Eur Radiol. 2022 Mar 31. doi: 10.1007/s00330-022-08702-w. Online ahead of print.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and a highly variable course. Pathologically increased ventilation-accessible by functional CT-is discussed as a potential predecessor of lung fibrosis. The purpose of this feasibility study was to investigate whether increased regional ventilation at baseline CT and morphological changes in the follow-up CT suggestive for fibrosis indeed occur in spatial correspondence.

METHODS: In this retrospective study, CT scans were performed at two time points between September 2016 and November 2020. Baseline ventilation was divided into four categories ranging from low, normal to moderately, and severely increased (C1-C4). Correlation between baseline ventilation and volume and density change at follow-up was investigated in corresponding voxels. The significance of the difference of density and volume change per ventilation category was assessed using paired t-tests with a significance level of p ≤ 0.05. The analysis was performed separately for normal (NAA) and high attenuation areas (HAA).

RESULTS: The study group consisted of 41 patients (73 ± 10 years, 36 men). In both NAA and HAA, significant increases of density and loss of volume were seen in areas of severely increased ventilation (C4) at baseline compared to areas of normal ventilation (C2, p < 0.001). In HAA, morphological changes were more heterogeneous compared to NAA.

CONCLUSION: Functional CT assessing the extent and distribution of lung parenchyma with pathologically increased ventilation may serve as an imaging marker to prospectively identify lung parenchyma at risk for developing fibrosis.

KEY POINTS: • Voxelwise correlation of serial CT scans suggests spatial correspondence between increased ventilation at baseline and structural changes at follow-up. • Regional assessment of pathologically increased ventilation at baseline has the potential to prospectively identify tissue at risk for developing fibrosis. • Presence and extent of pathologically increased ventilation may serve as an early imaging marker of disease activity.

PMID:35357537 | DOI:10.1007/s00330-022-08702-w

Oxid Med Cell Longev. 2022 Mar 20;2022:8200189. doi: 10.1155/2022/8200189. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause which leads to alveolar epithelial cell apoptosis followed by basement membrane disruption and accumulation of extracellular matrix, destroying the lung architecture. Oxidative stress is involved in the development of alveolar injury, inflammation, and fibrosis. Oxidative stress-mediated alveolar epithelial cell (AEC) apoptosis is suggested to be a key process in the pathogenesis of IPF. Therefore, the present study investigated whether grape seed proanthocyanidin extract (GSPE) could inhibit the development of pulmonary fibrosis via ameliorating epithelial apoptosis through the inhibition of oxidative stress. We found that GSPE significantly ameliorated the histological changes and the level of collagen deposition in bleomycin (BLM)-induced lungs. Moreover, GSPE attenuated lung inflammation by reducing the total number of cells in bronchoalveolar lavage (BAL) fluid and decreasing the expression of IL-6. We observed that the levels of H2O2 leading to oxidative stress were increased following BLM instillation, which significantly decreased with GSPE treatment both in vivo and in vitro. These findings showed that GSPE attenuated BLM-induced epithelial apoptosis in the mouse lung and A549 alveolar epithelial cell through the inhibition of oxidative stress. Furthermore, GSPE could attenuate mitochondrial-associated cell apoptosis via decreasing the Bax/Bcl-2 ratio. The present study demonstrates that GSPE could ameliorate bleomycin-induced pulmonary fibrosis in mice via inhibition of epithelial apoptosis through the inhibition of oxidative stress.

PMID:35355866 | PMC:PMC8958066 | DOI:10.1155/2022/8200189

Front Pharmacol. 2022 Mar 9;13:835979. doi: 10.3389/fphar.2022.835979. eCollection 2022.

