Cells. 2023 Feb 9;12(4):554. doi: 10.3390/cells12040554.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD) for which there are no effective treatments. Lung transplantation is the only viable option for patients with end-stage PF but is only available to a minority of patients. Lung lesions in ILDs, including IPF, are characterized by alveolar epithelial cell (AEC) senescence and apoptosis and accumulation of activated myofibroblasts and/or fibrotic lung (fL) fibroblasts (fLfs). These composite populations of fLfs show a high rate of basal proliferation, resist apoptosis and senescence, and have increased migration and invasiveness. They also more readily deposit ECM proteins. These features eventuate in progressive destruction of alveolar architecture and loss of lung function in patients with PF. The identification of new, safer, and more effective therapy is therefore mandatory for patients with IPF or related ILDs. We found that increased caveolin-1 and tumor suppressor protein, p53 expression, and apoptosis in AECs occur prior to and then with the proliferation of fLfs in fibrotic lungs. AECs with elevated p53 typically undergo apoptosis. fLfs alternatively demonstrate strikingly low basal levels of caveolin-1 and p53, while mouse double minute 2 homolog (mdm2) levels and mdm2-mediated degradation of p53 protein are markedly increased. The disparities in the expression of p53 in injured AECs and fLfs appear to be due to increased basal expression of caveolin-1 in apoptotic AECs with a relative paucity of caveolin-1 and increased mdm2 in fLfs. Therefore, targeting caveolin-1 using a caveolin 1 scaffolding domain peptide, CSP7, represents a new and promising approach for patients with IPF, perhaps other forms of progressive ILD or even other forms of organ injury characterized by fibrotic repair. The mechanisms of action differ in the injured AECs and in fLfs, in which differential signaling enables the preservation of AEC viability with concurrent limitation of fLf expansion and collagen secretion. The findings in three models of PF indicate that lung scarring can be nearly abrogated by airway delivery of the peptide. Phase 1 clinical trial testing of this approach in healthy volunteers has been successfully completed; Phase 1b in IPF patients is soon to be initiated and, if successful, will be followed by phase 2 testing in short order. Apart from the treatment of IPF, this intervention may be applicable to other forms of tissue injury characterized by fibrotic repair.

PMID:36831221 | DOI:10.3390/cells12040554

Cells. 2023 Feb 8;12(4):548. doi: 10.3390/cells12040548.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is currently difficult to cure and is known to follow a chronic progressive course, with the patient's survival period estimated at about three years. The disease occasionally exacerbates acutely, leading to a fatal outcome. In recent years, it has become evident that lipid metabolism is involved in the fibrosis of lungs, and various reports have been made at the cellular level as well as at the organic level. The balance among eicosanoids, sphingolipids, and lipid composition has been reported to be involved in fibrosis, with particularly close attention being paid to a bioactive lipid "lysophosphatidic acid (LPA)" and its pathway. LPA signals are found in a wide variety of cells, including alveolar epithelial cells, vascular endothelial cells, and fibroblasts, and have been reported to intensify pulmonary fibrosis via LPA receptors. For instance, in alveolar epithelial cells, LPA signals reportedly induce mitochondrial dysfunction, leading to epithelial damage, or induce the transcription of profibrotic cytokines. Based on these mechanisms, LPA receptor inhibitors and the metabolic enzymes involved in LPA formation are now considered targets for developing novel means of IPF treatment. Advances in basic research on the relationships between fibrosis and lipid metabolism are opening the path to new therapies targeting lipid metabolism in the treatment of IPF.

PMID:36831215 | DOI:10.3390/cells12040548

Biomolecules. 2023 Feb 9;13(2):333. doi: 10.3390/biom13020333.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), characterized by progressive worsening of dyspnea and irreversible decline in lung function, is a chronic and progressive respiratory disease with a poor prognosis. Chronic or repeated lung injury results in inflammation and an excessive injury-repairing response that drives the development of IPF. A number of studies have shown that the development and progression of IPF are associated with dysregulated expression of several chemokines and chemokine receptors, several of which have been used as predictors of IPF outcome. Chemokines of the CC family play significant roles in exacerbating IPF progression by immune cell attraction or fibroblast activation. Modulating levels of detrimental CC chemokines and interrupting the corresponding transduction axis by neutralizing antibodies or antagonists are potential treatment options for IPF. Here, we review the roles of different CC chemokines in the pathogenesis of IPF, and their potential use as biomarkers or therapeutic targets.

