Int J Mol Sci. 2024 Aug 16;25(16):8946. doi: 10.3390/ijms25168946.

ABSTRACT

Idiopathic pulmonary fibrosis remains a relevant problem of the healthcare system with an unfavorable prognosis for patients due to progressive fibrous remodeling of the pulmonary parenchyma. Starting with the damage of the epithelial lining of alveoli, pulmonary fibrosis is implemented through a cascade of complex mechanisms, the crucial of which is the TGF-β/SMAD-mediated pathway, involving various cell populations. Considering that a number of the available drugs (pirfenidone and nintedanib) have only limited effectiveness in slowing the progression of fibrosis, the search and justification of new approaches aimed at regulating the immune response, cellular aging processes, programmed cell death, and transdifferentiation of cell populations remains relevant. This literature review presents the key modern concepts concerning molecular genetics and cellular mechanisms of lung fibrosis development, based mainly on in vitro and in vivo studies in experimental models of bleomycin-induced pulmonary fibrosis, as well as the latest data on metabolic features, potential targets, and effects of vitamin D and its metabolites.

PMID:39201632 | DOI:10.3390/ijms25168946

Int J Mol Sci. 2024 Aug 13;25(16):8818. doi: 10.3390/ijms25168818.

ABSTRACT

Development of radiation medical countermeasures under the U.S. Food and Drug Administration Animal Rule requires the capability to translate an effective animal-to-human drug dose. One method of human dose translation is using a biomarker and determining drug doses that modulate the biomarker to the desired level. BIO 300 Oral Powder (BIO 300) is a prophylactic radiation medical countermeasure that is currently being developed following the Animal Rule. The present study aimed to identify biomarkers that can be used for human dose conversion by conducting transcriptomics of whole blood collected from BIO 300-treated CD2F1 mice in the presence and absence of total-body irradiation (TBI). Unirradiated mice were treated with vehicle or 50, 100, or 200 mg/kg BIO 300, and irradiated mice were treated with 200 mg/kg or BIO 300 or vehicle prior to TBI. Whole-blood samples were collected after the last dose of the drug and after irradiation. RNA sequencing demonstrated 100 and 200 mg/kg of BIO 300 doses caused significantly more differential gene expression at 48 h after drug dose compared to 50 mg/kg of BIO 300 (7648, 7680, and 55 significantly differently expressed genes, respectively). Interestingly, following TBI, there were no significantly differentially expressed genes between vehicle- and BIO 300-treated mice. Despite the lack of significant changes in gene expression, the transcriptomic profiles in both groups indicated differential changes in signaling pathways. Pathway analysis of the transcriptome profile from vehicle-treated/TBI mice revealed that many inflammatory signaling pathways were activated in these animals. Signaling pathways enriched in BIO 300-treated/TBI mice were involved in cellular stress and immune response and were predicted to be inhibited. In all, four signaling pathways of interest were identified that were differentially enriched in irradiated animals treated with BIO 300: pathogen-induced cytokine storm signaling, S100 family signaling, pulmonary fibrosis idiopathic signaling, and wound-healing signaling. These pathways should be explored to identify potential biomarkers of BIO 300 that can be used for human dose translation.

PMID:39201502 | DOI:10.3390/ijms25168818

Antioxidants (Basel). 2024 Jul 30;13(8):924. doi: 10.3390/antiox13080924.

