Arch Bronconeumol. 2023 Jul 22:S0300-2896(23)00232-6. doi: 10.1016/j.arbres.2023.07.017. Online ahead of print.

NO ABSTRACT

PMID:37537074 | DOI:10.1016/j.arbres.2023.07.017

J Intern Med. 2023 Aug 3. doi: 10.1111/joim.13707. Online ahead of print.

ABSTRACT

Millions of workers are exposed to substances known to cause occupational interstitial lung diseases (ILDs), particularly in developing countries. However, the burden of the disease is likely to be underestimated due to under-recognition, under-reporting, or both. The diagnosis of occupational ILD requires a high level of suspicion and a thorough occupational history, as occupational and non-occupational ILDs may be clinically, functionally and radiologically indistinguishable, leading to delayed diagnosis and inappropriate management. A potential occupational etiology should always be considered in the differential diagnosis of ILD, as removal from the workplace exposure, with or without treatment, is a key therapeutic intervention and may lead to significant improvement. In this article, we provide an overview of the "traditional" inorganic dust-related ILDs, but also address idiopathic pulmonary fibrosis and the immunologically mediated chronic beryllium disease, sarcoidosis and hypersensitivity pneumonitis, with emphasis on the importance of surveillance and prevention for reducing the burden of these conditions. To this end, health care professionals should be specifically trained about the importance of occupational exposures as a potential cause of ILD. This article is protected by copyright. All rights reserved.

PMID:37535448 | DOI:10.1111/joim.13707

Inflammopharmacology. 2023 Aug 3. doi: 10.1007/s10787-023-01286-x. Online ahead of print.

ABSTRACT

OBJECTIVE: Nintedanib (NIN) is an antifibrotic drug approved to slow the progression of idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-related interstitial lung disease (SSc-ILD). NIN can frequently cause gastrointestinal adverse effects. We aimed to investigate the NIN safety profile in a real life setting, comparing IPF and SSc-ILD patients and evaluating the strategies adopted to manage NIN adverse effects.

METHODS: Patients taking NIN for IPF or SSc-ILD were enrolled. Alongside epidemiological and disease-specific data, the period of NIN use and the need for dosage reduction and/or interruption were investigated. Particular attention was paid to possible adverse effects and strategies adopted to manage them.

RESULTS: Twenty-seven SSc-ILD and 82 IPF patients were enrolled. No significant differences emerged between the two cohorts regarding the frequency of any possible adverse effect. Although the rates of NIN dosage reduction or interruption were similar between the two subgroups, SSc-ILD presented a mean period before NIN dosage reduction and NIN interruption significantly shorter than IPF (3 ± 2.6 vs 10.5 ± 8.9 months-p < 0.001 and 2.3 ± 0.5 vs 10.3 ± 9.9 months-p = 0.008, respectively). Several different strategies were tried to manage NIN adverse effects: especially in SSc-ILD, the variable combination of diet adjustment set by a nutritionist, probiotics and diosmectite was ultimately successful in maintaining patients on an adequate dose of NIN.

CONCLUSION: We presented data on the NIN safety profile in a real life setting, which was similar between SSc-ILD and IPF. A combination of multiple managing strategies and dose adjustment appears essential to cope optimally with NIN adverse effects.

PMID:37535212 | DOI:10.1007/s10787-023-01286-x

Respirology. 2023 Aug 3. doi: 10.1111/resp.14563. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Racial disparities have been documented in care of many respiratory diseases but little is known about the impact of race on the treatment of interstitial lung diseases. The purpose of this study was to determine how race and ethnicity influence treatment of idiopathic pulmonary fibrosis.

METHODS: Adults with idiopathic pulmonary fibrosis (>18 years) were identified using TriNetX database and paired-wised comparisons were performed for antifibrotic treatment among White, Black, Hispanic and Asian patients. Mortality of treated and untreated IPF patients was compared after propensity score matching for age, sex, nicotine dependence, oxygen dependence and predicted FVC. Additional comparisons were performed in subgroups of IPF patients older than 65 years of age and with lower lung function.

RESULTS: Of 47,184 IPF patients identified, the majority were White (35,082), followed by Hispanic (6079), Black (5245) and Asian (1221). When subgroups were submitted to matched cohort pair-wise comparisons, anti-fibrotic usage was lower among Black patients compared to White (6.2% vs. 11.4%, p-value <0.0001), Hispanic (10.8% vs. 20.2%, p-value <0.0001) and Asian patients (9.6% vs. 14.7%, p-value = 0.0006). Similar treatment differences were noted in Black individuals older than 65 years and those with lower lung function. Mortality among White patients, but not Hispanic, Black, or Asian patients, was lower in patients on antifibrotic therapy versus not on therapy.

