D), glycated haemoglobin level (HbA1c), fasting insulin level and body mass index (BMI) to assess for causal effects of these traits on IPF. Further analyses using pleiotropy-robust and multivariable MR (MVMR) methods were additionally performed to account for trait complexity.

RESULTS: Results did not suggest that either T1D (OR=1.00, 95% CI 0.93 to 1.07, p=0.90) or T2D (1.02, 0.93 to 1.11, p=0.69) are in the causal pathway of IPF. No effects were suggested of HbA1c (1.19, 0.63 to 2.22, p=0.59) or fasting insulin level (0.60, 0.31 to 1.15, p=0.12) on IPF, but potential effects of BMI on IPF were indicated (1.44, 1.12 to 1.85, p=4.00×10-3). Results were consistent in MVMR, although no independent effects of T2D (0.91, 0.68 to 1.21, p=0.51) or BMI (1.01, 0.94 to 1.09, p=0.82) on IPF were observed when modelled together.

CONCLUSIONS: This study suggests that DM and IPF are unlikely to be causally linked. This comorbid relationship may instead be driven by shared risk factors or treatment effects.

PMID:39613458 | DOI:10.1136/thorax-2024-221472

Am J Hosp Palliat Care. 2024 Nov 29:10499091241304443. doi: 10.1177/10499091241304443. Online ahead of print.

ABSTRACT

BACKGROUND: Palliative care (PC) is underutilized in the idiopathic pulmonary fibrosis (IPF) patient population, particularly in outpatient settings, despite high symptom burden and complex care needs. There is no clinician consensus for the most effective method of integrating PC into routine medical visits for this patient population, despite acknowledgement of its benefits. The purpose of this quality improvement (QI) project was to pilot an adapted nurse practitioner-led standardized PC lever tool for IPF in an outpatient clinic and evaluate the secondary PC referral rates during the implementation period.

DESIGN: The lever tool was implemented over a 3-month period. De-identified patient health information from the health system's electronic medical record system was used to compare referrals to PC prior to and during the implementation of the lever tool.

RESULTS: The established workflow for the nurse practitioner-led implementation of the tool was feasible. There were increased PC referrals and increased PC encounters during the QI period, however the results were not statistically significant.

CONCLUSIONS: The findings of this QI project add to the limited existing literature evaluating PC referral methods for individuals with IPF in an outpatient setting. Further, the development process and workflow utilized confirms the feasibility of employing the nursing workforce to support the care needs of the IPF patient population.

PMID:39613142 | DOI:10.1177/10499091241304443

Epigenetics. 2024 Dec;19(1):2435682. doi: 10.1080/15592294.2024.2435682. Epub 2024 Nov 29.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening respiratory disease characterized by worsening lung function due to excessive scarring. The objective of this study was to investigate the role of the long non-coding RNA ANRIL (antisense non-coding RNA in the INK4 locus) in the development of IPF. Our research revealed a significant increase in ANRIL expression in pulmonary fibrosis, consistent with prior studies indicating elevated ANRIL levels in fibrotic tissues. In vitro experiments demonstrated that elevated ANRIL expression promoted fibroblast activation, as evidenced by the upregulation of fibrosis-related markers. Mechanistically, we found that ANRIL interacts with let-7d-5p, a microRNA involved in gene regulation, acting as a sponge for let-7d-5p. Functional experiments confirmed a potential influence of let-7d-5p on fibroblast activation through direct interaction with ANRIL. Furthermore, our investigation identified TGFBR1 as a potential mediator of ANRIL's fibrogenic effects. Silence of TGFBR1 mitigated the fibrotic phenotype induced by ANRIL overexpression. Collectively, these results suggest that ANRIL promotes fibroblast activation and fibrosis development, possibly through the let-7d-5p/TGFBR1 axis, indicating that ANRIL could be a potential therapeutic target for pulmonary fibrosis.

PMID:39612365 | DOI:10.1080/15592294.2024.2435682

J Cell Physiol. 2024 Nov 28. doi: 10.1002/jcp.31473. Online ahead of print.