ABSTRACT

Oxidative stress in the human lung is caused by both internal (e.g., inflammation) and external stressors (smoking, pollution, and infection) to drive pathology in a number of lung diseases. Cellular damage caused by oxidative damage is reversed by several pathways, one of which is the antioxidant response. This response is regulated by the transcriptional factor NRF2, which has the ability to regulate the transcription of more than 250 genes. In disease, this balance is overwhelmed, and the cells are unable to return to homeostasis. Several pharmacological approaches aim to improve the antioxidant capacity by inhibiting the interaction of NRF2 with its key cytosolic inhibitor, KEAP1. Here, we evaluate an alternative approach by overexpressing NRF2 from chemically modified RNAs (cmRNAs). Our results demonstrate successful expression of functional NRF2 protein in human cell lines and primary cells. We establish a kinetic transcriptomic profile to compare antioxidant response gene expression after treatment of primary human bronchial epithelial cells with either KEAP1 inhibitors or cmRNAs. The key gene signature is then applied to primary human lung fibroblasts and alveolar macrophages to uncover transcriptional preferences in each cell system. This study provides a foundation for the understanding of NRF2 dynamics in the human lung and provides initial evidence of alternative ways for pharmacological interference.

PMID:39199170 | DOI:10.3390/antiox13080924

Postgrad Med J. 2024 Aug 29:qgae102. doi: 10.1093/postmj/qgae102. Online ahead of print.

ABSTRACT

Defective telomerase function or telomere maintenance causes genomic instability. Alterations in telomere length and/or attrition are the primary features of rare diseases known as telomere biology disorders or telomeropathies. Recent advances in the molecular basis of these disorders and cutting-edge methods assessing telomere length have increased our understanding of this topic. Multiorgan manifestations and different phenotypes have been reported even in carriers within the same family. In this context, apart from dyskeratosis congenita, disorders formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective telomere maintenance mechanisms. Moreover, these patients are prone to developing specific cancer types and exhibit exceptional sensitivity and toxicity in standard chemotherapy regimens. The current review describes the diverse spectrum of clinical manifestations of telomere biology disorders in pediatric and adult patients, their correlation with pathogenic variants, and considerations during their management to increase awareness and improve a multidisciplinary approach.

PMID:39197110 | DOI:10.1093/postmj/qgae102

Front Cell Dev Biol. 2024 Aug 13;12:1426508. doi: 10.3389/fcell.2024.1426508. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown origin and the most common interstitial lung disease. However, therapeutic options for IPF are limited, and novel therapies are urgently needed. Histone deacetylases (HDACs) are enzymes that participate in balancing histone acetylation activity for chromatin remodeling and gene transcription regulation. Increasing evidence suggests that the HDAC family is linked to the development and progression of chronic fibrotic diseases, including IPF. This review aims to summarize available information on HDACs and related inhibitors and their potential applications in treating IPF. In the future, HDACs may serve as novel targets, which can aid in understanding the etiology of PF, and selective inhibition of single HDACs or disruption of HDAC genes may serve as a strategy for treating PF.

PMID:39193364 | PMC:PMC11347278 | DOI:10.3389/fcell.2024.1426508

Int J Gen Med. 2024 Aug 23;17:3649-3661. doi: 10.2147/IJGM.S435754. eCollection 2024.

ABSTRACT

OBJECTIVE: To explore serum KL-6 level and investigate its diagnostic value in interstitial lung diseases (ILDs).

METHODS: Serum KL-6 level was measured using the chemiluminescent enzyme immunoassay. Statistical analysis was performed for determining the KL-6 concentration of each group.

RESULTS: KL-6 level (U/mL) in the ILD group was 1388.321 ±1943.116, which was higher than that in the control group, showing a significant statistical difference. ROC curve analysis based on the receiver operating characteristic curve showed the optimal cut-off value of 402.5U/mL, sensitivity of 77.4%, specificity of 93.4%, and accuracy of 89.4%; through Chi-square test with the two groups, the positive rate of KL-6 in patients with ILD was proved to be significantly higher than that in the control group. KL-6 level was 1063.00±504.757 in the idiopathic pulmonary fibrosis (IPF) group, 1346.892 ±1827.252 in the connective tissue disease-associated interstitial lung disease (CTD-ILD) group, 467.889±288.859 in the organizing pneumonia (OP) group, 8252.333±6050.625 in the pulmonary alveolar proteinosis (PAP) group, and 359.200±392.707 in the sarcoidosis group. The rank sum test showed that the differences were statistically significant. KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group.