CONCLUSION: This study demonstrated that Black IPF patients had lower antifibrotic use compared to White, Hispanic and Asian patients. Our findings suggest that urgent action is needed to understand the reason why racial disparities exist in the treatment of IPF.

PMID:37534632 | DOI:10.1111/resp.14563

J Adv Vet Anim Res. 2023 Jun 30;10(2):196-204. doi: 10.5455/javar.2023.j669. eCollection 2023 Jun.

ABSTRACT

OBJECTIVE: This study was conducted to establish a rat model of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) using the combination of bleomycin (BLM) and lipopolysaccharides (LPS).

MATERIALS AND METHOD: Twenty-four male Sprague Dawley rats were allocated into two equal groups: the sham or the bleomycin and lipopolysaccharides-induced AE-IPF group (BLM-LPS). On Day 7, BLM intratracheally and LPS intraperitoneally were both used to administer AE-IPF. The BLM-LPS group and its respective sham group were terminated on Days 8, 14, or 21. Samples of bronchoalveolar lavage fluid (BALF) and lungs were taken and investigated for cell count and histopathology.

RESULTS: On Day 8, histological analysis revealed inflammatory cell infiltration with edema and hyaline membrane, and the BALF differential cell count revealed high neutrophil counts. By having a higher collagen density area and Ashcroft modified score than the sham group on Day 14, the BLM-LPS group displayed significantly lower oxygen saturation, alveolar air area, and a fibrotic appearance. However, there was a spontaneous resolution in inflammation and fibrotic appearance on Day 21 after the BLM administration.

CONCLUSIONS: By combining BLM and LPS, it was possible to create a successful rat model of AE-IPF. The present model showed the peak exacerbation on Day 8 and the fibrotic peak on Day 14, which gradually improved. The optimal time for the new AE-IPF therapeutic intervention was determined to be between Days 8 and 14.

PMID:37534065 | PMC:PMC10390678 | DOI:10.5455/javar.2023.j669

BMC Pulm Med. 2023 Aug 2;23(1):281. doi: 10.1186/s12890-023-02565-7.

ABSTRACT

OBJECTIVE: Create a timeline of diagnosis and treatment for IPF in the US.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed in collaboration with the OptumLabs Data Warehouse using an administrative claims database of Medicare Fee for Service beneficiaries. Adults 50 and over with IPF were included (2014 to 2019).

EXPOSURE: To focus on IPF, the following diagnoses were excluded: post-inflammatory fibrosis, hypersensitivity pneumonitis, rheumatoid arthritis, sarcoidosis, scleroderma, and connective tissue disease.

MAIN OUTCOMES AND MEASURES: Data were collected from periods prior, during, and following initial clinical diagnosis of IPF. This included prior respiratory diagnoses, number of respiratory-related hospitalizations, anti-fibrotic and oxygen use, and survival.

RESULTS: A total of 44,891 with IPF were identified. The most common diagnoses prior to diagnosis of IPF were upper respiratory infections (47%), acute bronchitis (13%), other respiratory disease (10%), chronic obstructive pulmonary disease and bronchiectasis (7%), and pneumonia (6%). The average time to a diagnosis of IPF was 2.7 years after initial respiratory diagnosis. Half of patients had two or more respiratory-related hospitalizations prior to IPF diagnosis. Also, 37% of patients were prescribed oxygen prior to diagnosis of IPF. These observations suggest delayed diagnosis. We also observed only 10.4% were treated with anti-fibrotics. Overall survival declined each year after diagnosis with median survival of 2.80 years.

CONCLUSIONS AND RELEVANCE: Our retrospective cohort demonstrates that IPF is often diagnosed late, usually preceded by other respiratory diagnoses and hospitalizations. Use of available therapies is low and outcomes remain poor.

PMID:37532984 | DOI:10.1186/s12890-023-02565-7

Eur J Pharm Sci. 2023 Jul 31:106552. doi: 10.1016/j.ejps.2023.106552. Online ahead of print.

ABSTRACT

BACKGROUND: Autotaxin (ATX) and lysophosphatidic acid (LPA) play an important role in pathogenesis of idiopathic pulmonary fibrosis (IPF). FTP-198 is an oral, novel and selective ATX inhibitor indicated for treating IPF. The study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 in healthy subjects.

