Lancet Respir Med. 2022 Jul 6:S2213-2600(22)00256-9. doi: 10.1016/S2213-2600(22)00256-9. Online ahead of print.

NO ABSTRACT

PMID:35809578 | DOI:10.1016/S2213-2600(22)00256-9

Cells. 2022 Jun 30;11(13):2095. doi: 10.3390/cells11132095.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with unknown etiology in which gradual fibrotic scarring of the lungs leads to usual interstitial pneumonia (UIP) and, ultimately, to death. IPF affects three million people worldwide, and the only currently available treatments include the antifibrotic drugs nintedanib and pirfenidone, which effectively reduce fibrosis progression are, unfortunately, not effective in curing the disease. In recent years, the paradigm of IPF pathogenesis has shifted from a fibroblast-driven disease to an epithelium-driven disease, wherein, upon recurrent microinjuries, dysfunctional alveolar type II epithelial cells (ATII) are not only unable to sustain physiological lung regeneration but also promote aberrant epithelial-mesenchymal crosstalk. This creates a drift towards fibrosis rather than regeneration. In the context of this review article, we discuss the most relevant mechanisms involved in IPF pathogenesis with a specific focus on the role of dysfunctional ATII cells in promoting disease progression. In particular, we summarize the main causes of ATII cell dysfunction, such as aging, environmental factors, and genetic determinants. Next, we describe the known mechanisms of physiological lung regeneration by drawing a parallel between embryonic lung development and the known pathways involved in ATII-driven alveolar re-epithelization after injury. Finally, we review the most relevant interventional clinical trials performed in the last 20 years with the aim of underlining the urgency of developing new therapies against IPF that are not only aimed at reducing disease progression by hampering ECM deposition but also boost the physiological processes of ATII-driven alveolar regeneration.

PMID:35805179 | DOI:10.3390/cells11132095

Respir Res. 2022 Jul 8;23(1):180. doi: 10.1186/s12931-022-02105-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a diffuse parenchymal lung disease characterized by exuberant deposition of extracellular matrix (ECM) proteins in the lung interstitium, which contributes to substantial morbidity and mortality in IPF patients. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, many of which have been implicated in the regulation of ECM degradation in lung fibrosis. However, the roles of MMP-2 and -9 (also termed gelatinases A and B) have not yet been explored in lung fibrosis in detail.

METHODS: AdTGF-β1 was applied via orotracheal routes to the lungs of WT, MMP-2 KO, MMP-9 KO and MMP-2/-9 dKO mice on day 0 to induce lung fibrosis. Using hydroxyproline assay, FlexiVent based lung function measurement, histopathology, western blot and ELISA techniques, we analyzed MMP-2 and MMP-9 levels in BAL fluid and lung, collagen contents in lung and lung function in mice on day 14 and 21 post-treatment.

RESULT: IPF lung homogenates exhibited significantly increased levels of MMP-2 and MMP-9, relative to disease controls. Enzymatically active MMP-2 and MMP-9 was increased in lungs of mice exposed to adenoviral TGF-β1, suggesting a role for these metalloproteinases in lung fibrogenesis. However, we found that neither MMP-2 or MMP-9 nor combined MMP-2/-9 deletion had any effect on experimental lung fibrosis in mice.

CONCLUSION: Together, our data strongly suggest that both gelatinases MMP-2 and MMP-9 play only a subordinate role in experimental lung fibrosis in mice.

PMID:35804363 | DOI:10.1186/s12931-022-02105-7

Exp Mol Med. 2022 Jul 8. doi: 10.1038/s12276-022-00796-y. Online ahead of print.

