BMC Pulm Med. 2024 Mar 20;24(1):145. doi: 10.1186/s12890-024-02942-w.

ABSTRACT

BACKGROUND: The potential pathogenic mechanism of idiopathic pulmonary fibrosis is widely recognized to involve immune dysregulation. However, the current pool of studies has yet to establish a unanimous agreement regarding the correlation between various types of immune cells and IPF.

METHODS: By conducting a two-sample Mendelian randomization analysis using publicly available genetic data, the study examined the causal relationship between IPF and 731 immune cells. To ensure the reliability of the results, combined sensitivity analyses and inverse Mendelian analyses were conducted. Moreover, within subgroups, multivariate Mendelian randomization analyses were utilized to investigate the autonomous causal connection between immune cell characteristics and IPF.

RESULTS: After adjusting for false discovery rate, it was discovered that 20 immunophenotypes exhibited a significant association with IPF. After subgrouping for multivariate Mendelian randomization analysis, there were six immunophenotypes that remained significantly associated with IPF. These included CD33 + HLA DR + CD14dim (OR = 0.96, 95% CI 0.93-0.99, P = 0.033), HLA DR + NK (OR = 0.92, 95% CI 0.85-0.98, P = 0.017), CD39 + CD8 + T cell %T cell (OR = 0.93, 95% CI 0.88-0.99, P = 0.024), CD3 on activated & secreting Treg (OR = 0.91, 95% CI 0.84-0.98, P = 0.026), PDL-1 on CD14- CD16 + monocyte (OR = 0.89, 95% CI 0.84-0.95, P = 8 × 10-4), and CD45 on CD33 + HLA DR + CD14- (OR = 1.08, 95% CI 1.01-1.15, P = 0.011).

CONCLUSION: Our study reveals a noteworthy association between IPF and various immune cells, providing valuable insights for clinical research and aiding the advancement of immunologically-based therapeutic strategies.

PMID:38509507 | DOI:10.1186/s12890-024-02942-w

BMC Pulm Med. 2024 Mar 20;24(1):143. doi: 10.1186/s12890-024-02957-3.

ABSTRACT

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AE-IPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations.

METHODS: The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population with AE-IPF, as defined by American Thoracic Society criteria, while excluding patients with an alternative cause for a respiratory decompensation. The primary endpoint of this trial is six-month survival. Secondary endpoints include supplement oxygen requirement and six-minute walk distance which will be assessed immediately prior to treatment and after completion of therapy on day 19, as well as at periodic subsequent visits.

DISCUSSION: The experimental AE-IPF therapy proposed in this clinical trial was adapted from treatment regimens used in other antibody-mediated diseases. The regimen is initiated with TPE, which is expected to rapidly reduce circulating autoantibodies, followed by rituximab to reduce B-cells and finally IVIG, which likely has multiple effects, including affecting feedback inhibition of residual B-cells by Fc receptor occupancy. We have reported potential benefits of this experimental therapy for AE-IPF in previous anecdotal reports. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03286556.

PMID:38509495 | DOI:10.1186/s12890-024-02957-3

Rheumatol Int. 2024 Mar 20. doi: 10.1007/s00296-024-05565-w. Online ahead of print.

ABSTRACT

Patients with rheumatic diseases (RDs) are prone to a number of comorbidities, particularly those affecting the respiratory system due to inflammatory and autoimmune mechanisms. Rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory idiopathic myopathies (IIMs) often present with progressive interstitial lung disease (ILD). The prevalence of ILD varies among patients with RDs, with 11% in RA, 47% in SSc, and 41% in IIMs. Some diagnostic markers, including KL-6, cytokines TNF-α and IL-6, and autoantibodies (anti-CCP), play a crucial role in assessing and predicting the course of pulmonary involvement in RDs. Lung fibrosis is a progressive disorder in SSc and RA, limiting the effiency of therapeutic interventions. Re-evaluating treatment approaches with disease-modifying anti-rheumatic drugs (DMARDs) is crucial for understanding their impact on the risk of lung affections. Despite initial concerns surrounding methotrexate, recent evidence points to its benefits in RA-associated interstitial lung disease (RA-ILD). Recognizing the intricate relationship between autoimmune RDs and lung affections is crucial for formulating effective treatment strategies. Emphasis is placed on collaborative efforts of rheumatologists and pulmonologists for early diagnosis, comprehensive care, and optimal patient outcomes in RA-ILD.