METHODS: A single-center, randomized, double-blind, placebo-controlled, single ascending-dose Phase I study was performed. Pharmacokinetics, pharmacodynamics, food effect on pharmacokinetics, elimination, safety and tolerability of FTP-198 were evaluated.

RESULTS: A total of 30 subjects were enrolled and completed the study. After oral administration of single ascending-dose of 100 mg, 300 mg and 400 mg FTP-198 under fasted condition, FTP-198 was absorbed with median time to reach peak concentration (Tmax) of 1.75, 2.75 and 3.5 hours, respectively and eliminated with mean elimination half-life (t1/2) of 8.77, 10.58 and 10.57 hours, respectively. Peak concentration (Cmax), plasma area under concentration-time curve from time 0 to the last measurable concentration (AUC0-t) and to infinity (AUC0-∞) increased in dose-proportional manner for 100 mg to 400 mg FTP-198. Food intake slightly increased the Cmax, AUC0-t and AUC0-∞ and prolonged Tmax, but not affecting t1/2 of FTP-198 compared with fasted state. The pharmacodynamic biomarker plasma lysophosphatidic acid (LPA) 18:2 decreased significantly for 100 mg to 400 mg FTP-198, with inhibition rate from baseline reaching approximately 80% at 24 hours post dosing, and higher dose of FTP-198 increased the time to maintain inhibitory plateau. FTP-198 was eliminated from the body almost with no unchanged drug excreted in urine and a small amount of unchanged drug detected in feces of human. Moreover, FTP-198 exhibited favorable safety and tolerability in healthy subjects.

CONCLUSION: Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 support further subsequent clinical development of FTP -198 in IPF patients.

PMID:37532064 | DOI:10.1016/j.ejps.2023.106552

Lung. 2023 Aug 2. doi: 10.1007/s00408-023-00640-8. Online ahead of print.

ABSTRACT

PURPOSE: The causal relationships between circulating adipokines and idiopathic pulmonary fibrosis (IPF) are yet to be established. We performed a two-sample Mendelian randomization (MR) study to investigate the causal roles of adipokines on IPF risk.

METHODS: We analyzed the summary data from genome-wide association studies (GWAS), including adiponectin, leptin, resistin and monocyte chemoattractant protein-1 (MCP-1) and IPF. The inverse-variance weighted (IVW) method was considered as the major method and the MR-Egger, weighted median, simple mode and weighted mode were utilized as complementary methods. We also performed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test and leave-one-out analysis.

RESULTS: The selected number of single nucleotide polymorphisms (SNPs) was 13 for adiponectin, 6 for leptin,12 for resistin, and 6 for MCP-1, respectively. The results showed a causal effect of the circulating adiponectin levels on the risk of IPF (OR 0.645, 95% CI 0.457-0.911, P = 0.013). However, we did not observe significant associations of genetic changes in serum leptin (OR 1.018, 95% CI 0.442-2.346, P = 0.967), resistin (OR 1.002, 95% CI 0.712-1.408, P = 0.993), and MCP-1 (OR 1.358, 95% CI 0.891-2.068, P = 0.155) with risk of developing IPF. There was no evidence of heterogeneity or horizontal pleiotropy. The sensitivity analyses confirmed that our results were stable and reliable.

CONCLUSIONS: The increase in serum adiponectin was associated causally with a decreased risk of developing IPF. There is no evidence to support a causal association between leptin, resistin or MCP-1 with risk of IPF. Further studies are needed to confirm our findings.

PMID:37530803 | DOI:10.1007/s00408-023-00640-8

Eur Radiol. 2023 Aug 1. doi: 10.1007/s00330-023-10010-w. Online ahead of print.

ABSTRACT

BACKGROUND: High-resolution computed tomography (HRCT), as the main tool for monitoring idiopathic pulmonary fibrosis (IPF), is characterized by subjective variability among radiologists and insensitivity to subtle changes. Recently, a few studies have aimed to decrease subjective bias by assessing the severity of IPF using computer software, i.e., Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER). However, these studies had diverse research directions. In this review, we systematically assess the effect of CALIPER in the management of IPF.

METHODS: A systematic review was conducted through a search of published studies in PubMed, Web of Science, Cochrane, Embase, Scopus, and CNKI databases from database inception through February 28, 2022. The methodological quality would be evaluated by using Methodological Index for Non-Randomized Studies (MINORS). Narrative synthesis summarized findings by participant characteristics, study design, and associations with outcomes.

