Front Physiol. 2022 Oct 6;13:980942. doi: 10.3389/fphys.2022.980942. eCollection 2022.

ABSTRACT

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

PMID:36277208 | PMC:PMC9582781 | DOI:10.3389/fphys.2022.980942

Oxid Med Cell Longev. 2022 Oct 12;2022:7686956. doi: 10.1155/2022/7686956. eCollection 2022.

ABSTRACT

Ferroptosis is a type of programmed cell death characterized by iron overload, oxidative stress, imbalance in lipid repair, and mitochondria-specific pathological manifestations. Growing number of molecular mechanisms and signaling pathways have been found to be involved in ferroptosis progression, including iron metabolism, amino acid metabolism, lipid metabolism, and energy metabolism. It is worth noting that ferroptosis is involved in the progression of fibrotic diseases such as liver cirrhosis, cardiomyopathy, and idiopathic pulmonary fibrosis, and inhibition of ferroptosis has acquired beneficial outcomes in rodent models, while studies on ferroptosis and renal fibrosis remains limited. Recent studies have revealed that targeting ferroptosis can effectively mitigate chronic kidney injury and renal fibrosis. Moreover, myofibroblasts suffer from ferroptosis during fiber and extracellular matrix deposition in the fibrotic cascade reaction and pharmacological modulation of ferroptosis shows great therapeutic effect on renal fibrosis. Here, we summarize the latest molecular mechanisms of ferroptosis from high-quality studies and review its therapeutic potential in renal fibrosis.

PMID:36275899 | PMC:PMC9581688 | DOI:10.1155/2022/7686956

Allergy Asthma Clin Immunol. 2022 Oct 21;18(1):93. doi: 10.1186/s13223-022-00734-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with limited treatment options. Plumbagin (PL) is an herbal extract with diverse pharmacological effects that have been recently used to treat various types of cancer. This study aims to explore the anti-fibrotic effect of PL and possible underlying mechanisms in IPF.

METHODS: We used a bleomycin-induced experimental mouse model of lung fibrosis to assess the potential anti-fibrotic effect of PL. Histological analysis of lung tissue samples by H&E and Masson's trichrome staining and hydroxyproline assay was performed to evaluate the fibrotic alterations. ELISA and real-time quantitative PCR were conducted to determine the amount of tumor necrosis factor-alpha (TNFα), tumor growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and endothelin-1 (ET-1).

RESULTS: Bleomycin exposure induced lung fibrosis, which was indicated by inflammation, collagen deposition, and structural damage. PL remarkably prevented bleomycin-induced lung fibrosis. Furthermore, PL significantly inhibited TNF-α and TGF-β production. PL also diminished the upregulated expression of CTGF and ET-1 induced by bleomycin.

CONCLUSION: Overall, our findings suggest PL as an anti-fibrotic agent acting via down-regulation of TGF-β/CTGF or ET-1 axis, as well as TNF-α, to improve lung fibrosis.

PMID:36271442 | DOI:10.1186/s13223-022-00734-7

Monaldi Arch Chest Dis. 2022 Oct 21. doi: 10.4081/monaldi.2022.2363. Online ahead of print.

ABSTRACT

Pleuroparenchymal fibroelastosis (PPFE) is a rare lung disease with unprecedented features characterized by fibroelastotic changes in the subpleural lung parenchyma affecting the upper lobes. PPFE is usually idiopathic, but it can be caused by infection, autoimmunity, bone marrow or lung transplantation, or a genetic predisposition. Histopathologic examination of lung biopsy samples reveals homogenous subpleural fibrosis and abundant elastic fibers, allowing for a definitive diagnosis. As PPFE mimics many interstitial lung diseases, clinicians face significant difficulties in making a definitive final diagnosis. Since most disease-related comorbid conditions manifest at an advanced stage, invasive tissue sampling for histopathologic evaluation is consistently impossible. Such a patient presentation highlights the importance of an analysis based solely on clinical findings, which would provide a definitive diagnosis without the need for a biopsy. Because of its exceptional and inconceivable presentation, PPFE creates a diagnostic dilemma. In light of our two cases and the literature data, we present a diagnostic assessment score assay that relies solely on clinical manifestations without histopathological tissue verification to shed light on the diagnosis of PPFE. This review focuses on PPFE identification through the use of a diagnostic assessment analysis to improve early disease recognition without the use of invasive diagnostic interventions to obtain biopsy samples for histopathologic evaluation. This analytic approach, while not diagnostic in and of itself, may provide a useful pathway for differential diagnosis and may preclude redundant initiatives.