CONCLUSION: Serum KL-6 level was confirmed to be highly sensitive, specific, and accurate in the diagnosis of ILD. Subgroup analysis showed that the KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group.

PMID:39193261 | PMC:PMC11348927 | DOI:10.2147/IJGM.S435754

Expert Rev Clin Pharmacol. 2024 Aug 27:1-19. doi: 10.1080/17512433.2024.2396121. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function.

AREAS COVERED: Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents.

EXPERT OPINION: New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process.

PMID:39192604 | DOI:10.1080/17512433.2024.2396121

Biomed Pharmacother. 2024 Aug 26;179:117341. doi: 10.1016/j.biopha.2024.117341. Online ahead of print.

ABSTRACT

BACKGROUND: Nintedanib is used to treat both idiopathic and progressive pulmonary fibrosis (IPF/PPF). Evidence of both an exposure-response relationship and an exposure-toxicity relationship has been found, suggesting the potential value of therapeutic drug monitoring (TDM). We aimed to define the therapeutic window of nintedanib in a real-world cohort.

METHODS: Data from two clinical studies were pooled for this analysis. To quantify exposure to nintedanib, a population-pharmacokinetic (PK) model was developed. Associations between PK and decline in forced vital capacity (FVC) and diffusing capacity (DLCO) were performed using linear-mixed-effect models (LMEM). The exposure-toxicity relationship was evaluated using a Cox proportional hazards model.

RESULTS: In total, 911 PK samples from 99 patients were used to develop the PK model. The LMEM with random slopes and intercepts included 517 pulmonary function tests (PFT) from 81 patients. The average administered nintedanib dose was associated with the rate of FVC decline (p=0.002). Per 50 mg decrease of daily dosage, the rate of FVC decline increased by 53.5 mL/year. Neither nintedanib exposure nor dose significantly affected DLCO decline and they were also not significantly associated with the occurrence of a dose-limiting toxicity (DLT). This may be explained by a large inter- and intrapatient variability in nintedanib PK.

CONCLUSION: Nintedanib dose was significantly associated with FVC loss. However, no significant relationship between nintedanib exposure and the occurrence of DLTs was found in this real-world population, and no therapeutic window could be established. The findings in this study indicate that nintedanib is an unsuitable candidate for performing TDM.

PMID:39191023 | DOI:10.1016/j.biopha.2024.117341

Respir Res. 2024 Aug 27;25(1):325. doi: 10.1186/s12931-024-02897-w.

ABSTRACT

BACKGROUND: Cough remains a persistent symptom in patients with idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). To inform future research, treatment and care models, we conducted the first systematic synthesis of evidence on its associated burden.

METHODS: A literature search was performed for articles published between January 2010 and October 2023 using databases including Embase, MEDLINE and the Cochrane Library. Studies in patients with IPF and other ILDs reporting cough-related measures were eligible for inclusion. Included studies were categorised based on the types of ILD they examined and their design. Study details, patient characteristics and outcomes were extracted, and the risk of bias was assessed. A narrative synthesis approach was employed to interpret the findings.

RESULTS: Sixty-one studies were included: 33 in IPF, 18 in mixed-ILDs, six in connective tissue disease-associated-ILDs and four in sarcoidosis. Across the studies, a range of tools to assess cough and its impact were used. The most frequently used measures of cough were cough severity visual analogue scale (VAS) and objective cough counts, whereas the most frequently used health-related quality of life (HRQoL)/impact measures were the St. George's Respiratory Questionnaire (SGRQ) and Leicester Cough Questionnaire (LCQ). In IPF, studies consistently reported correlations between various cough and HRQoL measures, including between cough VAS scores and objective cough counts, LCQ scores and SGRQ scores. Similar correlations were observed in studies in other ILDs, but data were more limited. Qualitative studies in both IPF and other ILDs consistently highlighted the significant cough-related burden experienced by patients, including disruption of daily activities, fatigue and social embarrassment. Although there were no studies specifically investigating the economic burden of cough, one study in patients with fibrotic ILD found cough severity was associated with workplace productivity loss.