PMID:36830702 | DOI:10.3390/biom13020333

Antioxidants (Basel). 2023 Feb 10;12(2):443. doi: 10.3390/antiox12020443.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has a detrimental prognosis despite antifibrotic therapies to which individual responses vary. IPF pathology is associated with oxidative stress, inflammation and increased activation of SRC family kinases (SFK). This pilot study evaluates individual responses to pirfenidone, nintedanib and SFK inhibitor saracatinib, markers of redox homeostasis, fibrosis and inflammation, in IPF-derived human bronchial epithelial (HBE) cells. Differentiated HBE cells from patients with and without IPF were analyzed for potential alterations in redox and profibrotic genes and pro-inflammatory cytokine secretion. Additionally, the effects of pirfenidone, nintedanib and saracatinib on these markers were determined. HBE cells were differentiated into a bronchial epithelium containing ciliated epithelial, basal, goblet and club cells. NOX4 expression was increased in IPF-derived HBE cells but differed on an individual level. In patients with higher NOX4 expression, pirfenidone induced antioxidant gene expression. All drugs significantly decreased NOX4 expression. IL-6 (p = 0.09) and IL-8 secretion (p = 0.014) were increased in IPF-derived HBE cells and significantly reduced by saracatinib. Finally, saracatinib significantly decreased TGF-β gene expression. Our results indicate that treatment responsiveness varies between IPF patients in relation to their oxidative and inflammatory status. Interestingly, saracatinib tends to be more effective in IPF than standard antifibrotic drugs.

PMID:36830000 | DOI:10.3390/antiox12020443

Bioengineering (Basel). 2023 Feb 14;10(2):251. doi: 10.3390/bioengineering10020251.

ABSTRACT

Patients affected by idiopathic pulmonary fibrosis (IPF) have a high mortality rate in the first 2-5 years from diagnosis. It is therefore necessary to identify a prognostic indicator that can guide the care process. The Gender-Age-Physiology (GAP) index and staging system is an easy-to-calculate prediction tool, widely validated, and largely used in clinical practice to estimate the risk of mortality of IPF patients at 1-3 years. In our study, we analyzed the GAP index through machine learning to assess any improvement in its predictive power in a large cohort of IPF patients treated either with pirfenidone or nintedanib. In addition, we evaluated this event through the integration of additional parameters. As previously reported by Y. Suzuki et al., our data show that inclusion of body mass index (BMI) is the best strategy to reinforce the GAP performance in IPF patients under treatment with currently available anti-fibrotic drugs.

PMID:36829744 | DOI:10.3390/bioengineering10020251

PLoS One. 2023 Feb 24;18(2):e0279878. doi: 10.1371/journal.pone.0279878. eCollection 2023.

ABSTRACT

BACKGROUND AND OBJECTIVES: The prognosis of idiopathic chronic fibrotic interstitial pneumonitis (CFIP) in patients with acute exacerbation (AE) is variable. We examined whether the imaging pattern on thoracic computed tomography (CT) or the severity of respiratory failure with AE-CFIP is associated with short-term prognosis.

METHODS: Patients admitted to two university hospitals were retrospectively analyzed and divided into derivation and validation cohorts. The distribution of newly appearing parenchymal abnormalities on thoracic CT was classified into peripheral, multifocal, and diffuse patterns. Respiratory failure was defined as severe if a fraction of inspired oxygen ≥ 0.5 was required to maintain percutaneous oxygen saturation ≥ 90% on admission. Factors associated with 90 day-mortality were analyzed using univariate and Cox proportional hazard regression.