PMID:36269206 | DOI:10.4081/monaldi.2022.2363

Ann Transl Med. 2022 Sep;10(18):992. doi: 10.21037/atm-22-4042.

ABSTRACT

BACKGROUND: Elevated expression of human epididymis protein 4 (HE4) was previously described in connective tissue disease-associated interstitial lung diseases (CTD-ILDs) and cystic fibrosis (CF), but the clinical significance of HE4 has remained unknown in idiopathic pulmonary fibrosis (IPF), which is a progressive fibrosing ILD with a heterogeneous course that is in urgent need of reliable biomarkers in its clinical practice.

METHODS: A total of 27 IPF patients with acute exacerbation status (AE-IPF), 32 IPF patients with stable status (S-IPF), and 29 sex-age matched healthy controls were retrospectively included. The levels of serum HE4 and Krebs von den Lungen-6 (KL-6) of the 3 cohorts were measured. In addition, the pulmonary expression of HE4 was evaluated in lung transplant specimens of IPF using immunohistochemistry and Western blot, and noncancerous lung tissue resected from early-stage lung cancer patients as controls. The endpoint of follow-up was March 1st, 2022, and the Cox regression model was used to analyze the prognostic value of HE4.

RESULTS: The levels of HE4 and KL-6 were obviously elevated in AE-IPF patients compared to S-IPF (296.4 vs. 178.1 pmol/L for HE4, P<0.001; 2,007.0 vs. 990.5 IU/mL for KL-6, P<0.001) or healthy controls (296.4 vs. 51.8 pmol/L for HE4, P<0.001; 2,007.0 vs. 181.0 IU/mL for KL-6, P<0.001). Significant correlations were observed between serum HE4 levels and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r=-0.526, P<0.001), percent predicted forced vital capacity (FVC%) (r=-0.344, P=0.024), gender-age-physiology (GAP) index (r=0.535, P<0.001), and oxygenation index (r=-0.550, P<0.001) in IPF patients. In histological analysis, overexpression of HE4 in mucosal epithelium of dilated bronchi was observed in IPF patients compared with controls. Multivariate cox regression revealed that serum levels of HE4 [hazard ratio (HR) =1.004, P=0.042] and GAP index (HR =1.374, P=0.010) were associated with worse survival in IPF patients.

CONCLUSIONS: The expression of serum HE4 was obviously elevated in IPF patients, especially in AE-IPF patients. In addition, serum HE4 could be utilized as a biomarker of disease severity and poor prognosis of IPF patients. These findings warrant further validation in larger, multi-center, and longitudinal cohorts.

PMID:36267722 | PMC:PMC9577718 | DOI:10.21037/atm-22-4042

Front Physiol. 2022 Oct 4;13:867473. doi: 10.3389/fphys.2022.867473. eCollection 2022.

ABSTRACT

We applied quantitative CT image matching to assess the degree of motion in the idiopathic ILD such as usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). Twenty-one normal subjects and 42 idiopathic ILD (31 UIP and 11 NSIP) patients were retrospectively included. Inspiratory and expiratory CT images, reviewed by two experienced radiologists, were used to compute displacement vectors at local lung regions matched by image registration. Normalized three-dimensional and two-dimensional (dorsal-basal) displacements were computed at a sub-acinar scale. Displacements, volume changes, and tissue fractions in the whole lung and the lobes were compared between normal, UIP, and NSIP subjects. The dorsal-basal displacement in lower lobes was smaller in UIP patients than in NSIP or normal subjects (p = 0.03, p = 0.04). UIP and NSIP were not differentiated by volume changes in the whole lung or upper and lower lobes (p = 0.53, p = 0.12, p = 0.97), whereas the lower lobe air volume change was smaller in both UIP and NSIP than normal subjects (p = 0.02, p = 0.001). Regional expiratory tissue fractions and displacements showed positive correlations in normal and UIP subjects but not in NSIP subjects. In summary, lung motionography quantified by image registration-based lower lobe dorsal-basal displacement may be used to assess the degree of motion, reflecting limited motion due to fibrosis in the ILD such as UIP and NSIP.