RESULTS: Ten studies were included. They evaluated the relationship between CALIPER-derived parameters and pulmonary function test (PFT) and mortality. CALIPER-derived parameters showed a significant correlation with PFT and mortality. Two studies reported that CALIPER could be used to stratify outcomes.

CONCLUSION: CALIPER-derived parameters can be used to evaluate prognosis and mortality. CALIPER-derived parameters combined with composite physiologic index (CPI) or Gender-Age-Physiology (GAP) could help clinicians implement targeted management by refining prognostic stratification. However, research has been constrained by small number of retrospective investigations and sample sizes. Therefore, it is essential to design prospective controlled studies and establish the staging system by CALIPER-derived parameters and combining them with CPI, FVC, or GAP.

CLINICAL RELEVANCE STATEMENT: It is beneficial for clinic to provide objective, sensitive, and accurate indicators of disease progression. It also helps the clinic to develop individualized treatment plans based on the stage of disease progression and provides evaluation of efficacy in drug trials.

KEY POINTS: • Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) is a quantitative CT analysis software that can be used to evaluate the progression of disease on CT. • The CALIPER-derived vessel-related structure shows great performance in the management of idiopathic pulmonary fibrosis. • CALIPER-derived parameters combined with composite physiologic index or Gender-Age-Physiology can be used to refine prognostic stratification.

PMID:37528299 | DOI:10.1007/s00330-023-10010-w

Am J Respir Cell Mol Biol. 2023 Aug;69(2):242-246. doi: 10.1165/rcmb.2023-0054LE.

NO ABSTRACT

PMID:37526393 | DOI:10.1165/rcmb.2023-0054LE

Adv Pharmacol. 2023;98:249-271. doi: 10.1016/bs.apha.2023.04.001. Epub 2023 Apr 20.

ABSTRACT

Increasing evidence suggests that there is acceleration of lung ageing in chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), with the accumulation of senescent cells in the lung. Senescent cells fail to repair tissue damage and release an array of inflammatory proteins, known as the senescence-associated secretory phenotype, which drive further senescence and disease progression. This suggests that targeting cellular senescence with senotherapies may treat the underlying disease process in COPD and IPF and thus reduce disease progression and mortality. Several existing or future drugs may inhibit the development of cellular senescence which is driven by chronic oxidative stress (senostatics), including inhibitors of PI3K-mTOR signalling pathways, antagomirs of critical microRNAs and novel antioxidants. Other drugs (senolytics) selectively remove senescent cells by promoting apoptosis. Clinical studies with senotherapies are already underway in chronic lung diseases.

PMID:37524489 | DOI:10.1016/bs.apha.2023.04.001

Adv Pharmacol. 2023;98:179-224. doi: 10.1016/bs.apha.2023.04.002. Epub 2023 Apr 27.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) results from the dysregulated process of injury and repair, which promotes scarring of the lung tissue and deposition of collagen-rich extracellular matrix (ECM) components, that make the lung unphysiologically stiff. IPF presents a serious concern as its pathogenesis remains elusive, and current anti-fibrotic treatments are only effective in slowing rather than halting disease progression. The IPF disease pathogenesis is incompletely defined, complex and incorporates interplay between different fibrogenesis signaling pathways. Preclinical IPF experimental models used to validate drug candidates present significant limitations in modeling IPF pathobiology, with their limited time frame, simplicity and inaccurate representation of the disease and the mechanical influences of IPF. Potentially more accurate mimetic disease models that capture the cell-cell and cell-matrix interaction, such as 3D cultures, organoids and precision-cut lung slices (PCLS), may yield more meaningful clinical predictions for drug candidates. Recent advances in developing anti-fibrotic compounds have positioned drug towards targeting components of the fibrogenesis signaling pathway of IPF or the extracellular microenvironment. The major goals in this area of research focus on finding ways to reverse or halt the disease progression by utilizing more disease-relevant experimental models to improve the qualification of potential drug targets for treating pulmonary fibrosis.

PMID:37524487 | DOI:10.1016/bs.apha.2023.04.002

Adv Pharmacol. 2023;98:111-144. doi: 10.1016/bs.apha.2023.02.002. Epub 2023 Mar 21.