RESULTS: In 59 patients with AE-CFIP of the derivation cohort, diffuse pattern on CT was associated with higher mortality within 90 days (43%) than peripheral/multifocal pattern (17%, p = 0.03). Additionally, compared with non-severe failure, severe respiratory failure was associated with higher mortality (47% vs. 21%, p = 0.06). Cox proportional hazard regression analysis demonstrated that a combination of diffuse pattern on CT and severe respiratory failure was associated with the poorest prognosis (hazard ratio [HR] 3.51 [interquartile range 1.26-9.80], p = 0.016) in the derivation cohort, which was confirmed in the validation cohort (n = 31, HR 4.30 [interquartile range 1.51-12.2], p = 0.006).

CONCLUSION: The combination of imaging pattern on thoracic CT and severity of respiratory failure was associated with the prognosis of idiopathic AE-CFIP.

PMID:36827247 | PMC:PMC9955596 | DOI:10.1371/journal.pone.0279878

Medicine (Baltimore). 2023 Feb 22;102(8):e32952. doi: 10.1097/MD.0000000000032952.

ABSTRACT

To investigate the characteristics of elderly-onset primary Sjögren syndrome (pSS) using chest high-resolution computed tomography and pulmonary function tests (PFTs). The data of 102 patients with pSS with interstitial lung disease were retrospectively analyzed. The chest high-resolution computed tomography, PFTs, and clinical and laboratory data were evaluated based on the age of onset: elderly-onset pSS (EopSS) (≥65 years) versus adult-onset pSS (AopSS) (<65 years). Among the 102 patients with pSS-interstitial lung disease, there were 34 of EopSS and 68 of AopSS. EopSS patients presented a significantly higher incidence of usual interstitial pneumonia (EopSS [38.2%] vs AopSS [11.8%], P = .005) and a significantly lower incidence of nonspecific interstitial pneumonia (EopSS [8.8%] vs AopSS [25%], P = .042). Unlike the AopSS group, the significant decreases in the vital capacity (VC) (the percentage of the predicted value of each parameter [%pred]) and the forced VC (%pred), PFTs showed that VC (%pred) and forced VC (%pred) were >80% in the EopSS group. Forced expiratory volume in 1 second significantly decreased and residual volume significantly increased in the EopSS group (P = .001). The percentage of small airway disease was significantly higher in the EopSS group (P = .021). Diffusing capacity of the lung for carbon monoxide/alveolar volume (%pred) was <80% in both groups with a lower percentage in the AopSS group. Usual interstitial pneumonia is more common in the EopSS group. Although there is no significant difference in ventilation dysfunction between the EopSS and AopSS groups, small airway disease is more common in the EopSS group, while restrictive ventilatory dysfunction is more common in the AopSS group. Therefore, the EopSS group has its own characteristics and it is worth studying and noting.

PMID:36827063 | DOI:10.1097/MD.0000000000032952

J Aerosol Med Pulm Drug Deliv. 2023 Feb 23. doi: 10.1089/jamp.2022.0020. Online ahead of print.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by lung scarring, which results in breathing difficulty. Currently, patients with IPF exhibit a poor survival rate and have access to very limited therapeutic options. Interferon beta (IFN-β) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis, and it has also been shown to exhibit therapeutic potential in IPF. However, clinical use of IFN-β did not lead to improved overall survival in IPF patients in existing studies. One possibility is the limited efficiency of IFN-β delivery through intravenous or subcutaneous injection. Materials and Methods: The aerosol particle size distribution was determined with a laser diffraction particle size analyzer to characterize the droplet size and fine particle fraction generated by three types of nebulizers: jet, ultrasonic, and mesh. A breathing simulator was used to assess the delivery efficiency of IFN-β, and the temperature in the medication reservoirs was monitored with a thermocouple during nebulization. To further evaluate the antifibrotic activity of IFN-β pre- and postnebulization, bleomycin (BLM)- or transforming growth factor-beta (TGF-β)-treated human lung fibroblast (HLF) cells were used. Cell viability was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Transwell migration assay and Q-PCR analysis were used to evaluate cell migration and the myofibroblast differentiation ability, respectively. IFN-β protein samples were prepared using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) sample loading buffer, and the expression of IFN-β was assessed by western blotting. Results: Among the current drug delivery systems, aerosolized medication has shown increased efficacy of drug delivery for treating respiratory diseases when compared with parenteral drugs. It was found that neither the structural integrity nor the biological function of nebulized IFN-β was compromised by the nebulization process of the mesh nebulizer. In addition, in BLM dose-response or TGF-β-induced lung fibroblast proliferation assays, these effects could be reversed by both parenteral and inhaled IFN-β nebulized with the mesh nebulizer. Nebulized IFN-β with the mesh nebulizer also significantly inhibited the migration and myofibroblast differentiation ability of TGF-β-treated HLF cells. Conclusions: The investigations revealed the potential efficacy of IFN-β in the treatment of IPF with the mesh nebulizer, demonstrating the higher efficiency of IFN-β delivered through the mesh nebulizer.