PMID:36267579 | PMC:PMC9577177 | DOI:10.3389/fphys.2022.867473

Front Endocrinol (Lausanne). 2022 Oct 4;13:1001563. doi: 10.3389/fendo.2022.1001563. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition with an unfavorable prognosis. A recent study has demonstrated that IPF patients exhibit characteristic alterations in the fatty acid metabolism in their lungs, suggesting an association with IPF pathogenesis. Therefore, in this study, we have explored whether the gene signature associated with fatty acid metabolism could be used as a reliable biological marker for predicting the survival of IPF patients.

METHODS: Data on the fatty acid metabolism-related genes (FAMRGs) were extracted from databases like Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, and Reactome pathway. The GSE70866 dataset with information on IPF patients was retrieved from the Gene Expression Omnibus (GEO). Next, the consensus clustering method was used to identify novel molecular subgroups. Gene Set Enrichment Analysis (GSEA) was performed to understand the mechanisms involved. The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the level of immune cell infiltration in the identified subgroups based on gene expression signatures of immune cells. Finally, the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate Cox regression analysis were performed to develop a prognostic risk model.

RESULTS: The gene expression signature associated with fatty acid metabolism was used to create two subgroups with significantly different prognoses. GSEA reveals that immune-related pathways were significantly altered between the two subgroups, and the two subgroups had different metabolic characteristics. High infiltration of immune cells, mainly activated NK cells, monocytes, and activated mast cells, was observed in the subgroup with a poor prognosis. A risk model based on FAMRGs had an excellent ability to predict the prognosis of IPF. The nomogram constructed using the clinical features and the risk model could accurately predict the prognosis of IPF patients.

CONCLUSION: The fatty acid metabolism-related gene expression signature could be used as a potential biological marker for predicting clinical outcomes and the level of infiltration of immune cells. This could eventually enhance the accuracy of the treatment of IPF patients.

PMID:36267568 | PMC:PMC9576944 | DOI:10.3389/fendo.2022.1001563

EBioMedicine. 2022 Oct 17;85:104304. doi: 10.1016/j.ebiom.2022.104304. Online ahead of print.

ABSTRACT

BACKGROUND: MicroRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported that systemically delivered miR-29 mimic MRG-201 reduced fibrosis in animal models, supporting the consideration of miR-29-based therapies for idiopathic pulmonary fibrosis (IPF).

METHODS: We generated MRG-229, a next-generation miR-29 mimic based on MRG-201 with improved chemical stability due to additional sugar modifications and conjugation with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide)1. We investigated the anti-fibrotic efficacy of MRG-229 on TGF-β1 treated human lung fibroblasts (NHLFs), human precision cut lung slices (hPCLS), and in vivo bleomycin studies; toxicology was assessed in two animal models, rats, and non-human primates. Finally, we examined miR-29b levels in a cohort of 46 and 213 patients with IPF diagnosis recruited from Yale and Nottingham Universities (Profile Cohort), respectively.

FINDINGS: The peptide-conjugated MRG-229 mimic decreased expression of pro-fibrotic genes and reduced collagen production in each model. In bleomycin-treated mice, the peptide-conjugated MRG-229 mimic downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, the peptide-conjugated MRG-229 mimic was well tolerated at clinically relevant doses with no adverse findings observed. In human peripheral blood from IPF patients decreased miR-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment.

INTERPRETATION: Collectively, our results provide support for the development of the peptide-conjugated MRG-229 mimic as a potential therapy in humans with IPF.

FUNDING: This work was supported by NIH NHLBI grants UH3HL123886, R01HL127349, R01HL141852, U01HL145567.

PMID:36265417 | DOI:10.1016/j.ebiom.2022.104304

Acta Histochem. 2022 Oct 17;124(8):151961. doi: 10.1016/j.acthis.2022.151961. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) represents a fatal pulmonary disease. Its mechanisms remain unclear and effective therapies are urgently needed. Glutaminolysis is involved in IPF pathology, but little is known about the role of ASCT2 responsible for cellular uptake of glutamine in IPF. We investigated the role of ASCT2 and its therapeutic implication in IPF through knockdown of ASCT2 in mice.

METHODS: Mouse IPF model was established through a single intratracheal administration of bleomycin, and lentivirus-coated ASCT2 siRNA was administrated into mice via caudal vein for knockdown of ASCT2. Mouse blood and lung tissues were collected for biochemical, histological, and molecular examinations.