ABSTRACT

Diffuse, progressive interstitial lung disease with few treatment options and low survival rates is known as idiopathic pulmonary fibrosis (IPF). Alveolar epithelial cell damage and dysfunction are the main features of IPF. TSC1 has been documented to exert a pivotal function in governing cellular growth, proliferation, and ontogenesis. This work investigated TSC1's function and mechanism in IPF. Mice were given BLM to cause pulmonary fibrosis, and A549 cells underwent epithelial mesenchymal transition (EMT) in response to TGF-β1. According to the data, TSC1 expression was reduced in IPF. Overexpression of TSC1 was established by adenopathy-associated virus in vivo and adenovirus in vitro to significantly block the EMT process. Besides, the findings from the RNA-sequencing analysis indicate that overexpression of TSC1 mitigated the EMT process by suppressing the activation of the AKT/mTOR pathway via downregulation of ACTN4 expression. To examine the upstream regulatory mechanism, we employed the SRAMP database to predict m6A modification of TSC1 mRNA, followed by verification of m6A modification levels and expression using MERIP-qPCR, Dot blot, RT-qPCR, and WB. The results indicated a high degree of m6A modification in TSC1 mRNA in pulmonary fibrosis. The expression of METTL3 was further found to be significantly elevated. METTL3 knockdown impeded EMT progression. METTL3 inhibits TSC1 expression by increasing TSC1 m6A modification through the reading protein YTHDF2. In conclusion, our study elucidated that the METTL3/YTHDF2/TSC1 signaling axis activates the AKT/mTOR pathway to promote the development of IPF. This study provides potential molecular-level therapeutic targets for IPF disease.

PMID:39606797 | DOI:10.1002/jcp.31473

Cureus. 2024 Oct 28;16(10):e72572. doi: 10.7759/cureus.72572. eCollection 2024 Oct.

ABSTRACT

Pulmonary fibrosis is a chronic condition typically affecting both lungs; however, cases of unilateral pulmonary fibrosis are exceedingly rare and often result from specific unilateral inflammatory conditions like radiation pneumonitis or infection. An even rarer occurrence is the unilateral proximal interruption of a pulmonary artery (PIPA), a developmental anomaly resulting from the failed connection of the sixth aortic arch to the pulmonary trunk. This condition can manifest alone or alongside other cardiac abnormalities. There are limited reports of pulmonary fibrosis associated with PIPA. In this case, a 33-year-old male with chronic mild asthma presented with bilateral shoulder pain. Initial radiographs showed reticular opacities and volume loss in the right lung with a rightward mediastinal shift, suggesting possible fibrosis. Further investigations with chest Computed Tomography (CT) and CT angiogram confirmed right-sided pulmonary fibrosis and the absence of the right pulmonary artery, with no other significant cardiopulmonary symptoms reported. This case highlights the complexity of diagnosing and managing rare unilateral pulmonary conditions.

PMID:39606523 | PMC:PMC11602208 | DOI:10.7759/cureus.72572

medRxiv [Preprint]. 2024 Nov 16:2024.11.15.24317403. doi: 10.1101/2024.11.15.24317403.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare disease that is challenging to diagnose. Patients with IPF often spend years awaiting a diagnosis after the onset of initial respiratory symptoms, and only a small percentage receive antifibrotic treatment. In this study, we examine the associations between social determinants of health (SDoH) and two critical factors: time to IPF diagnosis following the onset of initial respiratory symptoms, and whether the patient receives antifibrotic treatment. To approximate individual SDoH characteristics, we extract demographic-specific averages from zip code-level data using the American Community Survey (via the U.S. Census Bureau API). Two classification models are constructed, including logistic regression and XGBoost classification. The results indicate that for time-to-diagnosis, the top three SDoH factors are education, gender, and insurance coverage. Patients with higher education levels and better insurance are more likely to receive a quicker diagnosis, with males having an advantage over females. For antifibrotic treatment, the top three SDoH factors are insurance, gender, and race. Patients with better insurance coverage are more likely to receive antifibrotic treatment, with males and White patients having an advantage over females and patients of other ethnicities. This research may help address disparities in the diagnosis and treatment of IPF related to socioeconomic status.