PMID:36827329 | DOI:10.1089/jamp.2022.0020

Adv Respir Med. 2023 Jan 31;91(1):26-48. doi: 10.3390/arm91010005.

ABSTRACT

The respiratory system is a well-organized multicellular organ, and disruption of cellular homeostasis or abnormal tissue repair caused by genetic deficiency and exposure to risk factors lead to life-threatening pulmonary disease including idiopathic pulmonary fibrosis (IPF). Although there is no clear etiology as the name reflected, its pathological progress is closely related to uncoordinated cellular and molecular signals. Here, we review the advances in our understanding of the role of lung tissue cells in IPF pathology including epithelial cells, mesenchymal stem cells, fibroblasts, immune cells, and endothelial cells. These advances summarize the role of various cell components and signaling pathways in the pathogenesis of idiopathic pulmonary fibrosis, which is helpful to further study the pathological mechanism of the disease, provide new opportunities for disease prevention and treatment, and is expected to improve the survival rate and quality of life of patients.

PMID:36825939 | DOI:10.3390/arm91010005

Lung. 2023 Feb 24. doi: 10.1007/s00408-023-00608-8. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by excessive extracellular matrix deposition. No effective treatments are currently available for IPF. High-temperature requirement A3 (HtrA3) suppresses tumor development by antagonizing transforming growth factor β (TGF-β) signaling; however, little is known about the role of HtrA3 in IPF. This study investigated the role of HtrA3 in IPF and underlying mechanisms.

METHODS: Lung tissues were collected from patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis, and HtrA3 expression was measured in tissue samples. Then, HtrA3 gene knockout mice were treated with BLM to induce pulmonary fibrosis and explore the effects and underlying mechanism of HtrA3 on pulmonary fibrosis.

RESULTS: HtrA3 was up-regulated in the lung tissues of patients with IPF and the pulmonary fibrotic mouse model compared to corresponding control groups. HtrA3 knockout decreased pulmonary fibrosis-related protein expression, alleviated the symptoms of pulmonary fibrosis, and inhibited epithelial-mesenchymal transition (EMT) in BLM-induced lung tissue compared with BLM-induced wild-type mice. The TGF-β1/Smad signaling pathway was activated in fibrotic lung tissue, whereas HtrA3 knockout inhibited this pathway.

CONCLUSION: The expression level of HtrA3 is increased in fibrotic lungs. HtrA3 knockout alleviates the symptoms of pulmonary fibrosis probably via the TGF-β1/Smad signaling pathway. Therefore, HtrA3 inhibition is a potential therapeutic target for pulmonary fibrosis.

PMID:36823409 | DOI:10.1007/s00408-023-00608-8

BMC Pulm Med. 2023 Feb 22;23(1):70. doi: 10.1186/s12890-023-02362-2.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) of interstitial lung disease (ILD) (AE-ILD) is a life-threatening condition and the leading cause of 30-day mortality among patients who underwent pulmonary resection for lung cancer in Japan. This study was conducted to clarify the characteristics of the immune environment of lung tissues before the onset of AE-ILD.