ABSTRACT

Epithelial-mesenchymal transition (EMT), a process by which epithelial cells undergo a phenotypic conversion that leads to myofibroblast formation, plays a crucial role in the progression of idiopathic pulmonary fibrosis (IPF). Recently, it was revealed that hypoxia promotes alveolar EMT and that histone deacetylases (HDACs) are abnormally overexpressed in the lung tissues of IPF patients. In this study, we showed that HDAC3 regulated alveolar EMT markers via the AKT pathway during hypoxia and that inhibition of HDAC3 expression by small interfering RNA (siRNA) decreased the migration ability and invasiveness of diseased human lung fibroblasts. Furthermore, we found that HDAC3 enhanced the migratory and invasive properties of fibroblasts by positively affecting the EMT process, which in turn was affected by the increased and decreased levels of microRNA (miR)-224 and Forkhead Box A1 (FOXA1), respectively. Lastly, we found this mechanism to be valid in an in vivo system; HDAC3 siRNA administration inhibited bleomycin-induced pulmonary fibrosis in mice. Thus, it is reasonable to suggest that HDAC3 may accelerate pulmonary fibrosis progression under hypoxic conditions by enhancing EMT in alveolar cells through the regulation of miR-224 and FOXA1. This entire process, we believe, offers a novel therapeutic approach for pulmonary fibrosis.

PMID:35804191 | DOI:10.1038/s12276-022-00796-y

Turk J Anaesthesiol Reanim. 2022 Jun;50(3):228-231. doi: 10.5152/TJAR.2021.20450.

ABSTRACT

Coronavirus disease 19 infection clinical presentation varies from asymptomatic cases to acute respiratory distress syndromes. In some cases, pulmonary fibrosis is observed after or during the disease. Pirfenidone is an agent approved for the treatment of idiopathic pulmonary fibrosis. Here we report a patient treated with pirfenidone for pulmonary fibrosis related to coronavirus disease 19.

PMID:35801331 | DOI:10.5152/TJAR.2021.20450

Int J Chron Obstruct Pulmon Dis. 2022 Jul 1;17:1495-1506. doi: 10.2147/COPD.S368162. eCollection 2022.

ABSTRACT

PURPOSE: Pulmonary fibrosis and emphysema result in relatively maintained ventilation and reduced diffusing capacity. This pulmonary functional impairment complicates the evaluation of pulmonary function in patients with combined pulmonary fibrosis and emphysema (CPFE). Therefore, a single and easy-to-use pulmonary function index to evaluate patients with CPFE warrants further studies. Respiratory impedance can easily be provided by oscillometry and might be a candidate index to evaluate pulmonary function in patients with CPFE. As a preliminary study to assess the utility of respiratory impedance, we investigated the associations of physiological indices, including respiratory impedance, in patients with idiopathic pulmonary fibrosis (IPF) with and without emphysema.

PATIENTS AND METHODS: This retrospective study evaluated patients with IPF who did and did not satisfy the diagnostic criteria of CPFE. All patients underwent oscillometry, spirometry, and diffusing capacity for carbon monoxide (DLCO). Correlations of the obtained physiological indices were analyzed.

RESULTS: In total, 47 patients were included (18 and 29 patients with CPFE and IPF, respectively). Respiratory reactance (Xrs) at 5 Hz (X5) in the inspiratory phase was associated with forced vital capacity (FVC) % predicted in patients with CPFE (rS=0.576, P=0.012) and IPF (rS=0.539, P=0.003). Inspiratory X5 positively correlated with DLCO % predicted only in patients CPFE (rS=0.637, P=0.004).

CONCLUSION: Emphysema might associate Xrs with ventilation and diffusing capacity in patients with IPF and emphysema. Given the multiple correlations of Xrs with FVC and DLCO, this study warrants further studies to verify the utility of oscillometry in a large-scale study for patients with CPFE.

PMID:35801120 | PMC:PMC9255903 | DOI:10.2147/COPD.S368162

Arch Bronconeumol. 2022 Jun 4:S0300-2896(22)00329-5. doi: 10.1016/j.arbres.2022.04.007. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and frequently fatal disease. Currently there are national and multinational registries in Europe, United States, Australia and China to better understand the magnitude of the problem and the characteristics of the IPF patients. However, there are no national or regional registries in Latin America, so the objective of this study was to carry out a Latin American registry that would allow the identification of IPF patients in our region.

METHODOLOGY: A system consisting of 3 levels of control was designed, ensuring that patients met the diagnostic criteria for IPF according to international guidelines ATS/ERS/ALAT/JRS 2011. Demographic, clinical, serological, functional, tomographic, histological and treatment variables were recorded through a digital platform.