PMID:38509351 | DOI:10.1007/s00296-024-05565-w

BMJ Open Respir Res. 2024 Mar 20;11(1):e001834. doi: 10.1136/bmjresp-2023-001834.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a relatively rare disease with increasing incidence trends. Cardiovascular disease is a significant complication in IPF patients due to the role of common proatherogenic immune mediators. The prevalence of coronary artery disease (CAD) in IPF and the association between these distinct pathologies with overlapping pathophysiology remain less studied.

RESEARCH QUESTION: We hypothesised that IPF is an independent risk factor for CAD.

METHODS: We conducted a retrospective case-control study using the national inpatient sample (2017-2019). We included adult hospitalisations with IPF after excluding other interstitial lung diseases and other endpoints of CAD, acute coronary syndrome and old myocardial infarction. We examined their baseline characteristics, such as demographic data, hospital characteristics and socioeconomic status. The prevalence of cardiac risk factors and CAD was also compared between hospitalisations with and without IPF. Univariate and multivariate regression analysis was further performed to study the odds of CAD with IPF. The cases of IPF in the study population were propensity-matched, after which generalised linear modelling analysis was performed to validate the findings.

RESULTS: A total of 116 010 admissions were hospitalised in 2017-2019 with IPF, of which 55.6% were men with a mean age of 73 years. Adult hospitalisations with IPF were found to have a higher prevalence of diabetes mellitus (29.3% vs 24.0%; p<0.001), hypertension (35.6% vs 33.8%; p<0.001), hyperlipidaemia (47.7% vs 30.2%; p<0.0001) and tobacco abuse (41.7% vs 20.9%; p<0.001), while they had a lower prevalence of obesity (11.7% vs 15.3%; p<0.0001) compared with hospitalisations without IPF. Multivariate logistic regression analysis revealed 28% higher odds of developing CAD in IPF hospitalisations (OR -1.28; CI 1.22 to 1.33; p<0.001). Postpropensity matching, generalised linear modelling analysis revealed even higher odds of CAD with IPF (OR -1.77; CI 1.54 to 2.02; p<0.001) CONCLUSIONS: Our study found a higher prevalence of CAD in IPF hospitalisations and significantly higher odds of CAD among IPF cases. IPF remains a terminal lung disease that portends a poor prognosis, but addressing the cardiovascular risk factors in these patients can help reduce the case fatality rate due to the latter and potentially add to quality-adjusted life years.

PMID:38508700 | DOI:10.1136/bmjresp-2023-001834

Ann Clin Epidemiol. 2022 Oct 26;5(2):37-47. doi: 10.37737/ace.23006. eCollection 2023.

ABSTRACT

BACKGROUND: Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) has a high mortality. However, there is no established treatment for AE-IIPs. Therefore, we aimed to compare the efficacy of high- and low-dose corticosteroid therapies in AE-IIPs patients.

METHODS: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from July 2010 to March 2018. Adult patients with AE-IIPs who received high-dose (methylprednisolone at a dose of 500-1000 mg/day for 3 days starting within 4 days after admission) or low-dose (methylprednisolone at a dose of 100-200 mg/day for at least 5 days starting within 4 days after admission) corticosteroid therapy were identified. Eligible patients (n = 17,317) were divided into the high-dose (n = 16,998) and low-dose (n = 319) groups. A stabilized inverse probability of treatment weighting using propensity scores was performed to compare outcomes between the groups.

RESULTS: The primary outcome was in-hospital mortality, and the secondary outcomes were 28-day mortality, infections during hospitalization, length of hospitalization, duration of steroid use, and discharge to home. The in-hospital mortality rates of the high- and low-dose corticosteroid groups were 50.6% and 47.0%, respectively. In-hospital mortality did not significantly differ between the two groups after stabilized inverse probability of treatment weighting, and the odds ratio in the low-dose corticosteroid group was 0.86 (95% confidence interval: 0.64-1.16; p = 0.33). The secondary outcomes also did not significantly differ between the groups.

CONCLUSIONS: There was no significant difference in outcomes between patients with AE-IIPs who received high- and low-dose corticosteroid therapies.

PMID:38505731 | PMC:PMC10944999 | DOI:10.37737/ace.23006

J Thorac Dis. 2024 Feb 29;16(2):1397-1411. doi: 10.21037/jtd-24-28. Epub 2024 Feb 27.

ABSTRACT

BACKGROUND: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF) in clinic. Astragalus radix (AR; Huangqi) and Angelica sinensis radix (AS; Danggui) have been frequently used in the treatment of IPF. This study aimed to reveal the pharmacological effects and the mechanisms of the action of an AR-AS combination in treating IPF.