METHODS: This retrospective matched case-control study compared the immune phenotypes of helper T cells in lung tissues from patients with and without AE-ILD after surgery. In total, 135 patients who underwent surgical resection for lung cancer and were pathologically diagnosed with idiopathic interstitial pneumonia (IIP) at our institute between 2009 and 2018 were enrolled. Thirteen patients with AE-IIP and 122 patients without AE (non-AE) were matched using a propensity score analysis, and 12 cases in each group were compared. We evaluated the percentages of T helper (Th)1, Th2, Th17, regulatory T (Treg), and CD8 cells in CD3+ T cells and the Th1:Th2, Th17:Treg, and CD8:Treg ratios in patients with AE by immunostaining of lung tissues in the non-tumor area.

RESULTS: We found a significant difference in the lung Th17:Treg ratio between the AE and non-AE groups (1.47 and 0.79, p = 0.041). However, we detected no significant differences in the percentages of lung Th1 (21.3% and 29.0%), Th2 (34.2% and 42.7%), Th17 (22.3% and 21.6%), Treg (19.6% and 29.1%), and CD8+ T cells (47.2% and 42.2%) of CD3+ T cells between the AE and non-AE groups.

CONCLUSION: The ratio of Th17:Treg cells in lung tissues was higher in participants in the AE group than in those in the non-AE group.

CLINICAL TRIAL REGISTRATION: This study was approved by the ethics committee of our institute (2,016,095).

PMID:36814205 | PMC:PMC9945823 | DOI:10.1186/s12890-023-02362-2

Cell Death Discov. 2023 Feb 23;9(1):74. doi: 10.1038/s41420-023-01375-4.

NO ABSTRACT

PMID:36823139 | DOI:10.1038/s41420-023-01375-4

Eur Respir J. 2023 Feb 23:2201634. doi: 10.1183/13993003.01634-2022. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) induces permanent pulmonary dysfunction and is potentially lethal. The unpredictable occurrence of AE-IIPs remains an important clinical issue in the management of IIPs.

METHODS: In this multicentre, retrospective, observational study, a predictive score for AE-IIPs was designed using clinical factors based on multivariate Fine-Gray analysis in patients with IIPs.

RESULTS: Based on multivariate Fine-Gray analysis in an exploratory cohort of 487 patients with IIPs, the predictive score for AE-IIPs was determined as follows: 1 point each was added for honeycombing on high-resolution computed tomography (H), age >75 years (A), and lactate dehydrogenase level >222 U/L (L); the total score ranged from 0 to 3 (HAL score). The HAL score discriminated the risk of AE-IIPs with a c-index of 0.62 (95% confidence interval, 0.56-0.67); this discrimination was verified in a validation cohort of 402 patients with IIPs with a c-index of 0.67 (95% confidence interval, 0.60-0.73). In a combined cohort, the estimated cumulative risks for AE-IIPs at 1, 2, 3, 5, and 10 years were 1.9%, 3.5%, 5.1%, 7.7%, and 12.9% in the total score 0 group; 4.7%, 8.3%, 12.0%, 17.7%, and 28.4% in the total score 1 group; and 8.0%, 14.2%, 19.7%, 28.7%, and 43.0% in the total score ≥2 group. Subgroup analysis revealed that the HAL score was applicable to patients with and without idiopathic pulmonary fibrosis.

CONCLUSIONS: The HAL score discriminated the risk of AE-IIPs and could aid in the management of IIPs.

PMID:36822633 | DOI:10.1183/13993003.01634-2022

J Bras Pneumol. 2023 Feb 20;49(2):e20220280. doi: 10.36416/1806-3756/e20220280. eCollection 2023.

ABSTRACT

OBJECTIVE: To determine independent factors related to the use of oxygen and the oxygen flow rate in idiopathic pulmonary fibrosis (IPF) patients placed on a lung transplant waitlist and undergoing pulmonary rehabilitation (PR).