RESULTS: ASCT2 siRNA significantly lowered ASCT2 expression in mouse lung tissues. Knockdown of ASCT2 reduced pulmonary levels of glutamic acid, α-ketoglutarate, glutathione and ATP, mitigated pulmonary histological injury, and reduced serum concentrations of pulmonary injury parameters including SP-A, SP-D, KL-6 and CCL18 in IPF mice. Moreover, serum levels of fibrotic parameters HA, LN, PC-III and IV-C were lowered by ASCT2 depletion. Collagen production and pulmonary hydroxyproline levels were also decreased by ASCT2 siRNA in IPF mice, which was concomitant with downregulation of α-smooth muscle actin, collagen type Iα1 and transforming growth factor-β receptor II. Furthermore, ASCT2 deficiency downregulated the mRNA and protein expression of inflammatory cytokines IL-1β and TNF-α as well as macrophage marker F4/80 in lung tissues of IPF mice.

CONCLUSIONS: Inhibition of ASCT2 effectively mitigated pulmonary injury, fibrosis and inflammation in mice with bleomycin-induced IPF. ASCT2 could be a novel therapeutic target for treatment of IPF.

PMID:36265204 | DOI:10.1016/j.acthis.2022.151961

Comput Math Methods Med. 2022 Oct 8;2022:1685384. doi: 10.1155/2022/1685384. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common and highly lethal pulmonary interstitial lung disease. The current study is aimed at investigating reliable markers suitable for the treatment and identification of IPF. This study constructed the first 5-methylcytosine- (m5C-) and immune-related prognostic signature (m5CPS) based on coexpressed genes of m5C regulatory genes and immune-related genes. The m5CPS was established using the training cohort (n = 68) and verified using the test (n = 44) and validation (n = 64) cohorts. The area under the curve (AUC) values were utilized to evaluate the accuracy of m5CPS in predicting the survival of IPF patients. The Kaplan-Meier curves and Cox regression analyses were used to assess the prognostic effect of m5CPS. The AUC was utilized to evaluate the reliability of m5CPS in distinguishing IPF patients from healthy individuals. In terms of the results, m5CPS could predict the one-, three-, and five-year survival rates of IPF patients with high accuracy (AUC = .803-.973). In fact, m5CPS is not only an independent indicator of the poor prognosis of IPF patients (hazard ratio > 1; p < .05) but can also distinguish IPF patients from healthy individuals (AUC = .862). Also, m5CPS may affect the immune response and inflammatory response, and it was positively associated with the infiltration levels of active mast cells (p < .05). In sum, the current study establishes a novel m5CPS for IPF and reveals the role of m5CPS as a reliable marker for predicting the prognosis and disease status of IPF patients.

PMID:36262873 | PMC:PMC9574547 | DOI:10.1155/2022/1685384

Int Immunopharmacol. 2022 Oct 15;113(Pt A):109294. doi: 10.1016/j.intimp.2022.109294. Online ahead of print.

ABSTRACT

BACKGROUND: Discoidin Domain Receptor1 (DDR1) is a member of receptor tyrosine kinases (RTKs) which have been reported to be associated with idiopathic pulmonary fibrosis (IPF), but the mechanism remains unclear.

METHODS: Bleomycin-induced IPF mice model was performed in this study, and two DDR1 inhibitors were administered in vivo, to investigate the role of DDR1 in IPF. Lentivirus mediated DDR1-/- stable Raw264.7 macrophage cell line or DDR1 inhibitors treatment in vitro, to study the effect of DDR1 on inflammasome activation and macrophage responses. All of the mechanisms were further tested in the lung sections of IPF patients.

RESULT: Here, we reported that: (i) Both specific inhibitors of DDR1 dramatically alleviated the symptoms of bleomycin-induced IPF models. (ii) Immunofluorescence staining showed that DDR1 signaling is activated in macrophages. In vivo molecular biological analysis proved that DDR1 activation exacerbates IPF inflammation through inflammasome signaling, macrophage activation, and M1/M2 polarization. (iii) Extracellular matrix (ECM) such as Collagen 1 activates DDR1 in macrophage cell line Raw264.7 in vitro, to mediate inflammasome activation and macrophage responses. (iv) DDR1 activation in macrophage was confirmed in IPF patients' samples, which could be one of the mechanisms for the pathogenesis of IPF.