RESULTS: 761 IPF patients from 14 Latin American countries were included for analysis, 74.7% were male, with a mean age of 71.9+8.3 years. In general there was a long period of symptoms before definitive diagnosis (median 1 year). In functional tests, an average reduction of FVC (70.9%) and DLCO (53.7%) was detected. 72% received at least one antifibrotic drug (pirfenidone or nintedanib) and 11.2% of the patients had an acute exacerbation, of which 38 (45.2%) died from this cause.

CONCLUSIONS: Like other registries, we found that there is difficulty in the recognition and excessive delay in the diagnosis of IPF in Latin America. Most of the patients in REFIPI received antifibrotics; these were well tolerated and associated with fewer adverse events than those reported in clinical trials.

PMID:35798664 | DOI:10.1016/j.arbres.2022.04.007

BMJ Open Respir Res. 2022 Jul;9(1):e001276. doi: 10.1136/bmjresp-2022-001276.

ABSTRACT

BACKGROUND: The diagnosis of idiopathic pulmonary fibrosis (IPF) is often delayed up to several years. The objective of this study was to assess the impact of the diagnostic delay on progression-free survival, quality of life and hospitalisation rates.

METHODS: A total of 264 incident patients with IPF were included immediately after their diagnosis and followed for up to 5 years, with regular collection of clinical data, quality-of-life questionnaires and assessment of disease progression. Hospitalisation data were extracted from electronic patient records. Analyses were performed on the entire cohort and strata according to forced vital capacity (FVC) at diagnosis.

RESULTS: A long diagnostic delay (>1 year) was associated with worse progression-free survival compared with a short diagnostic delay (<1 year) (HR: 1.70, 95% CI: 1.18 to 2.46, p=0.004) especially in patients with mild disease at the time of diagnosis (FVC>80% predicted). Mean total scores of the St. George's respiratory questionnaire (SGRQ), a derived IPF-specific version of the SGRQ and the chronic obstructive pulmonary disease assessment test (CAT) were consistently higher in patients with long diagnostic delays, indicating worse quality of life. Mean hospitalisation rates were higher during the first year after diagnosis (Incidence rate ratio [IRR]: 3.28, 95% CI: 1.35 to 8.55, p=0.01) and during the entire follow-up (IRR: 1.74, 95% CI: 1.01 to 3.02, p=0.04).

CONCLUSION: A diagnostic delay of more than 1 year negatively impacts progression-free survival, quality of life and hospitalisation rates in patients with IPF. These findings highlight the importance of an early diagnosis for proper management of IPF.

TRIAL REGISTRATION NUMBER: NCT02755441.

PMID:35798532 | DOI:10.1136/bmjresp-2022-001276

Eur Respir J. 2022 Jul 7:2101469. doi: 10.1183/13993003.01469-2021. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary function, respiratory failure and death. Bleomycin (Blm)-induced lung fibrosis in mice replicates several clinical features of human IPF, including prominent lymphoid aggregates of predominantly B cells that accumulate in the lung adjacent to areas of active fibrosis. We have previously shown a requirement for B cells in the development of Blm-induced lung fibrosis in mice. To determine the therapeutic potential of inhibiting B cell function in pulmonary fibrosis, we examined the effects of anti-CD20 B-cell ablation therapy to selectively remove mature B cells from the immune system and inhibit Blm-induced lung fibrosis. Anti-CD20-B cell ablation did not reduce fibrosis in this model, however immune phenotyping of peripheral blood and lung resident cells revealed that anti-CD20 treated mice retained a high frequency of CD19+ CD138+ plasma cells (PCs). Interestingly, high levels of CD138+ cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes PCs, reduced the level of Blm-induced lung fibrosis, implicating PCs as important effector cells in the development and progression of pulmonary fibrosis.

PMID:35798357 | DOI:10.1183/13993003.01469-2021

ERJ Open Res. 2022 Jul 4;8(3):00226-2022. doi: 10.1183/23120541.00226-2022. eCollection 2022 Jul.