ABSTRACT

Renin-angiotensin system (RAS) plays an indispensable role in regulating blood pressure through its effects on fluid and electrolyte balance. As an aside, cumulative evidence from experimental to clinical studies supports the notion that dysregulation of RAS contributes to the pro-inflammatory, pro-oxidative, and pro-fibrotic processes that occur in pulmonary diseases like asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute lung injury (ALI). Pharmacological intervention of the various RAS components can be a novel therapeutic strategy for the treatment of these respiratory diseases. In this chapter, we first give a recent update on the RAS, and then compile, review, and analyse recent reports on targeting RAS components as treatments for respiratory diseases. Inhibition of the pro-inflammatory renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptor (AT1R) axis, and activation of the protective ACE2, AT2R, Ang (1-7), and Mas receptor axis have demonstrated varying degrees of efficacies in experimental respiratory disease models or in human trials. The newly identified alamandine/Mas-related G-protein-coupled receptor member D pathway has shown some therapeutic promise as well. However, our understanding of the RAS ligand-and-receptor interactions is still inconclusive, and the modes of action and signaling cascade mediating the newly identified RAS receptors remain to be better characterized. Clinical data are obviously lacking behind the promising pre-clinical findings of certain well-established molecules targeting at different pathways of the RAS in respiratory diseases. Translational human studies should be the focus for RAS drug development in lung diseases in the next decade.

PMID:37524485 | DOI:10.1016/bs.apha.2023.02.002

Exp Mol Med. 2023 Aug 1. doi: 10.1038/s12276-023-01066-1. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal, fibrotic, interstitial lung disease of unknown cause. Despite extensive studies, the underlying mechanisms of IPF development remain unknown. Here, we found that p300 was upregulated in multiple epithelial cells in lung samples from patients with IPF and mouse models of lung fibrosis. Lung fibrosis was significantly diminished by the alveolar type II (ATII) cell-specific deletion of the p300 gene. Moreover, we found that ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of p300 led to the transcriptional activation of the chemokines Ccl2, Ccl7, and Ccl12 through the cooperative action of p300 and C/EBPβ, which consequently promoted M2 macrophage polarization. Selective blockade of p300 activity in ATII cells resulted in the reprogramming of M2 macrophages into antifibrotic macrophages. These findings demonstrate a pivotal role for p300 in the development of lung fibrosis and suggest that p300 could serve as a promising target for IPF treatment.

PMID:37524875 | DOI:10.1038/s12276-023-01066-1

Am J Respir Crit Care Med. 2023 Jul 31. doi: 10.1164/rccm.202212-2257OC. Online ahead of print.

ABSTRACT

RATIONALE: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILA) is unknown.

OBJECTIVES: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression.

METHODS: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500 Kb window around rs35705950-T) using an IPF genome-wide association study (GWAS). We assessed PRS associations with area-under-the-receiver-operating-characteristic-curve (AUC) metrics for IPF, ILA, and ILA progression.

MEASUREMENTS AND MAIN RESULTS: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from GWAS, the PRS-M5B (odds ratio [OR] per standard deviation [SD] of the score 3.1, P=7.1x10-95) and PRS-NO-M5B (OR per SD 2.8, P=2.5x10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ~7-fold odds for IPF compared to those in the first quintile. A clinical model predicted IPF (AUC 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC 0.81). The PRS-NO-M5B was associated with ILA (OR 1.25) and ILA progression (OR 1.16) in European ancestry participants.

CONCLUSIONS: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

PMID:37523715 | DOI:10.1164/rccm.202212-2257OC

Aging Dis. 2023 Aug 1;14(4):1441-1457. doi: 10.14336/AD.2022.1202.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and highly lethal inflammatory interstitial lung disease characterized by aberrant extracellular matrix deposition. Macrophage activation by cytokines released from repetitively injured alveolar epithelial cells regulates the inflammatory response, tissue remodeling, and fibrosis throughout various phases of IPF. Our previous studies demonstrate that nuclear factor of activated T cells cytoplasmic member 3 (NFATc3) regulates a wide array of macrophage genes during acute lung injury pathogenesis. However, the role of NFATc3 in IPF pathophysiology has not been previously reported. In the current study, we demonstrate that expression of NFATc3 is elevated in lung tissues and pulmonary macrophages in mice subjected to bleomycin (BLM)-induced pulmonary fibrosis and IPF patients. Remarkably, NFATc3 deficiency (NFATc3+/-) was protective in bleomycin (BLM)-induced lung injury and fibrosis. Adoptive transfer of NFATc3+/+ macrophages to NFATc3+/- mice restored susceptibility to BLM-induced pulmonary fibrosis. Furthermore, in vitro treatment with IL-33 or conditioned medium from BLM-treated epithelial cells increased production of CCL2 and CXCL2 in macrophages from NFATc3+/+ but not NFATc3+/- mice. CXCL2 promoter-pGL3 Luciferase reporter vector showed accentuated reporter activity when co-transfected with the NFATc3 expression vector. More importantly, exogenous administration of recombinant CXCL2 into NFATc3+/- mice increased fibrotic markers and exacerbated IPF phenotype in BLM treated mice. Collectively, our data demonstrate, for the first time, that NFATc3 regulates pulmonary fibrosis by regulating CCL2 and CXCL2 gene expression in macrophages.