DISCUSSION: In this study, we firstly reported DDR1 activation in macrophages to play a role in IPF via inflammasome activation and macrophage responses. In addition, DDR1 inhibitors DDR1-IN-1 and DDR1-IN-2 exerted significant anti-inflammatory and anti-fibrotic effects in IPF, all of which provide a potentially effective therapeutic medication for clinical IPF treatment.

PMID:36257259 | DOI:10.1016/j.intimp.2022.109294

Med Phys. 2022 Oct 18. doi: 10.1002/mp.16053. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and usually fatal lung disease of unknown reasons, generally affecting the elderly population. Early diagnosis of IPF is crucial for triaging patients' treatment planning into anti-fibrotic treatment or treatments for other causes of pulmonary fibrosis. However, current IPF diagnosis workflow is complicated and time-consuming, which involves collaborative efforts from radiologists, pathologists, and clinicians and it is largely subject to inter-observer variability.

PURPOSE: The purpose of this work is to develop a deep learning-based automated system that can diagnose subjects with IPF among subjects with interstitial lung disease (ILD) using an axial chest computed tomography (CT) scan. This work can potentially enable timely diagnosis decisions and reduce inter-observer variability.

METHODS: Our dataset contains CT scans from 349 IPF patients and 529 non-IPF ILD patients. We used 80% of the dataset for training and validation purposes and 20% as the holdout test set. We proposed a two-stage model: at stage one, we built a Multi-Scale, domain knowledge-Guided Attention model (MSGA) that encouraged the model to focus on specific areas of interest to enhance model explainability, including both high- and medium- resolution attentions; at stage two, we collected the output from MSGA and constructed a random forest (RF) classifier for patient-level diagnosis, to further boost model accuracy. RF classifier is utilized as a final decision stage since it is interpretable, computationally fast, and can handle correlated variables. Model utility was examined by (1) accuracy, represented by the area under the receiver operating characteristic curve (AUC) with standard deviation (SD), and (2) explainability, illustrated by the visual examination of the estimated attention maps which showed the important areas for model diagnostics.

RESULTS: During the training and validation stage, we observe that when we provide no guidance from domain knowledge, the IPF diagnosis model reaches acceptable performance (AUC ± SD = 0.93 ± 0.07), but lacks explainability; when including only guided high- or medium- resolution attention, the learned attention maps are not satisfactory; when including both high- and medium- resolution attention, under certain hyperparameter settings, the model reaches the highest AUC among all experiments (AUC ± SD = 0.99 ± 0.01) and the estimated attention maps concentrate on the regions of interests for this task. Three best-performing hyperparameter selections according to MSGA were applied to the holdout test set and reached comparable model performance to that of the validation set.

CONCLUSIONS: Our results suggest that, for a task with only scan-level labels available, MSGA+RF can utilize the population-level domain knowledge to guide the training of the network, which increases both model accuracy and explainability. This article is protected by copyright. All rights reserved.

PMID:36254789 | DOI:10.1002/mp.16053

Respirol Case Rep. 2022 Oct 12;10(11):e01051. doi: 10.1002/rcr2.1051. eCollection 2022 Nov.

ABSTRACT

We report a rare case of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) after coronavirus disease 2019 (COVID-19) vaccination. Clinicians should be aware of this COVID-19 vaccination-induced AE in IPF.

PMID:36254333 | PMC:PMC9556549 | DOI:10.1002/rcr2.1051

J Toxicol Environ Health B Crit Rev. 2022 Oct 17:1-21. doi: 10.1080/10937404.2022.2131663. Online ahead of print.

ABSTRACT

The objectives of this systematic review of original articles published up until August 2021 and meta-analyses were to identify the links between occupational and non-occupational environmental exposures, types of occupations and idiopathic pulmonary fibrosis (IPF). Sixteen selected case-control studies were qualified as good level with Newcastle-Ottawa quality assessment scale. Sensitivity analyses highlighted the role of choice of control group, tobacco adjustment and diagnostic tools. Significantly increased risks of IPF were observed (OR (95%CI): for metals (1.42(1.05-1.92)), wood (OR:1.32(1.02-1.71)), and general dust (OR:1.32(1.08-1.63)) exposures. Subgroup analyses found a significantly elevated risk for: hardwood (OR:1.75 (1.13-2.70)), organic dusts (OR:1.72 (1.20-2.46)) and pesticides (OR:2.30 (1.30-4.08)), while no significant change was noted for softwoods and solvents. Smoking adjustments: general dust (1.45 (1.04-2.03)/organic dust (2.5 (1.49-4.22)/metals (1.87 (1.16-3)/wood dust OR: 1.16 (0.86-1.61)/pesticide exposure 2.4 (0.84-6.9) were calculated. Among agricultural workers, the risk was also increased (OR:2.06 (1.02-4.16)). Few environmental data were available and no significant associations detected. Thus, these meta-analyses highlighted the role of some occupational exposures in IPF occurrence. A more accurate and thorough assessment of exposures over the entire working life as well as on the duration and intensity of exposure and complex of multi-pollutant exposure is needed in future research and clinical practice.