ABSTRACT

BACKGROUND: Interstitial lung abnormalities (ILA) are specific spatial patterns on computed tomography (CT) scan potentially compatible with early interstitial lung disease. A proportion will progress; management involves risk stratification and surveillance. Elevated blood monocyte levels have been shown to associate with progression of idiopathic pulmonary fibrosis. The aims of the present study were: 1) to estimate the proportion of "early fibrotic" (EF)-ILAs (reticular±ground-glass opacities, excluding traction bronchiectasis and honeycombing) on CT scans of patients attending all-indications thoracic CTs, and proportion demonstrating radiological progression; and 2) to explore association between peripheral blood leukocyte levels and ILA progression.

METHODS: We analysed all thoracic CT reports in individuals aged 45-75 years performed between January 2015 and December 2020 in one large teaching hospital (Oxford, UK) to identify patient CT reports consistent with EF-ILA. CT-contemporaneous blood leukocyte counts were examined to explore contribution to progression and all-cause mortality, using multivariate Cox regression.

RESULTS: 40 711 patients underwent thoracic CT imaging during this period. 1259 (3.1%) demonstrated the EF-ILA pattern (mean±sd age 65.4±7.32 years; 735 (47.8%) male). EF-ILA was significantly associated with all-cause mortality (hazard ratio 1.87, 95% CI 1.25-2.78; p=0.002). 362 cases underwent at least one follow-on CT. Radiological progression was observed in 157 (43.4%) cases: increase in reticulation n=51, new traction bronchiectasis n=84, honeycombing n=22. Monocyte count, neutrophil count, monocyte:lymphocyte ratio, neutrophil:lymphocyte ratio and "systemic inflammatory response index" were significantly associated with radiological progression.

CONCLUSION: 3.1% of subjects requiring thoracic CT during a 6-year period demonstrated EF-ILA. Monocyte levels and blood leukocyte-derived indexes were associated with radiological progression and could indicate which patients may require closer follow-up.

PMID:35795307 | PMC:PMC9251369 | DOI:10.1183/23120541.00226-2022

Vavilovskii Zhurnal Genet Selektsii. 2022 May;26(3):308-318. doi: 10.18699/VJGB-22-37.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease with a prevalence of 2 to 29 per 100,000 of the world's population. Aging is a significant risk factor for IPF, and the mechanisms of aging (telomere depletion, genomic instability, mitochondrial dysfunction, loss of proteostasis) are involved in the pathogenesis of IPF. The pathogenesis of IPF consists of TGF-β activation, epithelial-mesenchymal transition, and SIRT7 expression decrease. Genetic studies have shown a role of mutations and polymorphisms in mucin genes (MUC5B), in the genes responsible for the integrity of telomeres (TERC, TERC, TINF2, DKC1, RTEL1, PARN), in surfactant-related genes (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2), immune system genes (IL1RN, TOLLIP), and haplotypes of HLA genes (DRB1*15:01, DQB1*06:02) in IPF pathogenesis. The investigation of the influence of reversible epigenetic factors on the development of the disease, which can be corrected by targeted therapy, shows promise. Among them, an association of a number of specific microRNAs and long noncoding RNAs was revealed with IPF. Therefore, dysregulation of transposons, which serve as key sources of noncoding RNA and affect mechanisms of aging, may serve as a driver for IPF development. This is due to the fact that pathological activation of transposons leads to violation of the regulation of genes, in the epigenetic control of which microRNA originating from these transposons are involved (due to the complementarity of nucleotide sequences). Analysis of the MDTE database (miRNAs derived from Transposable Elements) allowed the detection of 12 different miRNAs derived in evolution from transposons and associated with IPF (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). We described the relationship of transposons with TGF-β, sirtuins and telomeres, dysfunction of which is involved in the pathogenesis of IPF. New data on IPF epigenetic mechanisms can become the basis for improving results of targeted therapy of the disease using noncoding RNAs.

PMID:35795226 | PMC:PMC9170936 | DOI:10.18699/VJGB-22-37

Chron Respir Dis. 2022 Jan-Dec;19:14799731221114153. doi: 10.1177/14799731221114153.