METHODS: Sprague-Dawley rats were randomly divided into six groups (n=5): control, bleomycin (BLM) model, AR, AS, AR + AS, and prednisone (PDN) groups. A transforming growth factor-β1 (TGF-β1)-induced MRC-5 cell model were also used. Pulmonary fibrosis, inflammation, oxidative stress, and autophagy were evaluated by performing hematoxylin and eosin (H&E) staining, Masson staining, immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and hydroxyproline assay following the treatment of AR, AS, and the AR-AS herb pair.

RESULTS: Rats administered the AR-AS herb pair had lower α-smooth muscle actin (α-SMA), collagen I, fibronectin, and vimentin levels in lung tissues, and lower inflammatory cytokine levels in rat serum. In addition, the AR-AS herb pair induced mammalian target of rapamycin (mTOR)-mediated autophagy and reduced oxidative stress in BLM-induced rats. The effects of the AR and AS combination were confirmed in MRC-5 cells treated with TGF-β1. Specifically, the combination of AR and AS attenuated MRC-5 cell fibrosis, inflammation, and oxidative stress while inducing autophagy.

CONCLUSIONS: The combination of AR and AS protects against IPF by inducing autophagy via inhibiting the mTOR signaling pathway. The synergistic action of AR and AS is superior to that of either AR or AS alone.

PMID:38505077 | PMC:PMC10944740 | DOI:10.21037/jtd-24-28

J Thorac Dis. 2024 Feb 29;16(2):1034-1043. doi: 10.21037/jtd-23-481. Epub 2024 Feb 27.

ABSTRACT

BACKGROUND: In patients with fibrotic interstitial lung disease (ILD), a progressive pulmonary fibrosis (PPF) typically demonstrates worsening respiratory symptoms, lung function decline and continuing fibrosis. The goal of this study was to compare the three different diagnostic criteria of PPF.

METHODS: Except for idiopathic pulmonary fibrosis (IPF), all consecutive adult patients with fibrotic ILD were retrospectively examined for the three predefined diagnostic criteria of PPF. The three criteria assessed the disease progression in preceding 6 (0.5-year), 12 (1-year) and 24 (2-year) months respectively. The clinical characteristics, decline in predicted percent of forced vital capacity (FVC%) and survival of three groups were compared, followed by determination of risk factors for mortality.

RESULTS: We identified 246 patients by 0.5-year standard, 154 patients by 1-year standard and 281 patients by 2-year standard. Among them, 95% of patients in 1-year group were also included in 2-year group. The average 1-year decline in FVC% was -1.0%, -2.7%, and -4.1% for 0.5-, 1-, and 2-year group respectively. The 4-year survival rate was 74% in 0.5-year group, 66% in 1-year group, and 62% in 2-year group. In multivariate Cox model, only baseline predicted percent diffusing capacity of the lungs for carbon monoxide (DLCO%) <50% was correlated with mortality, with a hazard ratio of 3.4 (95% CI: 1.1-10.6, P=0.03).

CONCLUSIONS: In the current situations, both the 1- and 2-year criterion are the reasonable choice to define PPF both in researches and clinical practice, and DLCO% is an independent predictor for mortality of PPF.

PMID:38505056 | PMC:PMC10944769 | DOI:10.21037/jtd-23-481

J Thorac Dis. 2024 Feb 29;16(2):1234-1246. doi: 10.21037/jtd-23-1145. Epub 2024 Feb 21.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an unrepairable disease that results in lung dysfunction and decreased quality of life. Prevention of pulmonary fibrosis is challenging, while its pathogenesis remains largely unknown. Herein, we investigated the effect and mechanism of long non-coding RNA (lncRNA) DNM3OS/Antisense RNA in the pathogenesis of pulmonary fibrosis.

METHODS: EdU (5-ethynyl-2'-deoxyuridine) and wound healing assays were employed to evaluate the role of DNM3OS on cell proliferation and migration. Western blot detected the proteins expressions of alpha-smooth muscle actin (α-SMA), vimentin, and fibronectin. The interactions among genes were evaluated by RNA pull-down, luciferase reporter, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and chromatin Isolation by RNA purification (ChIRP) assays.

RESULTS: DNM3OS was upregulated by transforming growth factor beta 1 (TGF-β1) in a dose- and time-dependent manner. DNM3OS knockdown repressed the growth and migration of lung fibroblast, and fibrotic gene expression (CoL1α1, CoL3α1, α-SMA, vimentin, and fibronectin), while suppression of TSC2 accelerated the above process. DNM3OS recruited EZH2 to the promoter region of TSC2, increased the occupancy of EZH2 and H3K27me3, and thereby suppressed the expression of TSC2. HOXA5 promoted the transcription of DNM3OS.