CONCLUSIONS: Our study underscores the heterogeneity in assessing cough and its impact in IPF and other ILDs. The findings confirm the negative impact of cough on HRQoL in IPF and suggest a comparable impact in other ILDs. Our synthesis highlights the need for standardised assessment tools, along with dedicated studies, particularly in non-IPF ILDs and on the economic burden of cough.

PMID:39192278 | DOI:10.1186/s12931-024-02897-w

Discov Med. 2024 Aug;36(187):1616-1626. doi: 10.24976/Discov.Med.202436187.148.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a long-term, progressive, and irreversible pulmonary interstitial disease. The activation of Smad family member 2 (Smad2) and Smad3 transcription factors by transforming growth factor β-1 (TGF-β1) is a critical event in the pathogenesis of IPF. However, there is still a lack of understanding regarding the molecular mechanisms governing Smad2 and Smad3 proteins. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays a vital role in regulating protein stability within cells. However, its regulation of the TGF-β signaling pathway and its significance in IPF remain undiscovered. This study aims to clarify the function of USP7 in the TGF-β signaling pathway, while simultaneously exploring the specific molecular mechanisms involved. Additionally, this study seeks to evaluate the therapeutic potential of targeted USP7 inhibitors in IPF, thereby providing novel insights for the diagnosis and management of IPF.

METHODS: We first detected the expression of USP7 in lung tissues of mice with Bleomycin (BLM)-induced pulmonary fibrosis and in Beas-2B cells treated with or without TGF-β1 through Western blot analysis. Subsequently, we explored the influence of USP7 on fibrotic processes and the TGF-β1 signaling pathway, utilizing in vitro and in vivo studies. Finally, we assessed the effectiveness of USP7-specific inhibitors in an IPF murine model.

RESULTS: In the present study, USP7 was found to de-ubiquitinate Smad2 and Smad3, consequently increasing their stability and promoting the TGF-β1-induced production of profibrotic proteins including α-smooth muscle actin (α-SMA) and fibronectin 1 (FN-1). Inhibition or knockdown of USP7 resulted in decreased levels of Smad2 and Smad3 proteins, leading to reduced expression of FN-1, Collagen Type I Alpha 1 Chain (Col1A1), and α-SMA induced by TGF-β1 in human pulmonary epithelial cells. These findings demonstrate that overexpression of USP7 reduces Smad2/3 ubiquitination, whereas inhibition or knockdown of USP7 enhances their ubiquitination. USP7 is abundantly expressed in IPF lungs. The expressions of USP7, Smad2, and Smad3 were upregulated in bleomycin-induced lung injury. The USP7 inhibitor P22077 reduced the expression of FN-1 and type I collagen as well as Smad2/3 and collagen deposition in lung tissue in a model of pulmonary fibrosis induced by bleomycin.

CONCLUSIONS: This study demonstrates that USP7 promotes TGF-β1 signaling by stabilizing Smad2 and Smad3. The contribution of USP7 to the progression of IPF indicates it may be a viable treatment target.

PMID:39190377 | DOI:10.24976/Discov.Med.202436187.148

Am J Respir Crit Care Med. 2024 Aug 27. doi: 10.1164/rccm.202401-0065OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA).

OBJECTIVES: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor.

METHODS: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease.

MEASUREMENTS AND MAIN RESULTS: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis.

CONCLUSIONS: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

PMID:39189851 | DOI:10.1164/rccm.202401-0065OC

Front Vet Sci. 2024 Jul 31;11:1416124. doi: 10.3389/fvets.2024.1416124. eCollection 2024.