ABSTRACT

Pulmonary fibrosis is a group of life-threatening diseases with limited therapeutic options. The involvement of cannabinoid type 1 receptors (CB1R) has been indicated in fibrotic diseases, but whether or not the activation of CB1R can be a benefit for fibrosis treatment is controversial. In this study, we investigated the effects of arachidonoylcyclopropylamide (ACPA), as a selective CB1R agonist, on bleomycin (BLM)-induced pulmonary fibrosis. We showed that ACPA treatment significantly improved the survival rate of BLM-treated mice, alleviated BLM-induced pulmonary fibrosis, and inhibited the expressions of extracellular matrix (ECM) markers, such as collagen, fibronectin, and α-SMA. The enhanced expressions of ECM markers in transforming growth factor-beta (TGF-β)-challenged primary lung fibroblasts isolated from mouse lung tissues were inhibited by ACPA treatment in a dose-dependent manner, and the fibroblast migration triggered by TGF-β was dose-dependently diminished after ACPA administration. Moreover, the increased mRNA levels of CB1R were observed in both lung fibroblasts of BLM-induced fibrotic mice in vivo and TGF-β-challenged primary lung fibroblasts in vitro. CB1R-specific agonist ACPA significantly diminished the activation of TGF-β-Smad2/3 signaling, i.e., the levels of p-Smad2 and p-Smad3, and decreased the expressions of downstream effector proteins including slug and snail, which regulate ECM production, in TGF-β-challenged primary lung fibroblasts. Collectively, these findings demonstrated that CB1R-specific agonist ACPA exhibited antifibrotic efficacy in both in vitro and in vivo models of pulmonary fibrosis, revealing a novel anti-fibrosis approach to fibroblast-selective inhibition of TGF-β-Smad2/3 signaling by targeting CB1R.

PMID:35355726 | PMC:PMC8959577 | DOI:10.3389/fphar.2022.835979

Front Pharmacol. 2022 Mar 9;13:829673. doi: 10.3389/fphar.2022.829673. eCollection 2022.

ABSTRACT

Tissue remodeling/fibrosis is a main feature of idiopathic pulmonary fibrosis (IPF), which results in the replacement of normal lung parenchyma with a collagen-rich extracellular matrix produced by fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells is a key process in IPF, which leads to fibroblasts and myofibroblasts accumulation and excessive collagen deposition. DEC1, a structurally distinct class of basic helix-loop-helix proteins, is associated with EMT in cancer. However, the functional role of DEC1 in pulmonary fibrosis (PF) remains elusive. Herein, we aimed to explore DEC1 expression in IPF and bleomycin (BLM)-induced PF in mice and the mechanisms underlying the fibrogenic effect of DEC1 in PF in vivo and in vitro by Dec1-knockout (Dec1 -/-) mice, knockdown and overexpression of DEC1 in alveolar epithelial cells (A549 cells). We found that the expression of DEC1 was increased in IPF and BLM-injured mice. More importantly, Dec1 -/- mice had reduced PF after BLM challenge. Additionally, DEC1 deficiency relieved EMT development and repressed the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway in mice and in A549 cells, whereas DEC1 overexpression in vitro had converse effects. Moreover, the PI3K/AKT and Wnt/β-catenin signaling inhibitors, LY294002 and XAV-939, ameliorated BLM-meditated PF in vivo and relieved EMT in vivo and in vitro. These pathways are interconnected by the GSK-3β phosphorylation status. Our findings indicated that during PF progression, DEC1 played a key role in EMT via the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway. Consequently, targeting DEC1 may be a potential novel therapeutic approach for IPF.

PMID:35355710 | PMC:PMC8959854 | DOI:10.3389/fphar.2022.829673

Thorax. 2022 Mar 30:thoraxjnl-2021-218281. doi: 10.1136/thoraxjnl-2021-218281. Online ahead of print.

ABSTRACT

Patients with idiopathic pulmonary fibrosis (IPF) are at a high risk of lung cancer (LC). Antifibrotic therapy slows disease progression and possibly prolongs survival. However, whether antifibrotic therapy affects LC development in patients with IPF remains unknown. This multicentre retrospective study evaluated 345 patients with IPF. The incidence and prevalence of LC were significantly lower in patients with IPF receiving antifibrotic therapy than those not receiving. Subsequently, LC-related mortality was significantly lower in patients with IPF receiving antifibrotic therapy. These results suggest that antifibrotic therapy was possibly associated with a reduced risk of LC development in patients with IPF, which may be partly associated with its survival benefit.