PMID:36253946 | DOI:10.1080/10937404.2022.2131663

Sci Rep. 2022 Oct 17;12(1):17397. doi: 10.1038/s41598-022-22449-w.

ABSTRACT

There have been limited studies on the association between prognosis and body weight change in patients with idiopathic pulmonary fibrosis (IPF). This single-center retrospective observational study evaluated the impact of weight loss on outcomes in Korean patients with IPF receiving pirfenidone at a tertiary medical institution. We analyzed 215 IPF patients prescribed pirfenidone from January 1st, 2015 to December 31st, 2019. The patients were categorized into maintained weight (MW; weight gain or loss < 5%/year) and reduced weight (RW; weight loss ≥ 5%/year) groups. The mean age was 71.8 years and 175 (81.4%) were male. There were 54 (25.1%) patients in the RW group. All patients showed a decrease in body weight (baseline vs. after 1 year; 64.1 kg vs. 62.8 kg, P < 0.001). Although baseline lung function showed a difference, there was no difference in the rate of change (forced vital capacity [% of predicted]; P = 0.221, diffusing capacity of the lung for carbon monoxide [% of predicted]; P = 0.973). The MW group had a lower risk of all-cause mortality (P < 0.001). Weight loss appeared to be a significant risk factor for mortality in patients with IPF. Not only disease control with antifibrotic agents, but also efforts to prevent weight loss may be necessary.

PMID:36253395 | DOI:10.1038/s41598-022-22449-w

Magn Reson Imaging. 2022 Oct 14:S0730-725X(22)00177-1. doi: 10.1016/j.mri.2022.10.005. Online ahead of print.

ABSTRACT

PURPOSE: To compare imaging biomarkers from hyperpolarised 129Xe ventilation MRI and dynamic oxygen-enhanced MRI (OE-MRI) with standard pulmonary function tests (PFT) in interstitial lung disease (ILD) patients. To evaluate if biomarkers can separate ILD subtypes and detect early signs of disease resolution or progression.

STUDY TYPE: Prospective longitudinal.

POPULATION: Forty-one ILD (fourteen idiopathic pulmonary fibrosis (IPF), eleven hypersensitivity pneumonitis (HP), eleven drug-induced ILD (DI-ILD), five connective tissue disease related-ILD (CTD-ILD)) patients and ten healthy volunteers imaged at visit 1. Thirty-four ILD patients completed visit 2 (eleven IPF, eight HP, ten DIILD, five CTD-ILD) after 6 or 26 weeks.

FIELD STRENGTH/SEQUENCE: MRI performed at 1.5 T. Inversion recovery T1 mapping, dynamic MRI acquisition with varying oxygen levels, and hyperpolarised 129Xe ventilation MRI. Subjects underwent standard spirometry and gas transfer testing.

ASSESSMENT: Five 1H MRI and two 129Xe MRI ventilation metrics were compared with spirometry and gas transfer measurements.

STATISTICAL TEST: To evaluate differences at visit 1 among subgroups: ANOVA or Kruskal-Wallis rank tests with correction for multiple comparisons. To assess the relationships between imaging biomarkers, PFT, age and gender, at visit 1 and for the change between visit 1 and 2: Pearson correlations and multilinear regression models.

RESULTS: The global PFT tests could not distinguish ILD subtypes. Ventilated volumes were lower in ILD patients than in HVs when measured with 129Xe MRI (HV 97.4 ± 2.6, CTD-ILD: 91.0 ± 4.8 p = 0.017, DI-ILD 90.1 ± 7.4 p = 0.003, HP 92.6 ± 4.0 p = 0.013, IPF 88.1 ± 6.5 p < 0.001), but not with OE-MRI. 129Xe reported more heterogeneous ventilation in DI-ILD and IPF than in HV, and OE-MRI reported more heterogeneous ventilation in DI-ILD and IPF than in HP or CTD-ILD. The longitudinal changes reported by the imaging biomarkers did not correlate with the PFT changes between visits.