PMID:37523510 | DOI:10.14336/AD.2022.1202

PLoS Genet. 2023 Jul 31;19(7):e1010825. doi: 10.1371/journal.pgen.1010825. Online ahead of print.

ABSTRACT

Finding disease-relevant tissues and cell types can facilitate the identification and investigation of functional genes and variants. In particular, cell type proportions can serve as potential disease predictive biomarkers. In this manuscript, we introduce a novel statistical framework, cell-type Wide Association Study (cWAS), that integrates genetic data with transcriptomics data to identify cell types whose genetically regulated proportions (GRPs) are disease/trait-associated. On simulated and real GWAS data, cWAS showed good statistical power with newly identified significant GRP associations in disease-associated tissues. More specifically, GRPs of endothelial and myofibroblasts in lung tissue were associated with Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease, respectively. For breast cancer, the GRP of blood CD8+ T cells was negatively associated with breast cancer (BC) risk as well as survival. Overall, cWAS is a powerful tool to reveal cell types associated with complex diseases mediated by GRPs.

PMID:37523391 | DOI:10.1371/journal.pgen.1010825

Front Immunol. 2023 Jul 13;14:1185443. doi: 10.3389/fimmu.2023.1185443. eCollection 2023.

ABSTRACT

RATIONALE: Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial.

OBJECTIVES: We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype.

METHODS: We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients.

MEASUREMENTS AND RESULTS: An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased.

CONCLUSION: A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.

PMID:37520566 | PMC:PMC10374842 | DOI:10.3389/fimmu.2023.1185443

Clin Chest Med. 2023 Sep;44(3):575-584. doi: 10.1016/j.ccm.2023.06.003.

ABSTRACT

Interstitial lung disease (ILD), a clinically recognized group of diseases resulting in pulmonary fibrosis, affects up to 200 individuals per 100,000 in the United States. Sarcoidosis has a wide range of clinical manifestations including pulmonary fibrosis. Health disparities are prevalent in both ILD and sarcoidosis around socioeconomic status, race, gender, and geographic location. This review outlines the known health disparities, discusses possible determinants of disparities, and outlines a path to achieve equity in ILD and sarcoidosis.

PMID:37517836 | DOI:10.1016/j.ccm.2023.06.003

Exp Anim. 2023 Jul 28. doi: 10.1538/expanim.23-0048. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a poor prognosis disease that affects approximately 5 million people worldwide, and the detailed mechanisms underlying the pathogenesis of IPF remain unclear. Bleomycin-induced pulmonary fibrosis has been widely used as a representative animal model of IPF that induces fibrosis in lung tissue. The lungs of rodent consist of five lobes and each bronchus enters each lobe of the lung at a different bifurcation angle, path length, and diameter. The method of administration of bleomycin is considered as important thing to establish appropriate animal models. We conducted a time-dependent histopathological study to examine how pulmonary fibrosis develops in each lung lobe when bleomycin is intratracheally sprayed in ICR mice. And we then explored the suitable points for evaluation of anti-fibrotic agents in this model. As a result, we found that homogeneous fibrosis was induced in the 5 lobes of the lungs following initial inflammation. The expression of TGF-β1 and pSmad2 was observed from Day 1, and their positivity increased until Day 21. In conclusion, we have observed a detailed time course of histological changes in bleomycin-induced pulmonary fibrosis in ICR mice using the aerosolization technique. We found that our protocol can induce a highly homogeneous lesion in the lung and that the most suitable time point to assess anti-fibrotic agents is 14 days after treatment in this model.

PMID:37518267 | DOI:10.1538/expanim.23-0048