ABSTRACT

Canine idiopathic pulmonary fibrosis (CIPF) is a progressive fibrotic interstitial lung disease of unknown etiology, afflicting aging West Highland white terriers (WHWTs) and leading to progressive respiratory failure. Fibroblast activation protein (FAP), a protease overexpressed in many cancers, is upregulated in idiopathic pulmonary fibrosis in humans. The aim of this study was to investigate FAP as a marker of active fibrosis in lung biopsies from WHWTs affected with CIPF, as well as the potential of plasmatic FAP as a biomarker. After establishing a scoring system to evaluate the severity and activity of fibrosis on histopathological lung sections, anti-FAP immunohistochemistry was performed on healthy and CIPF samples. FAP expression was characterized using both visual and digital quantitative pathology software analyses and then correlated to fibrosis severity and activity. Levels of plasmatic FAP in WHWTs affected with CIPF were measured by enzyme-linked immunosorbent assay and compared with healthy dogs. Lung samples from 22 WHWTs affected with CIPF were collected. According to the fibrosis scoring system, they were classified as cases of mild (5), moderate (9) and severe (8) fibrosis and were attributed scores of fibrosis activity. Fifteen healthy lung samples were classified as non-fibrotic. Healthy lung samples were FAP-negative, whereas fibroblasts were FAP-positive in 20 CIPF samples. FAP immunohistochemical expression correlated mildly with fibrosis severity (p < 0.05; R 2 = 0.22) but highly with fibrosis activity scores (p < 0.001; R 2 = 0.68). Digital image analysis detected a higher percentage of FAP-positive cells in areas of active fibrosis (p < 0.001) and FAP-positive cells were distributed outside mature fibrosis lesions, clustered in active fibrosis areas or scattered within alveolar septa. On the other hand, plasmatic FAP was significantly lower in dogs affected with CIPF compared with healthy dogs (p < 0.01). In conclusion, this study provides a valuable histological scoring system to assess the severity and activity of fibrosis in CIPF. It demonstrates that FAP is a good cellular marker of fibrotic activity in CIPF, and thus constitutes a promising target to be exploited for diagnostic and therapeutic applications. Additionally, it suggests that plasmatic FAP, although non-specific, could be altered in CIPF.

PMID:39188902 | PMC:PMC11346374 | DOI:10.3389/fvets.2024.1416124

BMC Pulm Med. 2024 Aug 26;24(1):409. doi: 10.1186/s12890-024-03228-x.

ABSTRACT

PURPOSE: This study aimed to elucidate the causal relationship between Obstructive Sleep Apnea (OSA) and Chronic Respiratory Diseases (CRDs), employing Mendelian Randomization (MR) to overcome limitations inherent in observational studies.

METHODS: Utilizing a two-sample MR approach, this study analyzed genetic variants as instrumental variables to investigate the causal link between OSA and various CRDs, including chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, and idiopathic pulmonary fibrosis (IPF). Data were sourced from the FinnGen Consortium (OSA, n = 375,657) and UK Biobank, focusing on genome-wide associations between single-nucleotide polymorphisms (SNPs) and the diseases. Instrumental variables were selected based on strict criteria, and analyses included a random-effects inverse-variance weighted method supplemented by several sensitivity analyses.

RESULTS: The study suggests a protective effect of OSA against COPD (OR = 0.819, 95% CI 0.722-0.929, P-value = 0.002), which becomes non-significant after adjusting for BMI, indicating a potential mediating role of BMI in the OSA-COPD nexus. No significant causal links were found between OSA and other CRDs (asthma, IPF, bronchiectasis) or between COPD, asthma, and OSA.

CONCLUSIONS: Our findings reveal a BMI-mediated protective effect of OSA on COPD, with no causal connections identified between OSA and other CRDs. These results emphasize the complex relationship between OSA, BMI, and COPD, guiding future clinical strategies and research directions, particularly in light of the study's genetic analysis limitations.

PMID:39187806 | DOI:10.1186/s12890-024-03228-x

Chest. 2024 Aug 24:S0012-3692(24)05049-9. doi: 10.1016/j.chest.2024.08.018. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with lung cancer, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD) have high symptom burden, poor quality of life, and high healthcare utilization at the end of life. While proactive integration of palliative care in lung cancer can improve outcomes, it is unclear whether similar practices have been adopted in COPD and IPF care.