PMID:35354649 | DOI:10.1136/thoraxjnl-2021-218281

BMC Vet Res. 2022 Mar 30;18(1):121. doi: 10.1186/s12917-022-03202-x.

ABSTRACT

BACKGROUND: Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial fibrosing lung disease, manifesting as cough, exercise intolerance and ultimately, dyspnea and respiratory failure. It mainly affects West Highland white terriers (WHWTs), lacks curable treatment and has a poor prognosis. Aspiration of gastroesophageal refluxate may play a role in the development of CIPF. In the first part of this study, we completed label-free quantitative proteomic analysis of bronchoalveolar lavage fluid (BALF) from CIPF and healthy WHWTs. In the second part, we evaluated potential protein markers of reflux aspiration from canine gastric juice and vomitus and whether these were present in BALF from the two groups.

RESULTS: Across all BALF samples, 417 proteins were identified, and of these, 265 proteins were identified by two or more unique tryptic peptides. Using the 265 high confidence assignments, the quantitative proteome profiles were very similar in the two cohorts, but they could be readily resolved by principal component analysis on the basis of differential protein expression. Of the proteins that were differentially abundant in the two groups, several (including inflammatory and fibrotic markers) were elevated in CIPF, and a smaller, more diverse group of proteins were diminished in CIPF. No protein markers indicative of reflux aspiration were identified.

CONCLUSIONS: Label-free proteomics allowed discrimination between CIPF and healthy WHWTs, consistent with fibrotic process but did not provide clear evidence for gastrointestinal aspiration. The measurement of proteins may provide a proteomics signature of CIPF that could be used to evaluate treatment options.

PMID:35354473 | DOI:10.1186/s12917-022-03202-x

J Chin Med Assoc. 2022 Mar 31. doi: 10.1097/JCMA.0000000000000719. Online ahead of print.

ABSTRACT

BACKGROUND: Two antifibrotic medications, pirfenidone and nintedanib, have been approved as treatments for idiopathic pulmonary fibrosis (IPF), a life-threatening interstitial lung disease. However, there is insufficient current data regarding clinical predictors of survival for IPF patients in the era of antifibrotics.

METHODS: We retrospectively analyzed the medical records of IPF patients treated between April 2017 and May 2020. Univariate and multivariate Cox hazard proportional models were used to identify independent predictors of mortality among these patients with IPF.

RESULTS: A total of 40 IPF patients (average age: 75.58 ± 8.34 years) were included in the study, 27 (67.5%) of whom were treated with antifibrotic drugs. In the entire cohort, 14 (35%) patients died, and the overall survival of the study population was 48.52 ± 5 months (median: NA [29, NA] months). The univariate and multivariate Cox hazard proportional models indicated that chest tightness, finger clubbing, acute exacerbation after medication, decreased FVC%, and decreased FEV1% were clinical factors linked to all-cause mortality among all patients, although without statistical significance at the multivariate level. Meanwhile, only finger clubbing was a significant mortality predictor among patients who received antifibrotic medications. A mortality scoring system was built upon the aforementioned risk factors, with the exclusion of FVC%, whose individual mortality score was nearly zero.

CONCLUSION: Chest tightness, finger clubbing, acute exacerbation after medication, and decreased FVC% were clinical factors associated with mortality in IPF patients, although without statistical significance. A scoring system including these factors can be used to predict all-cause mortality in IPF patients. The mere intake of antifibrotic medications was not a significant mortality predictor in this study. This might be owed to the retrospective nature of the study, where many patients started the medications after the deterioration of their pulmonary function rather than from the start.

PMID:35353790 | DOI:10.1097/JCMA.0000000000000719

Am J Respir Crit Care Med. 2022 Mar 30. doi: 10.1164/rccm.202111-2607PP. Online ahead of print.

ABSTRACT

BACKGROUND: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a "pre-test" probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF.