DATA CONCLUSION: Neither 129Xe ventilation nor OE-MRI biomarkers investigated in this study were able to differentiate between ILD subtypes, suggesting that ventilation-only biomarkers are not indicated for this task. Limited but progressive loss of ventilated volume as measured by 129Xe-MRI may be present as the biomarker of focal disease progresses. OE-MRI biomarkers are feasible in ILD patients and do not correlate strongly with PFT. Both OE-MRI and 129Xe MRI revealed more spatially heterogeneous ventilation in DI-ILD and IPF.

PMID:36252693 | DOI:10.1016/j.mri.2022.10.005

Int Immunopharmacol. 2022 Oct 14;113(Pt A):109316. doi: 10.1016/j.intimp.2022.109316. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease with high mortality and limited treatment. Only two drugs are currently approved for the treatment of IPF, but both have limitations and neither drug could prolong survival time of patients. The etiology of IPF is unclear, but there is growing evidence that B cells and B cell receptor signaling play important roles in the pathogenesis of IPF. Zanubrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK), which is a key enzyme downstream of B cell receptor signaling pathway, has approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). While its role in pulmonary fibrosis remains unknown. In this study, we explored the potential effect and mechanisms of zanubrutinib on pulmonary fibrosis in vivo and in vitro.

METHODS: In the in vivo experiments, different doses of zanubrutinib were administered in a mouse model of bleomycin-induced pulmonary fibrosis, and pathological manifestations and lung function indices were evaluated. In vitro experiments were performed using TGF-β1-stimulated fibroblasts to evaluate the effect of zanubrutinib on the activation and autophagy phenotype of fibroblasts and to explore the underlying signaling pathway mechanism.

RESULTS: In vivo experiments demonstrated that zanubrutinib effectively attenuated bleomycin (BLM)-induced pulmonary fibrosis in mice. An in vitro mechanistic study indicated that zanubrutinib suppresses collagen deposition and myofibroblast activation by inhibiting the TGF-β1/Smad pathway and induces autophagy through the TGF-β1/mTOR pathway.

CONCLUSIONS: Zanubrutinib alleviated bleomycin-induced lung fibrosis in mice by inhibiting the TGF-β1 signaling pathway.

PMID:36252483 | DOI:10.1016/j.intimp.2022.109316

Respir Med. 2022 Sep 24;203:106992. doi: 10.1016/j.rmed.2022.106992. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) is a life-threatening clinical event that occurs during the clinical course of idiopathic pulmonary fibrosis (IPF). Several studies have reported that AE also occurs in interstitial lung disease (ILD) other than IPF. However, the incidence, clinical features, risk factors for AE, and major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated ILD (ANCA-ILD) patients have not been well established.

METHODS: We retrospectively reviewed the data of 54 ANCA-ILD patients and 304 IPF patients. We investigated the frequency of AE, post-AE prognoses, risk factors for AE, and major causes of death in ANCA-ILD patients. We also compared the data of ANCA-ILD with that of IPF.

RESULTS: Fourteen (25.9%) ANCA-ILD patients and 84 (27.6%) IPF patients developed AE. The median survival times (MSTs) after AE in ANCA-ILD and IPF patients were 35.5 and 60 days, respectively (p = 0.588, log-rank test). In a multivariate analysis, the percentage of predicted forced vital capacity (%FVC) [O.R. 0.750 (95% CI 0.570, 0.986), p < 0.01] and serum C-reactive protein (CRP) [O.R. 2.202 (95% CI 1.037, 4.674), p < 0.01] were independent risk factors for AE. AE was the most frequent cause of death in ANCA-ILD and IPF patients.

CONCLUSION: ANCA-ILD patients could develop AE, and the frequency of AE in ANCA-ILD is similar to that in IPF. AE is the most frequent cause of death in ANCA-ILD patients. A low %FVC and a high serum CRP level were independent predictive factors for AE in ANCA-ILD. The prognosis after AE in ANCA-ILD was poor, as it was in IPF.