RESEARCH QUESTION: Do patients with COPD and IPF have different patterns of healthcare and palliative care use at the end of life compared to lung cancer?

STUDY DESIGN AND METHODS: We retrospectively identified deceased patients with lung cancer, COPD, or IPF with ≥1 outpatient visit at [removed] in the last six months of life. We compared outpatient palliative care and opioid prescriptions, inpatient palliative care, hospitalizations, intensive care use, and in-hospital death in the last 6 months of life between each group. We used multivariable logistic regression to calculate adjusted odds ratios of each outcome, with lung cancer as the reference group.

RESULTS: Among 1,819 patients, patients with COPD and IPF were more likely to be male and older at the time of death, compared to patients with lung cancer. Compared to lung cancer, patients with COPD and IPF had a lower adjusted odds (p<0.001) of receiving outpatient palliative care (aOR COPD: 0.26, 95% CI: 0.19-0.36; aOR IPF: 0.48, 95% CI: 0.32-0.70), outpatient opioids (aOR COPD: 0.50, 95% CI: 0.40-0.63; aOR IPF: 0.40, 95% CI: 0.29-0.54), and a higher odds of end-of-life ICU use (COPD aOR: 2.88, 95% CI: 2.11-3.93; IPF aOR: 4.15, 95% CI: 2.66-6.49). Patients with IPF had higher odds of receiving inpatient palliative care (aOR: 2.02, 95% CI: 1.30-3.13, p=0.002).

INTERPRETATION: Patients with COPD and IPF are less likely to receive outpatient palliative care and opioid prescriptions and more likely to use end-of-life intensive care than patients with lung cancer. Further research should explore health system barriers contributing to differences in care patterns to optimize quality of life and align with patient goals of care.

PMID:39186972 | DOI:10.1016/j.chest.2024.08.018

Biochem Biophys Res Commun. 2024 Aug 20;739:150567. doi: 10.1016/j.bbrc.2024.150567. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is a severe and progressive lung disease characterized by lung tissue scarring. Transforming growth factor beta 1 (TGFβ1) is crucial in causing pulmonary fibrosis by promoting the activation of fibroblasts and their differentiation into myofibroblasts, which are responsible for excessive extracellular matrix deposition. This study aimed to identify genes activated by TGFβ1 that promote fibrosis and to understand the regulatory pathway controlling myofibroblast. Endothelin-1 (ET-1) was identified as the top-ranking gene in the fibrosis-related gene set using quantitative PCR array analysis. TGFβ1 upregulated EGR1 expression through the ERK1/2 and JNK1/2 MAPK pathways. EGR1 and p-SMAD2 proteins interacted with the ET-1 gene promoter region to regulate TGFβ1-induced ET-1 expression in IMR-90 pulmonary fibroblasts. Mice lacking the Egr1 gene showed reduced ET-1 levels in a model of pulmonary fibrosis induced by intratracheal administration of bleomycin. These findings suggest that targeting EGR1 is a promising approach for treating pulmonary fibrosis, especially idiopathic pulmonary fibrosis, by affecting ET-1 expression and profibrotic reactions.