METHODS: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into "high" (70-100%), "intermediate" (30-70%), or "low" (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into "definite" (90-100%), "high confidence" (70-89%), "low confidence" (51-69%), or "low" (0-50%) probability of IPF.

FINDINGS: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF ("pre-test probability of IPF") with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior into a "post-test probability of IPF". The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases.

INTERPRETATION: The present approach will help incorporate the clinical judgement into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

PMID:35353660 | DOI:10.1164/rccm.202111-2607PP

Am J Pathol. 2022 Mar 26:S0002-9440(22)00103-1. doi: 10.1016/j.ajpath.2022.03.003. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a dramatic disease without cure. The FDA-approved drugs, Pirfenidone and Nintedanib, only slow disease progression. The clinical investigation of novel therapeutic approaches for IPF is an unmet clinical need. Nucleotide-binding oligomerization domain-like receptor or NOD-like receptors (NLRs) are pattern recognition receptors (PRRs) capable of binding a large variety of stress factors. NLRP3 once activated promotes IL-1β, IL-18 production and innate immune responses. Multiple reports indicate that the inflammasome NLRP3 is overactivated in IPF patients, leading to increased production of class I interleukin and collagens. Similarly, data from animal models of PF, confirm the role of NLRP3 in the development of chronic lung injury and pulmonary fibrosis. In this report, we review evidence of NLRP3 activation in IPF, of NLRP3 inhibition in different animal models of fibrosis, and highlight the recent advances in direct and indirect NLRP3 inhibitors.

PMID:35351468 | DOI:10.1016/j.ajpath.2022.03.003

ERJ Open Res. 2022 Mar 21;8(1):00571-2021. doi: 10.1183/23120541.00571-2021. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic interstitial lung disease. We performed size-based quantitation of pulmonary arterial remodelling in IPF and examined the role of endothelial-to-mesenchymal transition (EndMT) and effects on lung physiology.

METHODS: Resected lung tissues from 11 normal controls (NCs), and 13 IPF patients were differentially stained using the Movat Pentachrome technique. Size-based classification for pulmonary arteries was conducted in NC and IPF tissues. For each pulmonary artery, arterial size, luminal diameter, thickness of the intima, media and adventitia, and elastin deposition were quantified using Image ProPlus7.0 software. In addition, immunohistochemical staining was performed for EndMT markers and collagen.

RESULTS: Large and medium-size arterial numbers were significantly reduced in IPF compared to NCs (p<0.0001). Intima thickness was highest in the arterial range of 200-399 μm and 600-1000 μm (p<0.0001), while medial and adventitial thickness was significant across 200-1000 μm (p<0.05) compared to NC. Medial thickness was found to significantly affect the diffusing capacity of the lungs for carbon monoxide (D LCO) (r=-0.8, p=0.01). Total arterial elastin in IPF was higher across all arterial ranges except 100-199 μm in IPF than in NC, with the greatest differences in 200-399 μm (p<0.001) and 600-1000 μm (p<0.001). Total elastin also negatively correlated with D LCO (r'=-0.63, p=0.04) in IPF. An increase in EndMT markers and collagen type I/ IV was observed.

CONCLUSIONS: This is the first study demonstrating size-based differences in pulmonary arteries in IPF and its detrimental effect on lung physiology. The process of EndMT might be central to these vascular remodelling changes and could be a potential novel therapeutic target.

PMID:35350273 | PMC:PMC8943284 | DOI:10.1183/23120541.00571-2021

Front Bioeng Biotechnol. 2022 Mar 8;10:844119. doi: 10.3389/fbioe.2022.844119. eCollection 2022.