CONCLUSIONS: HOXA5-induced DNM3OS promoted the proliferation, migration, and expression of fibrosis-related genes in human embryo lung fibroblast via recruiting EZH2 to epigenetically suppress the expression of TSC2.

PMID:38505042 | PMC:PMC10944743 | DOI:10.21037/jtd-23-1145

J Thorac Dis. 2024 Feb 29;16(2):1128-1140. doi: 10.21037/jtd-23-1057. Epub 2024 Feb 26.

ABSTRACT

BACKGROUND: Pirfenidone and nintedanib were approved by the Food and Drug Administration (FDA) for the treatment of idiopathic pulmonary fibrosis (IPF). These two drugs can slow the progression of the disease, but the specific mechanisms are not fully understood. In the current study, bleomycin (BLM) induced pulmonary fibrosis in mice was accompanied by high p-JAK2 expression in lung tissue, mainly in the nucleus. The expression of p-JAK2 significantly decreased after intragastric administration of pirfenidone and nintedanib. p-JAK2 is reportedly expressed mainly in the cytoplasm and exerts its effect by activating downstream p-STAT3 in the nucleus.

METHODS: In vivo experiments, pulmonary fibrosis was induced in mice with BLM and then treated with pirfenidone and nintedanib. The levels of transforming growth factor-β (TGF-β1), SP-A, SP-D and KL-6 in serum were measured by enzyme-linked immunosorbent assay (ELISA). Pathological staining was performed to assess lung fibrosis in mice, Western blot was performed to detect the expression levels of relevant proteins, and immunofluorescence was performed to observe the fluorescence expression of p-JAK2. In cellular experiments, MLE12 was stimulated with TGF-β1 and intervened with TGF-β1 receptor inhibitor and si-JAK2, pirfenidone and nintedanib, respectively, and the related protein expression levels were detected by Western blot.

RESULTS: In both in vivo and in vitro experiments, pirfenidone and nintedanib were found to attenuate the expression of lung fibrosis markers by inhibiting the expression of JAK2, which may reduce the entry of p-JAK2 into the nucleus by downregulating JAK2 phosphorylation through inhibition of the TGF-β receptor. In contrast, inhibition of JAK2 expression greatly reduced the expression of TGF-β receptor and α-smooth muscles actin (a myofibroblast activation marker).

CONCLUSIONS: In both in vivo and in vitro experiments, the present study demonstrated that TGF-β1 promotes JAK2 phosphorylation through a non-classical pathway, and conversely, inhibition of JAK2 expression affects the TGF-β1 signalling pathway. Therefore, we speculate that TGF-β1 and JAK2 signaling pathways interact with each other and participate in fibrosis.

PMID:38505034 | PMC:PMC10944717 | DOI:10.21037/jtd-23-1057

Ann Clin Epidemiol. 2022 Feb 9;4(2):53-62. doi: 10.37737/ace.22008. eCollection 2022.

ABSTRACT

BACKGROUND: This study aimed to develop criteria for identifying patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) from Japanese administrative data and validate the pre-existing criteria.

METHODS: This retrospective, multi-center validation study was conducted at eight institutes in Japan to verify the diagnostic accuracy of the disease name for AE-IPF. We used the Japanese Diagnosis Procedure Combination data to identify patients with a disease name that could meet the diagnostic criteria for AE-IPF, who were admitted to the eight institutes from January 2016 to February 2019. As a reference standard, two respiratory physicians performed a chart review to determine whether the patients had a disease that met the diagnostic criteria for AE-IPF. Furthermore, two radiologists interpreted the chest computed tomography findings of cases considered AE-IPF and confirmed the diagnosis. We calculated the positive predictive value (PPV) for each disease name and its combination.

RESULTS: We included 830 patients; among them, 216 were diagnosed with AE-IPF through the chart review. We combined the groups of disease names and yielded two criteria: the criteria with a high PPV (0.72 [95% confidence interval 0.62 to 0.81]) and that with a slightly less PPV (0.61 [0.53 to 0.68]) but more true positives. Pre-existing criteria showed a PPV of 0.40 (0.31 to 0.49).

CONCLUSION: The criteria derived in this study for identifying AE-IPF from Japanese administrative data show a fair PPV. Although these criteria should be carefully interpreted according to the target population, our findings could be utilized in future database studies on AE-IPF.