PMID:39186868 | DOI:10.1016/j.bbrc.2024.150567

Mol Pharm. 2024 Aug 26. doi: 10.1021/acs.molpharmaceut.4c00571. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by unpredictable progression and limited therapeutic options. Current diagnosis relies on high resolution computed tomography (HRCT), which may not adequately capture early signs of deterioration. The enzyme autotaxin (ATX) emerges as a prominently expressed extracellular secretory enzyme in the lungs of IPF patients. The objective of this study was to evaluate the effectiveness of 18F-labeled ATX-targeted tracer [18F]ATX-1905, in comparison with [18F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration. Lung tissue assessments encompassed inflammation severity via H&E staining, and Ashcroft scoring via Masson staining, alongside quantification of ATX expression through ELISA. Positron emission tomography (PET) imaging employing [18F]FDG and [18F]ATX-1905 tracked disease progression pre- and post-treatment. The extent of pulmonary fibrosis corresponded to changes in ATX expression levels in the BPF mouse model. Notably, [18F]ATX-1905 exhibited elevated uptake in BPF lungs during the progression of the disease, particularly evident at the early stage (Day 9). This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer. Conversely, [18F]FDG uptake, peaking at Day 15, decreased subsequently, likely reflective of diminished inflammation. A 2-week treatment regimen using either pirfenidone or nintedanib resulted in notable reductions of ATX expression levels and fibrosis degrees within lung tissues, based on ELISA and Masson staining, as evidenced by PET imaging with [18F]ATX-1905. [18F]FDG uptake also decreased following the treatment period. Additionally, PET/CT imaging extended to a nonhuman primate (NHP) BPF model. The uptake of [18F]ATX-1905 (SUVmax = 2.2) was significantly higher than that of [18F]FDG (SUVmax = 0.7) in fibrotic lung tissue. Using our novel ATX-specific radiotracer [18F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [18F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients.

PMID:39186477 | DOI:10.1021/acs.molpharmaceut.4c00571

Chron Respir Dis. 2024 Jan-Dec;21:14799731241274785. doi: 10.1177/14799731241274785.

ABSTRACT

INTRODUCTION: Multiple studies focusing on chronic lung diseases (i.e. COPD), have indicated that the quality of life (QoL) can be impacted by disease-related fears. In the context of Interstitial Lung Diseases (ILD), however, these have never been systematically examined. Therefore, the aim of the present study was to develop and evaluate an appropriate measuring tool, and to investigate the influence of disease-related anxieties on QoL in ILD.

METHOD: N = 166 ILD patients participated in the study and completed an itempool on disease-related fears, based on the COPD-Anxiety-Questionnaire (CAF-R) and expert assessments. Further, demographic and psychological variables were assessed (anxiety: GAD-7, QoL: K-BILD; Beliefs about Health: KKG). Psychometric properties were analyzed (factor structure, reliability, validity). Regression analyses were used to calculate the differential predictive power of disease-related anxieties on QoL.

RESULTS: The factor structure was confirmed (Scales: Fear-of-Dependence-and-Progression, Fear-of-Social-Exclusion-and-Isolation, Fear-of-Physical-Activity, Fear-of-Dyspnea, and Sleep-related- Complaints). The Scales showed satisfying reliabilities (α = 0.68 to 0.89) and good validity. Disease-related anxieties proved to be differential predictors for different scales of the K-BILD (ß = -0.15 to ß = -0.58, all ps < .01).

CONCLUSIONS: The ILD-Anxiety-Questionnaire (IAQ) is an easy-to-use, valid measurement tool for assessing disease-related anxieties. These vary in their impact on different aspects of QoL. Therefore, it might aid in specifying the indication for potential psychological supplementary interventions. Additional long-term studies are required to investigate how specific anxieties affect both overall and condition-specific QoL in diverse situations.

PMID:39186048 | DOI:10.1177/14799731241274785

Front Immunol. 2024 Aug 9;15:1379480. doi: 10.3389/fimmu.2024.1379480. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by progressive fibrosis, leading to impaired gas exchange and high mortality. The etiology of IPF is complex, with potential links to autoimmune disorders such as hypothyroidism. This study explores the relationship between hypothyroidism and IPF, focusing on the mediating role of plasma proteins.

METHODS: A two-sample Mendelian randomization (MR) approach was employed to determine the impact of hypothyroidism on IPF and the mediating role of 4,907 plasma proteins, all in individuals of European ancestry. Sensitivity analyses, external validation, and reverse causality tests were conducted to ensure the robustness of the findings. Additionally, the function of causal SNPs was evaluated through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses.