ABSTRACT

In idiopathic pulmonary fibrosis (IPF), basal-like cells are atypically present in the alveolar region, where they may affect adjacent stromal cells by paracrine mechanisms. We here aimed to confirm the presence of basal-like cells in peripheral IPF lung tissue in vivo, to culture and characterize the cells in vitro, and to investigate their paracrine effects on IPF fibroblasts in vitro and in bleomycin-injured rats in vivo. Basal-like cells are mainly localized in areas of pathological bronchiolization or honeycomb cysts in peripheral IPF lung tissue. Single-cell RNA sequencing (scRNA-seq) demonstrated an overall homogeneity, the expression of the basal cell markers cytokeratin KRT5 and KRT17, and close transcriptomic similarities to basal cells in the majority of cells cultured in vitro. Basal-like cells secreted significant levels of prostaglandin E2 (PGE2), and their conditioned medium (CM) inhibited alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1) and upregulated matrix metalloproteinase-1 (MMP-1) and hepatocyte growth factor (HGF) by IPF fibroblasts in vitro. The instillation of CM in bleomycin-injured rat lungs resulted in reduced collagen content, improved lung architecture, and reduced α-SMA-positive cells. Our data suggested that basal-like cells may limit aberrant fibroblast activation and differentiation in IPF through paracrine mechanisms.

PMID:35350187 | PMC:PMC8957873 | DOI:10.3389/fbioe.2022.844119

Clin Exp Rheumatol. 2022 Mar 9. Online ahead of print.

ABSTRACT

OBJECTIVES: The classification interstitial pneumonia with autoimmune features (IPAF) includes patients with interstitial lung disease (ILD) associated with autoimmune characteristics insufficient to reach classification criteria for a specific autoimmune disease (SAD). These criteria are divided into three domains: clinical, serological and morphological. The latter domain does not include the usual interstitial pneumonia (UIP) pattern, which is deemed not to be significantly associated with SAD. Therefore, the enrolment of these patients is more difficult, requiring at least one item from both of the other domains. The objective of this study is to evaluate the rate of progression towards SAD of a cohort of UIP patients satisfying only one IPAF domain (we called this group "UIPAF") compared with classic idiopathic pulmonary fibrosis (IPF).

METHODS: We prospectively enrolled IPF patients with radiologic and/or histologic UIP pattern, followed jointly by rheumatologists and pulmonologists from January 2017 to January 2021, with a minimum follow-up of 12 months.

RESULTS: We enrolled 190 IPF patients, 38 (20%) of whom were classified as UIPAF. IPF and UIPAF patients were similar for general characteristics, severity and prognosis, at presentation and at annual check-up. However, 28.9% of UIPAF patients progressed towards SAD, compared with 2% of IPF patients (χ2=30.4, p≤0.0001).

CONCLUSIONS: The association between a single clinical or serological domain of IPAF and UIP pattern is predictive for the development of a SAD if compared with isolated UIP. ILD can be the first manifestation of SAD, even with a UIP pattern, therefore, the morphological domain of IPAF criteria could be removed.

PMID:35349416

J Am Heart Assoc. 2022 Mar 29:e023021. doi: 10.1161/JAHA.121.023021. Online ahead of print.

ABSTRACT

Background Platelet-derived growth factor is a major regulator of the vascular remodeling associated with pulmonary arterial hypertension. We previously showed that protein widely 1 (PW1+) vascular progenitor cells participate in early vessel neomuscularization during experimental pulmonary hypertension (PH) and we addressed the role of the platelet-derived growth factor receptor type α (PDGFRα) pathway in progenitor cell-dependent vascular remodeling and in PH development. Methods and Results Remodeled pulmonary arteries from patients with idiopathic pulmonary arterial hypertension showed an increased number of perivascular and vascular PW1+ cells expressing PDGFRα. PW1nLacZ reporter mice were used to follow the fate of pulmonary PW1+ progenitor cells in a model of chronic hypoxia-induced PH development. Under chronic hypoxia, PDGFRα inhibition prevented the increase in PW1+ progenitor cell proliferation and differentiation into vascular smooth muscle cells and reduced pulmonary vessel neomuscularization, but did not prevent an increased right ventricular systolic pressure or the development of right ventricular hypertrophy. Conversely, constitutive PDGFRα activation led to neomuscularization via PW1+ progenitor cell differentiation into new smooth muscle cells and to PH development in male mice without fibrosis. In vitro, PW1+ progenitor cell proliferation, but not differentiation, was dependent on PDGFRα activity. Conclusions These results demonstrate a major role of PDGFRα signaling in progenitor cell-dependent lung vessel neomuscularization and vascular remodeling contributing to PH development, including in idiopathic pulmonary arterial hypertension patients. Our findings suggest that PDGFRα blockers may offer a therapeutic add-on strategy to combine with current pulmonary arterial hypertension treatments to reduce vascular remodeling. Furthermore, our study highlights constitutive PDGFRα activation as a novel experimental PH model.