ABSTRACT

OBJECTIVES: The peak expiratory flow rate (PEFR) is known to decrease in patients with sarcopenia. However, little is known about the clinical impact of the PEFR in idiopathic pulmonary fibrosis (IPF). This study aimed to confirm whether a decrease in PEFR over 6 months was associated with survival in IPF patients.

METHODS: Consecutive IPF patients who had been assessed at a single center were retrospectively analyzed. The relative decline in PEFR over 6 months was assessed. Survival analyses were performed by univariate and multivariate Cox proportional hazard models.

RESULTS: A total of 61 eligible cases (average age 70 years) were examined, and 21 patients (34.4%) died. The univariate Cox regression analysis showed that the body mass index, baseline % predicted forced vital capacity (FVC), baseline % predicted PEFR, % predicted diffusion capacity for carbon monoxide (DLCO), relative decline in FVC, and relative decline in PEFR were prognostic factors. On multivariate analyses, relative decline in PEFR (hazard ratio [HR] 1.037, p < .05) and baseline % predicted FVC (HR 0.932, p < .001) were independent prognostic factors, whereas relative decline in FVC was not.

CONCLUSION: A decrease in PEFR after 6 months may predict worse survival in patients with IPF.

PMID:35792724 | DOI:10.1177/14799731221114153

Phytomedicine. 2022 Jun 29;104:154301. doi: 10.1016/j.phymed.2022.154301. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a refractory disease. Therefore, developing effective therapies for IPF is the need of the hour.

PURPOSE: Yiqi Huoxue Formula (YQHX) is an herbal formula comprising three herbal medicines: Ligusticum chuanxiong Hort. (Chuanxiong Rhizoma, CR), Panax notoginseng (Burk.) F. H. Chen (Notoginseng Radix Et Rhizoma, NR) and Panax ginseng C. A. Mey. (Ginseng Radix Et Rhizoma, GR). This study aims to determine the anti-pulmonary fibrosis effect of YQHX and explore its mechanism of action.

STUDY: Design and Methods: The chemical components in the GR, CR and NR extracts were identified by High Performance Liquid Chromatography. A TGF-β1-induced myofibroblast cell model was used to test the anti-fibrosis effect of GR, CR, NR and YQHX. RNA-sequencing was used to identify the differentially expressed genes (DEGs) after YQHX treatment. Subsequently, gene enrichment analysis and key transcription factors (TFs) prediction for YQHX-regulated DEGs was performed. The active constituents of GR, CR and NR were obtained from the Traditional Chinese Medicine Database and Analysis Platform. Targets of the active constituents were predicted using the similarity ensemble approach search server and Swiss Target Prediction tool. YQHX-targeted key TFs that transcribed the DEGs were screened out. Then, the effect of YQHX on the bleomycin-induced pulmonary fibrosis mouse model was studied. Finally, one of the predicted TFs, STAT3, was selected to validate the prediction accuracy.

RESULTS: Seven, two, and five compounds were identified in the GR, CR, and NR extracts, respectively. YQHX and its constituents-GR, CR and NR-inhibited the expression of fibrotic markers, including α -SMA and fibronectin, indicating that YQHX inhibited TGF-β1-induced myofibroblast activation. RNA-sequencing identified 291 genes that were up-regulated in the TGF-β1 group but down-regulated after YQHX treatment. In total, 55 key TFs that transcribed YQHX-regulated targets were predicted. A regulatory network of 24 active ingredients and 232 corresponding targets for YQHX was established. Among YQHX's predicted targets, 20 were TFs. On overlapping YQHX-targeted TFs and DEGs' key TFs, six key TFs, including HIF1A, STAT6, STAT3, PPARA, DDIT3 and AR, were identified as the targets of YQHX. Additionally, YQHX alleviated bleomycin-induced pulmonary fibrosis in a mouse model by inhibiting the phosphorylation of STAT3 in the lungs of pulmonary fibrosis mice.