CONCLUSION: The findings suggest that hypothyroidism, through altered plasma protein expression, particularly CXCL10, may contribute to the pathogenesis of IPF. This novel insight highlights the potential of CXCL10 as a therapeutic target in IPF, especially in patients with hypothyroidism. The study emphasizes the need for further research into the complex interplay between autoimmune disorders and IPF, with a view towards developing targeted interventions for IPF management.

PMID:39185418 | PMC:PMC11341476 | DOI:10.3389/fimmu.2024.1379480

Front Pharmacol. 2024 Aug 9;15:1451447. doi: 10.3389/fphar.2024.1451447. eCollection 2024.

ABSTRACT

BACKGROUND: Pirfenidone is an antifibrotic medication approved for idiopathic pulmonary fibrosis (IPF). Fybro®, a generic version of pirfenidone developed in South Korea, gained approval and is available in 200 mg and in higher-dose formulations of 400 and 600 mg. This real-world prospective cohort study investigated the safety and effectiveness of Fybro®.

METHODS: A nationwide observational study was conducted in patients with IPF. Patients were followed up for 6 months, with a subset of patients being followed up for 12 months. Data on lung function and adverse events were collected. Patient adherence to fewer-pill (400 and/or 600 mg tablets) and multiple-pill (200 mg tablets) regimens were compared.

RESULTS: Of the 359 enrolled patients, 352 received pirfenidone (Fybro®) at least once and were included in the analysis. The mean age was 69.0 years and 82.4% of patients were male. The median treatment duration was 186.0 days. A total of 253 patients (71.9%) experienced adverse events, with decreased appetite being the most common (16.5%). The adjusted decline rates in lung function were -1.5% and -2.2% predicted per year for forced vital capacity and diffusing capacity, respectively. No significant differences were observed based on the pirfenidone dose. For a daily intake of 1,200 or 1800 mg of pirfenidone, a significantly longer duration of drug administration was observed with the fewer-pill regimen than with multiple-pill regimen.

CONCLUSION: The safety and effectiveness of Fybro® observed in this real-world cohort study are consistent with previous studies. Using higher-strength tablets to reduce pill burden may improve medication adherence.

PMID:39185314 | PMC:PMC11341391 | DOI:10.3389/fphar.2024.1451447

J Thorac Imaging. 2024 Aug 26. doi: 10.1097/RTI.0000000000000803. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease, with a median survival time of 2 to 5 years. The focus of this study is to establish a novel imaging biomarker.

MATERIALS AND METHODS: In this study, 79 patients (19% female) with a median age of 70 years were studied retrospectively. Fully automated body composition analysis (BCA) features (bone, muscle, total adipose tissue, intermuscular, and intramuscular adipose tissue) were combined into Sarcopenia, Fat, and Myosteatosis indices and compared between patients with a survival of more or less than 2 years. In addition, we divided the cohort at the median (high=≥ median, low=<median) of the respective BCA index and tested the impact on the overall survival using the Kaplan-Meier methodology, a log-rank test, and adjusted multivariate Cox-regression analysis.

RESULTS: A high Sarcopenia and Fat index and low Myosteatosis index were associated with longer median survival (35 vs. 16 mo for high vs. low Sarcopenia index, P=0.066; 44 vs. 14 mo for high vs. low Fat index, P<0.001; and 33 vs. 14 mo for low vs. high Myosteatosis index, P=0.0056) and better 5-year survival rates (34.0% vs. 23.6% for high vs. low Sarcopenia index; 47.3% vs. 9.2% for high vs. low Fat index; and 11.2% vs. 42.7% for high vs. low Myosteatosis index). Adjusted multivariate Cox regression showed a significant impact of the Fat (HR=0.71, P=0.01) and Myosteatosis (HR=1.12, P=0.005) on overall survival.

CONCLUSION: The fully automated BCA provides biomarkers with a predictive value for the overall survival in patients with IPF.

PMID:39183570 | DOI:10.1097/RTI.0000000000000803