PMID:35348002 | DOI:10.1161/JAHA.121.023021

Oxid Med Cell Longev. 2022 Mar 19;2022:6197219. doi: 10.1155/2022/6197219. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease (ILD) characterized by the proliferation of fibroblasts and aberrant accumulation of extracellular matrix. These changes are accompanied by structural destruction of the lung tissue and the progressive decline of pulmonary function. In the past few decades, researchers have investigated the pathogenesis of IPF and sought a therapeutic approach for its treatment. Some studies have shown that the occurrence of IPF is related to pulmonary inflammatory injury; however, its specific etiology and pathogenesis remain unknown, and no effective treatment, with the exception of lung transplantation, has been identified yet. Several basic science and clinical studies in recent years have shown that statins, the traditional lipid-lowering drugs, exert significant antifibrotic effects, which can delay the progression of IPF and impairment of pulmonary function. This article is aimed at summarizing the current understanding of the pathogenesis of IPF, the progress of research on the use of statins in IPF models and clinical trials, and its main molecular targets.

PMID:35345828 | PMC:PMC8957418 | DOI:10.1155/2022/6197219

J Res Med Sci. 2022 Jan 29;27:3. doi: 10.4103/jrms.JRMS_219_19. eCollection 2022.

ABSTRACT

BACKGROUND: The adaptive immune system plays a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) has been reported previously. However, the association between airway and circulating autoantibodies (AAbs) levels is unclear. The aim of this study is to investigate the link between the AAb levels in airway and circulation in stable patients with IPF.

MATERIALS AND METHODS: From June 2016 to March 2017, 21 stable IPF patients and 22 healthy volunteers were recruited. We established Luminex interacting AAbs with bead-antigen complex to detect the immunoglobulin G antibodies levels of ten autoantigens which were matched serum (Se) and sputum (Sp) samples collected from recruited subjects, including Smith (Sm), Anti-ribosomal P antibody (P0), Sjögren syndrome type A antigen (SSA), La/Sjögren syndrome type B antigen (SSB), DNA topoisomerase (Scl-70), histidyl-tRNA synthetase (Jo-1), U1 small nuclear ribonucleoprotein (U1-SnRNP), thyroid peroxidase, Proteinase 3, and Myeloperoxidase. Spearman's rank correlation matrix was applied to explore the associations of Ab profiles between Se and Sp.

RESULTS: For IPF patients, Spearman's correlation matrix showed multiple intercorrelations among Sp-AAbs and Sp-AAbs (P < 0.05), while only the levels of AAb against Sm and anti-La in Se were correlated with those Sp-AAb counterparts (P < 0.05). For healthy individuals, only anti-La in Se was associated with those Sp-AAb counterparts (P < 0.05). For IPF patients, there was a positive correlation between carbon monoxide diffusing capacity (DLCO)% predicted and Sp-anti-P0 level (r = 0.464, P = 0.034). Forced vital capacity% predicted was positively correlated with Sp-anti-Scl-70 level (r = 0.466, P = 0.033).

CONCLUSION: Comparing to Se-AAbs, Sp-AAbs are more associated with clinical parameters in the patients with IPF. In order to better understand the role of autoimmunity in the pathogenesis of IPF, detection of Sp-AAbs for local autoimmune responses may be a good choice.

PMID:35342449 | PMC:PMC8943581 | DOI:10.4103/jrms.JRMS_219_19

Metabol Open. 2022 Mar 17;14:100179. doi: 10.1016/j.metop.2022.100179. eCollection 2022 Jun.