CONCLUSIONS: This study provides pharmacological support for the use of YQHX in the treatment of IPF. The potential mechanism of action of YQHX is speculated to involve the modulation of core TFs and inhibition of pathogenetic gene expressions in IPF.

PMID:35792448 | DOI:10.1016/j.phymed.2022.154301

BMJ Case Rep. 2022 Jul 5;15(7):e251483. doi: 10.1136/bcr-2022-251483.

NO ABSTRACT

PMID:35790325 | DOI:10.1136/bcr-2022-251483

J Allergy Clin Immunol Pract. 2022 Jul 1:S2213-2198(22)00654-7. doi: 10.1016/j.jaip.2022.06.031. Online ahead of print.

ABSTRACT

BACKGROUND: YKL-40 (chitinase 3-like-1) and Krebs von den Lungen-6 (KL-6) are two promising biomarkers that may have an important role in the management of interstitial lung diseases (ILD).

OBJECTIVES: The aim of this study was to investigate the values of KL-6 and YKL-40 as biomarkers in the diagnosis and prognosis of patients with hypersensitivity pneumonitis (HP).

METHODS: Cross-sectional study conducted in 49 patients diagnosed with HP due to exposure to birds (n = 32) or fungi (n = 17), 48 patients with other ILD and 67 healthy volunteers. HP patients were divided into fibrotic and non-fibrotic. Serum and sputum YKL-40 and KL-6 levels were determined using commercial ELISA kits. ROC curves were used to determine the sensitivity and specificity of both biomarkers for the diagnosis of HP. Pulmonary function tests were performed in patients during follow-up.

RESULTS: KL-6 and YKL-40 levels were significantly higher in serum of HP patients exposed to birds with a fibrotic pattern than in controls (p < 0.0001 and 0.0055 respectively). Serum KL-6 levels were also significantly higher in fibrotic HP patients exposed to fungi compared with the control group (p = 0.0001). In HP patients exposed to fungi, sputum KL-6 and YKL-40 levels were higher in those with a fibrotic pattern (p = 0.0289 and 0.016 respectively). ROC analysis showed that the range between 55-121 ng/ml for serum YKL-40 levels and 346-1441 U/ml for serum KL-6 levels had the best sensitivity and specificity for discriminating between HP patients, healthy controls and patients with idiopathic pulmonary fibrosis (IPF). In HP patients, serum KL-6 levels correlated negatively with total lung capacity (TLC, r = -0.485; p = 0.0103) and diffusing capacity of the lungs for carbon monoxide (DLCO, r = -0.534; p = 0.0002) at 12 months.

CONCLUSIONS: Both KL-6 and YKL-40 proteins seem to be capable of distinguishing HP patients from healthy individuals and from patients with IPF. Their sensitivity and specificity confirm their potential role as biomarkers. KL-6 may also be a predictor of disease progression.

PMID:35788062 | DOI:10.1016/j.jaip.2022.06.031

Am J Physiol Lung Cell Mol Physiol. 2022 Jul 5. doi: 10.1152/ajplung.00565.2020. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal lung disorder characterized by aberrant extracellular matrix deposition in the interstitium. Pirfenidone is an anti-fibrotic agent used to treat patients with IPF. Pirfenidone shows a pleiotropic mode of action, but its underlying anti-fibrotic mechanism is unclear. Transient receptor potential vanilloid 4 (TRPV4), which is a mechanosensitive calcium channel, was recently shown to be related to pulmonary fibrosis. To clarify the anti-fibrotic mechanisms of pirfenidone, we investigated whether TRPV4 blockade has a pharmacological effect in a murine model of pulmonary fibrosis and whether pirfenidone contributes to suppression of TRPV4. Our synthetic TRPV4 antagonist and pirfenidone treatment attenuated lung injury in the bleomycin mouse model. TRPV4-mediated increases in intracellular calcium were inhibited by pirfenidone. Additionally, TRPV4-stimulated interleukin-8 release from cells was reduced and a delay in cell migration was abolished by pirfenidone. Furthermore, pirfenidone decreased TRPV4 endogenous ligands in bleomycin-administered mouse lungs and their production by microsomes of human lungs. We found TRPV4 expression in the bronchiolar and alveolar epithelium and activated fibroblasts of the lungs in patients with IPF. Finally, we showed that changes in forced vital capacity of patients with IPF treated with pirfenidone were significantly correlated with metabolite levels of TRPV4 endogenous ligands in bronchoalveolar lavage fluid. These results suggest that the anti-fibrotic action of pirfenidone is partly mediated by TRPV4 and that TRPV4 endogenous ligands in bronchoalveolar lavage fluid may be biomarkers for distinguishing responders to pirfenidone.