PMID:38504851 | PMC:PMC10760466 | DOI:10.37737/ace.22008

BMC Pulm Med. 2024 Mar 19;24(1):141. doi: 10.1186/s12890-024-02929-7.

ABSTRACT

BACKGROUND: Although inverse associations have been found between medication adherence and healthcare use and spending outcomes in many clinical settings, no studies to date have examined these relationships for patients with idiopathic pulmonary fibrosis (IPF) initiating nintedanib. We build on our prior study that used group-based trajectory modeling (GBTM) to compare inpatient hospitalization and medical care spending outcomes between groups of patients with different nintedanib adherence trajectories.

METHODS: This analysis used 100% Medicare data and included beneficiaries with IPF who initiated nintedanib during 10/01/2014-12/31/2018. The sample consisted of community-dwelling older adults (≥ 66 years) with continuous coverage in Medicare Parts A (inpatient care), B (outpatient care) and D (prescription drugs) for one year before (baseline) and after (follow-up) initiating nintedanib. Patients were assigned to the GBTM-derived adherence trajectory group closest to their own nintedanib adherence experience. All-cause and IPF-related hospitalization events and total medical spending were measured during the follow-up period. Unadjusted and adjusted regression models were estimated to compare outcomes between patients in different nintedanib adherence trajectories.

RESULTS: Among the 1,798 patients initiating nintedanib, the mean age was 75.4 years, 61.1% were male, and 91.1% were non-Hispanic white. The best-fitting GBTM had five adherence trajectories: high adherence, moderate adherence, high-then-poor adherence, delayed-poor adherence, and early-poor adherence. All-cause hospitalizations and total all-cause medical spending were higher among patients in the high-then-poor, delayed-poor and early-poor adherence trajectories than those in the high adherence trajectory. For example, adjusted total all-cause medical spending was $4,876 (95% CI: $1,470 to $8,282) higher in the high-then-poor adherence trajectory, $3,639 (95% CI: $1,322 to $5,955) higher in the delayed-poor adherence trajectory and $3,907 (95% CI: $1,658 to $6,156) higher in the early-poor adherence trajectory compared with the high adherence trajectory. IPF-related hospitalizations and medical care spending were higher among those in the high-then-poor adherence trajectory compared with those in the high adherence trajectory.

CONCLUSIONS: Poor adherence to nintedanib was associated with all-cause hospitalizations and medical costs. Therefore, improved adherence programs, such as support programs, can be implemented to reduce economic burden.

PMID:38504247 | DOI:10.1186/s12890-024-02929-7

BMC Pulm Med. 2024 Mar 20;24(1):142. doi: 10.1186/s12890-024-02961-7.

ABSTRACT

BACKGROUND: The question as to whether or not diabetes mellitus increases the risk of idiopathic pulmonary fibrosis (IPF) remains controversial. This study aimed to investigate the causal association between type 1 diabetes (T1D), type 2 diabetes (T2D), and IPF using Mendelian randomization (MR) analysis.

METHODS: We used two-sample univariate and multivariate MR (MVMR) analyses to investigate the causal relationship between T1D or T2D and IPF. We obtained genome-wide association study (GWAS) data for T1D and T2D from the European Bioinformatics Institute, comprising 29,652 T1D samples and 101,101 T1D single nucleotide polymorphisms (SNPs) and 655,666 T2D samples and 5,030,727 T2D SNPs. We also used IPF GWAS data from the FinnGen Biobank comprising 198,014 IPF samples and 16,380,413 IPF SNPs. All cases and controls in these datasets were derived exclusively from European populations. In the univariate MR analysis, we employed inverse variance-weighted (IVW), weighted median (WM), and MR-Egger regression methods. For the MVMR analysis, we used the multivariate IVW method primarily, and supplemented it with multivariate MR-Egger and multivariate MR- least absolute shrinkage and selection operator methods. Heterogeneity tests were conducted using the MR-IVW and MR-Egger regression methods, whereas pleiotropic effects were assessed using the MR-Egger intercept. The results of MR and sensitivity analyses were visualized using forest, scatter, leave-one-out, and funnel plots.

RESULTS: Univariate MR revealed a significant causal relationship between T1D and IPF (OR = 1.118, 95% CI = 1.021-1.225, P = 0.016); however, no significant causal relationship was found between T2D and IPF (OR = 0.911, 95% CI = 0.796-1.043, P = 0.178). MVMR analysis further confirmed a causal association between T1D and IPF (OR = 1.133, 95% CI = 1.011-1.270, P = 0.032), but no causal relationship between T2D and IPF (OR = 1.009, 95% CI = 0.790-1.288, P = 0.950). Sensitivity analysis results validated the stability and reliability of our findings.