ABSTRACT

Idiopathic lung fibrosis (ILF) is a severe and life threatening lung disorder that is characterized by scarring of lung tissue, leading to thickening and stiffening of affected areas. This study looked at the role played by PI3K-Akt/PKB-mToR signaling pathway in the pathogenesis of N-Nitrosodimethylamine (NDMA)-induced lung fibrotic injury, and the effects of syringic acid (SYR) and ascorbic acid (ASC) treatments in male Wistar rats. Pulmonary fibrosis was induced by intraperitoneal injection of 10 mg/kg NDMA once daily, thrice (consecutively) a week for four weeks, and this condition was treated daily with SYR (50 mg/kg) and ASC (100 mg/kg) acids orally for four weeks. Fibrogenesis, following NDMA administration was marked by a significant increase in collagen-1 and α-SMA levels, while oxidative stress was marked by a significant decrease in GSH level, GST, GPx, CAT, and SOD activities. Also, NDMA significantly increased lung Bax, p53, caspase-3, TNF-α, IL-1β, NFkB, and decreased Bcl-2, mdm2, cyclin D1 and Nrf-2 levels. Looking at the PI3K-Akt-mTOR signaling pathway, NDMA administration significantly activated lung PI3K, Akt, and mTOR, and deactivated PTEN, FoxO1 and TSC2. Treatments with SYR and ASC significantly reduced oxidative stress by restoring the antioxidant systems via Nrf2 activation, decreased the levels of inflammatory markers through inhibition of NFkB, downregulated p53, Bax, and caspase-3 via up-regulation of mdm2 and cyclin D1. SYR and ASC also regulated the PI3K-Akt-mTOR signaling pathway via the deactivation of PI3K, Akt, and mTOR, and up-regulation of PTEN, FoxO1 and TSC2. Overall, SYR and ASC modulate the PI3K-Akt-mTOR signaling pathway via inhibition of oxidative stress, inflammation and apoptosis in NDMA-induced lung fibrosis.

PMID:35340717 | PMC:PMC8943260 | DOI:10.1016/j.metop.2022.100179

Curr Res Transl Med. 2022 Mar 23;70(3):103343. doi: 10.1016/j.retram.2022.103343. Online ahead of print.

ABSTRACT

Belumosudil (BLM) is a ROCK inhibitor that has been firstly developed by Surface Logix, later acquired by Kadmon Pharmaceuticals for the treatment of chronic graft-versus-host disease (cGVHD), Psoriasis Vulgaris (PV), idiopathic pulmonary fibrosis (IPF), hepatic impairment (HI), diffuse cutaneous systemic sclerosis (dcSSc). BLM received a breakthrough therapy designation and priority review from the FDA, which reviewed the NDA under the real-time oncology review (RTOR) pilot programme and approved it six weeks ahead of the PDUFA deadline of August 30, 2021. On July 16th, 2021, The USFDA authorized BLM under the brand name REZUROCKTM for the treatment of cGVHD in adults and pediatric patients aged ≥ 12 years after the failure of at least two prior lines of systemic therapy. It has been granted orphan drug status by the FDA on August 9, 2020, for the treatment of systemic sclerosis. The European Union (EU) granted Quality Regulatory Clinical Ireland Limited, Ireland, orphan drug status for BLM (KD025) for the treatment of cGVHD on October 17, 2019. BLM is under regulatory assessment by Therapeutic Good Administration (TGA) Australia, Health Canada, MHRA (UK), and The Swiss Agency for Therapeutic Products (Swissmedic), Switzerland for cGVHD. A clinical trial is ongoing in the United States for cutaneous systemic sclerosis. This review article summarizes the milestones in the development of BLM chemistry, Chemical synthesis and development, mechanism of action, pharmacokinetics (PK), pharmacodynamics (PD), adverse effects, regulatory status, and ongoing clinical trials (CT) of BLM.

PMID:35339032 | DOI:10.1016/j.retram.2022.103343

Respir Med Res. 2022 Mar 3;81:100900. doi: 10.1016/j.resmer.2022.100900. Online ahead of print.