PMID:35787697 | DOI:10.1152/ajplung.00565.2020

BMJ Open Respir Res. 2022 Jul;9(1):e001310. doi: 10.1136/bmjresp-2022-001310.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) greatly impacts quality of life and eventually leads to premature death from respiratory failure. Inhaled treprostinil was associated with improvements in forced vital capacity (FVC) and reduced exacerbations of underlying lung disease in post hoc analyses from a phase 3 study in patients with precapillary pulmonary hypertension due to interstitial lung disease. These results, combined with preclinical evidence of treprostinil's antifibrotic activity, support its investigation in the treatment of IPF.

METHODS AND ANALYSIS: The TETON programme consists of two replicate, 52-week, randomised, double-blind placebo-controlled, phase 3 studies, each enrolling 396 subjects (NCT04708782, NCT05255991). Eligible subjects must have a diagnosis of IPF confirmed by central imaging review, along with an FVC ≥45%. Stable background use of pirfenidone or nintedanib is allowed. The primary endpoint is change in absolute FVC at week 52. Secondary endpoints include time to clinical worsening (first event of death, respiratory hospitalisation or ≥10% decline in % predicted FVC), time to first acute exacerbation of IPF, overall survival, change in % predicted FVC and change in the King's Brief Interstitial Lung Disease Questionnaire at week 52. Safety parameters include adverse events, hospitalisations, oxygenation and laboratory parameters. Patients who complete week 52 will be eligible to enter an open-label extension study.

ETHICS AND DISSEMINATION: Studies will be conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice, Declaration of Helsinki principles, and local regulatory, ethical and legal requirements. Results will be published in a peer-reviewed publication.

PMID:35787522 | DOI:10.1136/bmjresp-2022-001310

Tuberk Toraks. 2022 Jun;70(2):113-121. doi: 10.5578/tt.20229801.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown etiology with an unpredictable course. We aimed to investigate the effects of the presence of hiatal hernia (HH) and its consequences on the clinical manifestation of IPF.

MATERIALS AND METHODS: Patients diagnosed with IPF with or without hiatal hernia were retrospectively compared in terms of clinical findings, total fibrosis scores (TFS), and lung function in the interstitial lung diseases (ILD) outpatient clinic.

RESULT: A total of 142 IPF patients were included in the study. HH was detected in 62.7% (n= 89) of the patients. There was no statistically significant difference between IPF patients with or without HH in terms of age, gender, smoking history, and anti-reflux drug use (p> 0.05). There was no statistically significant difference between IPF patients with or without HH in terms of symptoms such as dyspnea, cough, regurgitation, heartburn, nausea, dysphagia, chest pain, and hoarseness (p> 0.05). In addition, no statistically significant difference was found between IPF patients with or without HH in terms of mortality rate, survival time after diagnosis, and exacerbations (p> 0.05). Six-minute walking distance and SpO2 change, percentage of predicted forced vital capacity (FVC) value, and percentage of predicted diffusing capacity for carbon monoxide (DLCO) value did not differ significantly between the groups (p> 0.05). There was no statistically significant difference between the groups in terms of total fibrosis score (p= 0.668).

CONCLUSIONS: According to the results of this study, 62.7% (n= 89) of IPF patients had HH, and there was no difference in clinical outcomes, TFS, and pulmonary functions between IPF patients with or without HH.