CONCLUSION: Univariate and multivariate analyses demonstrated a causal relationship between T1D and IPF, whereas no evidence was found to support a causal relationship between T2D and IPF. Therefore, in clinical practice, patients with T1D should undergo lung imaging for early detection of IPF.

PMID:38504175 | DOI:10.1186/s12890-024-02961-7

Cureus. 2024 Feb 15;16(2):e54268. doi: 10.7759/cureus.54268. eCollection 2024 Feb.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), which shares a radiographic pattern with the usual interstitial pneumonia (UIP), is a specific form of chronic and progressive interstitial lung disorder resulting in persistent fibrosis and impaired lung function. Most of the patients suffer from dyspnea which adversely affects health-related quality of life (HRQOL). The underlying etiology of the disease is not yet understood, but research done on the subject reveals that aberrant repair mechanisms and dysregulated immune responses may be the cause. It can affect any age group but predominantly affects patients who are above 50 years of age. It has been observed that in addition to age, the reasons are also related to smoking, pollution, and inhalation of harmful elements. As the cause of IPF is still unknown and there is no cure yet, presently, it is treated to delay lung function loss with antifibrotic medications, nintedanib, and pirfenidone. However, both nintedanib and perfenidone have side effects which affect different patients in different ways and with different levels of severity, thereby making the treatment even more challenging for medical practitioners. The present systematic review aims at studying the efficacy of pirfenidone and nintedanib in relieving symptoms and in extending survival in patients. A detailed search was done in relevant articles listed in PubMed, ScienceDirect, and the New England Journal of Medicine between 2018 and 2023. It was observed that the most accepted way of measuring the progression of IPF is the evaluation of pulmonary function by assessing the forced vital capacity (FVC). Several studies have shown that the decline in FVC over a period of 6-12 months is directly associated with a higher mortality rate. The outcomes were similar in both male and female irrespective of age, gender, and ethnicity. However, some patients being treated with pirfenidone and nintedanib experienced various side-effects which were mainly gastrointestinal like diarrhea, dyspepsia, and vomiting. In the case of pirfenidone, some patients also experienced photosensitivity and skin rashes. In cases where the side-effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. The survival rate in patients with IPF is marked by a median of 3-5 years that is even lower than many cancers; hence, the treatment should be started as soon as the disease is detected. However, further research is needed to establish the etiology of IPF and to establish treatments that can stop its progression.

PMID:38500898 | PMC:PMC10945152 | DOI:10.7759/cureus.54268

Phytomedicine. 2024 Jan 17;128:155368. doi: 10.1016/j.phymed.2024.155368. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by the abnormal proliferation of fibroblast and excessive deposition of extracellular matrix (ECM), accompanied by inflammation and ultimately respiratory failure. Yinhuang granule (YHG), with clinical properties of clearing heat, detoxifying and anti-inflammation, is commonly used to heal upper respiratory diseases in China for decades.

PURPOSE: To explore the improvement of YHG on bleomycin (BLM)-induced IPF in mice and its possible engaged mechanism.

METHODS: The mortality rate was recorded, lung function was determined and hematoxylin-eosin (H&E) staining was carried out to explore the alleviation of YHG on BLM-caused IPF in mice. Hydroxyproline, collagen I and collagen III contents were detected, and Sirius red and Masson staining were conducted to evaluate YHG's alleviation on lung fibrosis. The underlying mechanism was predicted by network pharmacology, and confirmed by Real-time polymerase chain reaction (RT-PCR), Western-blot (WB) and enzyme linked immunosorbent assay (ELISA). The binding affinity between related key proteins and active compounds in YHG was calculated by using molecular docking, and further validated by cellular thermal shift assay (CESTA).

RESULTS: YHG (400, 800 mg/kg) weakened lung damage and pulmonary fibrosis in mice induced by BLM. Network pharmacology and experimental validation displayed that inflammation and angiogenesis participated in the YHG-provided improvement on IPF, and key involved molecules included tumor necrosis factor-α (TNFα), vascular endothelial growth factor-A (VEGFA), interleukine-6 (IL-6), etc. The data of molecular docking presented that some main active compounds from YHG had a high binding affinity with TNFR1 or VEGFR2, and some of them were further validated by CESTA.