ABSTRACT

BACKGROUND: There are few data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19) infection in patients with idiopathic pulmonary fibrosis (IPF). The objective of this study is to describe the characteristics and outcomes of IPF patients confirmed COVID-19 infection.

METHODS: In this retrospective, multi-center, cohort study, patients from 4 hospital medical records with known IPF and a COVID-19 diagnosis were identified. Demographic and clinical outcome data were abstracted through a review of electronic medical records.

RESULTS: Records for 46 patients with IPF and COVID-19 were abstracted. The mean age was 65±10 years. The most common symptom was dyspnea, followed by fever and cough. Ground-glass opacities (n = 35, 83.3%) and consolidations (n = 11, 26.1%) were the main imaging features of the disease in thorax computed tomography (CT). Twenty-four patients (52.1%) required hospitalization. Among the hospitalized patients, 16 (66.6%) were admitted to the intensive care unit (ICU), and 10 (41.6%) underwent invasive mechanical ventilation. Thirteen patients (28.2%) died of COVID-19 complications. Mortality rate was significantly associated with lower DLCO/VA, long term oxygen therapy and consolidation finding on CT of thorax (p<0.05). On multivariable analysis, neither factor was associated with hospitalization or mortality.

CONCLUSIONS: IPF patients represent a vulnerable population for COVID-19, according to the high rate of hospitalization, ICU requirement, and mortality rate. Measures to minimize the risk of COVID-19 infection remain key to protect IPF patients.

PMID:35338917 | DOI:10.1016/j.resmer.2022.100900

Chest. 2022 Mar 22:S0012-3692(22)00545-1. doi: 10.1016/j.chest.2022.03.025. Online ahead of print.

ABSTRACT

BACKGROUND: Cough is a common symptom of interstitial lung disease (ILD) and negatively impacts health-related quality of life (QOL). Previous studies have shown that among patients with idiopathic pulmonary fibrosis, cough may predict progression of lung disease and perhaps even respiratory hospitalizations and mortality.

RESEARCH QUESTION: Does cough-specific QOL predict disease progression, respiratory hospitalization, lung transplantation, and death among patients with ILD?

STUDY DESIGN AND METHODS: We analyzed data from the Pulmonary Fibrosis Foundation Registry, which is comprised of a multi-center population of well-characterized patients with interstitial lung disease. We first examined associations between patient factors and baseline scores on the Leicester cough questionnaire (LCQ), a cough-specific QOL tool, utilizing a proportional odds model. Next, we examined associations between baseline LCQ scores and patient-centered clinical outcomes as well as pulmonary function parameters, utilizing a univariable and multivariable proportional hazards model that was adjusted for clinically relevant variables, including measures of disease severity.

RESULTS: 1,447 patients with ILD were included in our study. In our multivariable proportional odds model, we found that the following patient factors were associated with worse cough-specific QOL: younger age, diagnosis of "other ILD", gastroesophageal reflux disease, and lower % predicted forced vital capacity. Multivariable Cox regression models, adjusting for several variables, including baseline disease severity, showed that a one-point decrease in LCQ score (indicating lower cough-specific QOL) was associated with a 6.5% higher risk of respiratory-related hospitalization (hazard ratio [HR], 1.065 [95% confidence interval (CI), 1.025-1.107]), a 7.4% higher risk of death (HR, 1.074 [95% CI, 1.020-1.130]), and an 8.7% higher risk of lung transplant (HR, 1.087 [95% CI 1.022-1.156]).

INTERPRETATION: Among a large population of well-characterized patients with interstitial lung disease, cough-specific QOL was independently associated with respiratory hospitalization, death, and lung transplantation.

PMID:35337809 | DOI:10.1016/j.chest.2022.03.025

Rev Mal Respir. 2022 Mar 22:S0761-8425(22)00135-8. doi: 10.1016/j.rmr.2022.03.004. Online ahead of print.

NO ABSTRACT

PMID:35337709 | DOI:10.1016/j.rmr.2022.03.004