PMID:39606330 | PMC:PMC11601738 | DOI:10.1101/2024.11.15.24317403

bioRxiv [Preprint]. 2024 Apr 30:2024.04.30.591719. doi: 10.1101/2024.04.30.591719.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation. IPF results from maladaptive responses to lung epithelial injury, but the underlying mechanisms remain unclear. Here, we show that deficiency in the innate immune receptor, toll-like receptor 5 (TLR5), is associated with IPF in humans and with increased susceptibility to epithelial injury and experimental fibrosis in mice, while activation of lung epithelial TLR5 through a synthetic flagellin analogue protects from experimental fibrosis. Mechanistically, epithelial TLR5 activation induces antimicrobial gene expression and ameliorates dysbiosis after lung injury. In contrast, TLR5 deficiency in mice and IPF patients is associated with lung dysbiosis. Elimination of the microbiome in mice through antibiotics abolishes the protective effect of TLR5 and reconstitution of the microbiome rescues the observed phenotype. In aggregate, TLR5 deficiency is associated with IPF and dysbiosis in humans and in the murine model of pulmonary fibrosis. Furthermore, TLR5 protects against pulmonary fibrosis in mice and this protection is mediated by effects on the microbiome.

ONE-SENTENCE SUMMARY: Deficiency in the innate immune receptor TLR5 is a risk factor for pulmonary fibrosis, because TLR5 prevents microbial dysbiosis after lung injury.

PMID:39605370 | PMC:PMC11601505 | DOI:10.1101/2024.04.30.591719

Eur Respir J. 2024 Nov 27:2401070. doi: 10.1183/13993003.01070-2024. Online ahead of print.

ABSTRACT

OBJECTIVE: Gene expression (transcriptomics) studies have revealed potential mechanisms of interstitial lung disease (ILD), yet sample sizes of studies are often limited and between-subtype comparisons are scarce. The aim of this study was to identify and validate consensus transcriptomic signatures of ILD subtypes.

METHODS: We performed a systematic review and meta-analysis of fibrotic ILD transcriptomics studies using an individual participant data approach, and included studies examining bulk transcriptomics of human adult ILD samples and excluding those focusing on individual cell populations. Patient-level data and expression matrices were extracted from 43 studies and integrated using a multivariable integrative algorithm to develop ILD classification models.

RESULTS: Using 1459 samples from 24 studies, we identified transcriptomic signatures for idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), idiopathic nonspecific interstitial pneumonia (NSIP), and systemic sclerosis-associated ILD (SSc-ILD) against control samples, which were validated on 308 samples from 8 studies (area under receiver operating curve [AUC]=0.99 [95% CI: 0.99-1.00], HP AUC=0.91 [0.84-0.99], NSIP AUC=0.94 [0.88-0.99], SSc-ILD AUC=0.98 [0.93-1.00]). Significantly, meta-analysis allowed, for the first time, identification of robust lung transcriptomics signatures to discriminate IPF (AUC=0.71 [0.63-0.79]) and HP (AUC=0.76 [0.63-0.89]) from other fibrotic ILDs, and unsupervised learning algorithms identified putative molecular endotypes of ILD associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted. Transcriptomics signatures were reflective of both cell-specific and disease-specific changes in gene expression.

CONCLUSION: We present the first systematic review and largest meta-analysis of fibrotic ILD transcriptomics to date, identifying reproducible transcriptomic signatures with clinical relevance.

PMID:39603671 | DOI:10.1183/13993003.01070-2024

Eur Respir J. 2024 Nov 27;100(101):0000001. doi: 10.1183/13993003.0000-0000. Print 2023 Dec.

NO ABSTRACT

PMID:39603667 | DOI:10.1183/13993003.0000-0000