PMID:36252462 | DOI:10.1016/j.rmed.2022.106992

PLoS One. 2022 Oct 17;17(10):e0276215. doi: 10.1371/journal.pone.0276215. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe lung disease with a poor prognosis and few treatment options. In the most widely used experimental model for this disease, bleomycin is administered into the lungs of mice, causing a reaction of inflammation and consequent fibrosis that resembles the progression of human IPF. The inflammation and fibrosis together induce changes in gene expression that can be analyzed with reverse transcription quantitative real-time PCR (RT-qPCR), in which accurate normalization with a set of stably expressed reference genes is critical for obtaining reliable results. This work compares ten commonly used candidate reference genes in the late, fibrotic phase of bleomycin-induced pulmonary fibrosis and ranks them from the most to the least stable using NormFinder and geNorm. Sdha, Polr2a and Hprt were identified as the best performing and least variable reference genes when alternating between normal and fibrotic conditions. In order to validate the findings, we investigated the expression of Tnf and Col1a1, representing the hallmarks of inflammation and fibrotic changes, respectively. With the best three genes as references, both were found to be upregulated relative to untreated controls, unlike the situation when analyzed solely with Gapdh, a commonly used reference gene. We therefore recommend Sdha, Polr2a and Hprt as reference genes for RT-qPCR in the 4-week bleomycin challenge that represents the late fibrotic phase.

PMID:36251700 | DOI:10.1371/journal.pone.0276215

JAMA Intern Med. 2022 Oct 17. doi: 10.1001/jamainternmed.2022.4696. Online ahead of print.

ABSTRACT

IMPORTANCE: Particulate matter 2.5 μm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.5 composition with adverse outcomes remain unclear.

OBJECTIVE: To investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD.

DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, international, prospective cohort study, patients were enrolled in the Simmons Center for Interstitial Lung Disease Registry at the University of Pittsburgh in Pittsburgh, Pennsylvania; 42 sites of the Pulmonary Fibrosis Foundation Registry; and 8 sites of the Canadian Registry for Pulmonary Fibrosis. A total of 6683 patients with fILD were included (Simmons, 1424; Pulmonary Fibrosis Foundation, 1870; and Canadian Registry for Pulmonary Fibrosis, 3389). Data were analyzed from June 1, 2021, to August 2, 2022.

EXPOSURES: Exposure to PM2.5 and its constituents was estimated with hybrid models, combining satellite-derived aerosol optical depth with chemical transport models and ground-based PM2.5 measurements.

MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to test associations of exposures 5 years before enrollment with baseline forced vital capacity and diffusion capacity for carbon monoxide. Multivariable Cox models were used to test associations of exposure in the 5 years before censoring with mortality, and linear mixed models were used to test associations of exposure with a decrease in lung function. Multiconstituent analyses were performed with quantile-based g-computation. Cohort effect estimates were meta-analyzed. Models were adjusted for age, sex, smoking history, race, a socioeconomic variable, and site (only for Pulmonary Fibrosis Foundation and Canadian Registry for Pulmonary Fibrosis cohorts).

RESULTS: Median follow-up across the 3 cohorts was 2.9 years (IQR, 1.5-4.5 years), with death for 28% of patients and lung transplant for 10% of patients. Of the 6683 patients in the cohort, 3653 were men (55%), 205 were Black (3.1%), and 5609 were White (84.0%). Median (IQR) age at enrollment across all cohorts was 66 (58-73) years. A PM2.5 exposure of 8 μg/m3 or more was associated with a hazard ratio for mortality of 4.40 (95% CI, 3.51-5.51) in the Simmons cohort, 1.71 (95% CI, 1.32-2.21) in the Pulmonary Fibrosis Foundation cohort, and 1.45 (95% CI, 1.18-1.79) in the Canadian Registry for Pulmonary Fibrosis cohort. Increasing exposure to sulfate, nitrate, and ammonium PM2.5 constituents was associated with increased mortality across all cohorts, and multiconstituent models demonstrated that these constituents tended to be associated with the most adverse outcomes with regard to mortality and baseline lung function. Meta-analyses revealed consistent associations of exposure to sulfate and ammonium with mortality and with the rate of decrease in forced vital capacity and diffusion capacity of carbon monoxide and an association of increasing levels of PM2.5 multiconstituent mixture with all outcomes.

CONCLUSIONS AND RELEVANCE: This cohort study found that exposure to PM2.5 was associated with baseline severity, disease progression, and mortality among patients with fILD and that sulfate, ammonium, and nitrate constituents were associated with the most harm, highlighting the need for reductions in human-derived sources of pollution.

PMID:36251286 | DOI:10.1001/jamainternmed.2022.4696