CONCLUSION: YHG effectively improved the BLM-induced IPF in mice via reducing inflammation and angiogenesis.

PMID:38498951 | DOI:10.1016/j.phymed.2024.155368

Ann Am Thorac Soc. 2024 Mar 18. doi: 10.1513/AnnalsATS.202310-850RL. Online ahead of print.

NO ABSTRACT

PMID:38498902 | DOI:10.1513/AnnalsATS.202310-850RL

Inflammation. 2024 Mar 18. doi: 10.1007/s10753-024-02006-5. Online ahead of print.

ABSTRACT

The apoptosis-prone property of alveolar epithelial cells plays a crucial role in pulmonary fibrosis(PF), but the role of pyroptosis in it is still unclear. Toll-like receptor 9(TLR9) has been reported to play a vital role in the pathogenesis of many diseases. However, the effect of TLR9 on alveolar epithelial cells in PF has not been fully elucidated. Gene expression microarray related to Idiopathic pulmonary fibrosis(IPF) was obtained from the Gene Expression Omnibus(GEO) database. In the mouse model of bleomycin-induced PF, adeno-associated virus(AAV6) was used to interfere with TLR9 to construct TLR9 knockdown mice to study the role of TLR9 in PF, and the specific mechanism was studied by intratracheal instillation of NLR family pyrin domain containing 3(NLRP3) activator. In vitro experiments were performed using A549 cells. Bleomycin-induced pyroptosis in the lung tissue of PF mice increased, and TLR9 protein levels also increased, especially in alveolar epithelial cells. The levels of fibrosis and pyroptosis in lung tissue of TLR9 knockdown mice were improved. We found that TLR9 can bind to the NLRP3, thereby increasing the activation of the NLRP3/caspase-1 inflammasome pathway. When we use the NLRP3 activator, the levels of fibrosis and pyroptosis in lung tissue of TLR9 knockout mice can be counteracted. Pyroptosis of alveolar epithelial cells plays a vital role in PF, and TLR9 can promote NLRP3-mediated pyroptosis of alveolar epithelial cells to aggravate the progression of PF and may become a feasible target for the prevention and treatment of PF.

PMID:38498270 | DOI:10.1007/s10753-024-02006-5

Respirol Case Rep. 2024 Mar 15;12(3):e01323. doi: 10.1002/rcr2.1323. eCollection 2024 Mar.

ABSTRACT

Two cases of intractable chronic cough improved significantly with humidified high flow therapy (HHFT). A 59-year-old woman with Primary Sjogren's disease and interstitial lung disease, was trialled on a Fisher and Paykel myAIRVO™ system. She reported sustained benefits of uninterrupted sleep and increased socialization with tapering use of HHFT. A 67-year-old woman with idiopathic pulmonary fibrosis also benefited from the use of myAIRVO™. She had relentless cough with minimal movement, and nocturnal cough causing fragmented sleep. Her cough subsided considerably with continuous HHFT, but recurred without. Both patients reported significant reductions in the cough visual analogue scale. The mechanisms by which HHFT improve intractable cough may include reducing airway dryness, inhibition of neutrophil inflammation and mucus obstruction, and splinting of the airways. HHFT significantly improved cough and health-related quality of life in two patients with interstitial lung disease. Further research is warranted to explore the role of domiciliary HHFT.

PMID:38496302 | PMC:PMC10942843 | DOI:10.1002/rcr2.1323

J Cell Mol Med. 2024 Apr;28(7):e18191. doi: 10.1111/jcmm.18191.

ABSTRACT

Epigenetic modifications are involved in fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and contribute to the silencing of anti-fibrotic genes. H3K27me3, a key repressive histone mark, is catalysed by the methyltransferase enhancer of Zeste homologue 2 (EZH2), which is regulated by the post-translational modification, O-linked N-Acetylglucosamine (O-GlcNAc). In this study, we explored the effects of O-GlcNAc and EZH2 on the expression of antifibrotic genes, cyclooxygenase-2 (Cox2) and Heme Oxygenase (Homx1). The expression of Cox2 and Hmox1 was examined in primary IPF or non-IPF lung fibroblasts with or without EZH2 inhibitor EZP6438, O-GlcNAc transferase (OGT) inhibitor (OSMI-1) or O-GlcNAcase (OGA) inhibitor (thiamet G). Non-IPF cells were also subjected to TGF-β1 with or without OGT inhibition. The reduced expression of Cox2 and Hmox1 in IPF lung fibroblasts is restored by OGT inhibition. In non-IPF fibroblasts, TGF-β1 treatment reduces Cox2 and Hmox1 expression, which was restored by OGT inhibition. ChIP assays demonstrated that the association of H3K27me3 is reduced at the Cox2 and Hmox1 promoter regions following OGT or EZH2 inhibition. EZH2 levels and stability were decreased by reducing O-GlcNAc. Our study provided a novel mechanism of O-GlcNAc modification in regulating anti-fibrotic genes in lung fibroblasts and in the pathogenesis of IPF.