PMID:35785875 | DOI:10.5578/tt.20229801

Environ Toxicol. 2022 Jul 4. doi: 10.1002/tox.23603. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial pulmonary disease with slow onset and high mortality. Epithelial-mesenchymal transition (EMT) is a significant condition for tissue fibrosis, and lncRNA-Snhg6 (small nucleolar RNA host gene 6) is related to EMT in some cancer cells, but its role in pulmonary fibrosis remains obscure. Here, we found that TGF-β1 and Snhg6 were up-regulated in lung tissues of BLM-induced lung fibrosis mouse, and Snhg6 expression was significantly increased in primary lung fibroblasts after BLM treatment. Snhg6 knockdown notably alleviated the pulmonary dysfunction, and the increase of fibrosis area and collagen deposition induced by BLM. MiR-26a-5p was downregulated in BLM-induced fibrotic lung tissues, and it was negatively regulated by Snhg6. Silencing Snhg6 markedly alleviated the TGF-β1-induced increase in fibrotic marker expression, cell proliferation, migration and differentiation, as well as the nuclear transport of p-Smad2/3 by modulating miR-26a-5p expression in mouse lung fibroblasts. Moreover, overexpressing Snhg6-induced collagen accumulation and fibroblast activation in fibroblasts, which was reversed by treatment with miR-26a-5p mimic or oxymatrine (an inhibitor of TGF-β1-Smads pathway). Interestingly, silencing Snhg6 in vivo mitigated BLM-driven pulmonary fibrosis by regulating the miR-26a-5p/TGF-β1-Smads axis. Our data revealed that Snhg6 contributed to the process of BLM-driven lung fibrosis in mouse by modulating the miR-26a-5p/TGF-β1-Smads axis, suggesting that Snhg6 might be a therapeutic target for lung fibrosis.

PMID:35785413 | DOI:10.1002/tox.23603

Front Pharmacol. 2022 Jun 15;13:919388. doi: 10.3389/fphar.2022.919388. eCollection 2022.

ABSTRACT

Overview: Idiopathic pulmonary fibrosis (IPF) is a disease caused by many factors, eventually resulting in lung function failure. Jinbei oral liquid (JBOL) is a traditional Chinese clinical medicine used to treat pulmonary diseases. However, the pharmacological effects and mechanism of the action of JBOL on IPF remain unclear. This study investigated the protective effects and mechanism of the action of JBOL on IPF using network pharmacology analysis, followed by in vivo and in vitro experimental validation. Methods: The components of JBOL and their targets were screened using the TCMSP database. IPF-associated genes were obtained using DisGeNET and Drugbank. The common targets of JBOL and IPF were identified with the STRING database, and a protein-protein interaction (PPI) network was constructed. GO and KEGG analyses were performed. Sprague-Dawley rats were injected with bleomycin (BLM) to establish an IPF model and treated orally with JBOL at doses of 5.4, 10.8, and 21.6 ml/kg. A dose of 54 mg/kg of pirfenidone was used as a control. All rats were treated for 28 successive days. Dynamic pulmonary compliance (Cdyn), minute ventilation volume (MVV), vital capacity (VC), and lung resistance (LR) were used to evaluate the efficacy of JBOL. TGF-β-treated A549 cells were exposed to JBOL, and epithelial-to-mesenchymal transition (EMT) changes were assessed. Western blots were performed. Results: Two hundred seventy-eight compounds and 374 targets were screened, and 103 targets related to IPF were identified. Core targets, including MAPK1 (ERK2), MAPK14 (p38), JUN, IL-6, AKT, and others, were identified by constructing a PPI network. Several pathways were involved, including the MAPK pathway. Experimentally, JBOL increased the levels of the pulmonary function indices (Cdyn, MVV, and VC) in a dose-dependent manner and reduced the RL level in the BLM-treated rats. JBOL increased the epithelial marker E-cadherin and suppressed the mesenchymal marker vimentin expression in the TGF-β-treated A549 cells. The suppression of ERK1/2, JNK, and p38 phosphorylation by JBOL was validated. Conclusion: JBOL had therapeutic effects against IPF by regulating pulmonary function and EMT through a systemic network mechanism, thus supporting the need for future clinical trials of JBOL.

PMID:35784749 | PMC:PMC9240387 | DOI:10.3389/fphar.2022.919388