PMID:38494860 | DOI:10.1111/jcmm.18191

Tissue Cell. 2024 Mar 12;88:102349. doi: 10.1016/j.tice.2024.102349. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung condition that produces symptoms including coughing which may cause by excessive accumulation of scar tissue inflammatory and oxidative stress exacerbation. Sumatriptan, utilized for migraine treatment as a selective 5-HT1B/1D receptor agonist, has demonstrated significant anti-inflammatory and antioxidant properties in multiple preclinical investigations. Operating primarily on serotonin receptors, sumatriptan leverages the diverse physiological functions of serotonin, playing a pivotal role in regulating both inflammation and oxidative stress which is particularly relevant in the context of IPF.

MATERIALS & METHODS: Thirty-five male Wistar rats were divided to five group, including: Sham (without IPF induction), control (BLM 5 mg/kg, intraperitoneally), and three fibrosis group with sumatriptan (0.5, 1, and 3 mg/kg, i.p. for 2 weeks) administration. IPF was induced by injection of BLM (single dose, 5 mg/kg intratracheally). Lung tissues were separated for measurement of myeloperoxidase (MPO) as an oxidative stress hallmark, and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-β), and transforming growth factor-β (TGF-β) as inflammatory markers as well as alpha smooth muscle actin (α-SMA). Also, for histological investigations, tissue damages were assessed by Hematoxylin-eosin (H&E) and Masson's trichrome staining method.

RESULTS: BLM-induced fibrosis could increase α-SMA, MPO, TNF-α, IL-1β, and TGF-β, while treatment with sumatriptan has reversed the α-SMA, MPO, and IL-1β levels. Moreover, the results of H&E and Masson's trichrome staining indicated that sumatriptan (1 and 3 mg/kg) reduced tissue damages, alveolar wall thickness, collagen accumulation, and pulmonary fibrosis induced by BLM.

CONCLUSION: According to the data achieved from this study, Sumatriptan appears to have therapeutic benefits in IPF, possibly via reducing α-SMA as well as inflammation and the toxicity caused by oxidative stress.

PMID:38492426 | DOI:10.1016/j.tice.2024.102349

BMC Pulm Med. 2024 Mar 15;24(1):136. doi: 10.1186/s12890-024-02946-6.

ABSTRACT

BACKGROUND: Lung cancer (LC) is an important comorbidity of interstitial lung disease (ILD) and has a poor prognosis. The clinical characteristics and outcome of each ILD subtype in LC patients have not been sufficiently investigated. Therefore, this study aimed to evaluate the difference between idiopathic pulmonary fibrosis (IPF) and non-IPF ILD as well as prognostic factors in patients with ILD-LC.

METHODS: The medical records of 163 patients diagnosed with ILD-LC at Asan Medical Center from January 2018 to May 2023 were retrospectively reviewed. Baseline characteristics and clinical outcomes were compared between the IPF-LC and non-IPF ILD-LC groups, and prognostic factors were analyzed using the Cox proportional-hazard model.

RESULTS: The median follow-up period was 11 months after the cancer diagnosis. No statistically significant differences were observed in clinical characteristics and mortality rates (median survival: 26 vs. 20 months, p = 0.530) between the groups. The independent prognostic factors in patients with ILD-LC were higher level of Krebs von den Lungen-6 (≥ 1000 U/mL, hazard ratio [HR] 1.970, 95% confidence interval [CI] 1.026-3.783, p = 0.025) and advanced clinical stage of LC (compared with stage I, HR 3.876 for stage II, p = 0.025, HR 5.092 for stage III, p = 0.002, and HR 5.626 for stage IV, p = 0.002). In terms of treatment, surgery was the significant factor for survival (HR 0.235; 95% CI 0.106-0.520; p < 0.001).

CONCLUSIONS: No survival difference was observed between IPF-LC and non-IPF ILD-LC patients. A higher level of Krebs von den Lungen-6 may act as a prognostic marker in ILD-LC patients.

PMID:38491506 | DOI:10.1186/s12890-024-02946-6