METHODS: This was a retrospective quasi-experimental study presenting functional capacity and health-related quality of life (HRQoL) data from lung transplant candidates with IPF referred for PR and receiving ambulatory oxygen therapy. The patients were divided into three groups on the basis of the oxygen flow rate: 0 L/min (the control group), 1-3 L/min, and 4-5 L/min. Data on functional capacity were collected by means of the six-minute walk test, and data on HRQoL were collected by means of the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), being collected before and after 36 sessions of PR including aerobic and strength exercises.

RESULTS: The six-minute walk distance improved in all three groups (0 L/min: Δ 61 m, p < 0.001; 1-3 L/min: Δ 58 m, p = 0.014; and 4-5 L/min: Δ 35 m, p = 0.031). Regarding HRQoL, SF-36 physical functioning domain scores improved in all three groups, and the groups of patients receiving ambulatory oxygen therapy had improvements in other SF-36 domains, including role-physical (1-3 L/min: p = 0.016; 4-5 L/min: p = 0.040), general health (4-5 L/min: p = 0.013), social functioning (1-3 L/min: p = 0.044), and mental health (1-3 L/min: p = 0.046).

CONCLUSIONS: The use of ambulatory oxygen therapy during PR in lung transplant candidates with IPF and significant hypoxemia on exertion appears to improve functional capacity and HRQoL.

PMID:36820744 | DOI:10.36416/1806-3756/e20220280

Ann Transl Med. 2023 Jan 31;11(2):78. doi: 10.21037/atm-22-6161.

ABSTRACT

BACKGROUND: The transcription factors (TFs)-microRNA (miRNA)-messenger RNA (mRNA) network plays an important role in a variety of diseases. However, the relationship between the TFs-miRNA-mRNA network and idiopathic pulmonary fibrosis (IPF) remains unclear.

METHODS: The GSE110147 and GSE53845 datasets from the Gene Expression Omnibus (GEO) database were used to process differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), as well as Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The GSE13316 dataset was used to perform differentially expressed miRNAs (DEMs) analysis and TFs prediction. Finally, a TFs-miRNA-mRNA network related to IPF was constructed, and its function was evaluated by Gene Ontology (GO) and KEGG analyses. Also, 19 TFs in the network were verified by quantitative real time polymerase chain reaction (qRT-PCR).

RESULTS: Through our analysis, 53 DEMs and 2,630 DEGs were screened. The GSEA results suggested these genes were mainly related to protein digestion and absorption. The WGCNA results showed that these DEGs were divided into eight modules, and the GO and KEGG analyses results of blue module genes showed that these 86 blue module genes were mainly enriched in cilium assembly and cilium organization. Moreover, a TFs-miRNA-mRNA network comprising 25 TFs, 11 miRNAs, and 60 mRNAs was constructed. Ultimately, the functional enrichment analysis showed that the TFs-miRNA-mRNA network was mainly related to the cell cycle and the phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway. Furthermore, experimental verification of the TFs showed that ARNTL, TRIM28, EZH2, BCOR, and ASXL1 were sufficiently up-regulated in the transforming growth factor (TGF)-β1 treatment groups, while BCL6, BHLHE40, FOXA1, and EGR1 were significantly down-regulated.

CONCLUSIONS: The novel TFs-miRNA-mRNA network that we constructed could provide new insights into the underlying molecular mechanisms of IPF. ARNTL, TRIM28, EZH2, BCOR, ASXL1, BCL6, BHLHE40, FOXA1, and EGR1 may play important roles in IPF and become effective biomarkers for diagnosis and treatment.

PMID:36819574 | PMC:PMC9929790 | DOI:10.21037/atm-22-6161

Can Respir J. 2023 Feb 8;2023:5088207. doi: 10.1155/2023/5088207. eCollection 2023.

ABSTRACT

BACKGROUND: The ILD-GAP scoring system has been widely used to predict the prognosis of patients with interstitial lung disease (ILD). The ability of the ILD-GAP scoring system combined with the Charlson Comorbidity Index score (CCIS) (ILD-GAPC) to predict ILD prognosis was investigated.

METHODS: In ILD patients, including idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD), treated between April 2013 and April 2017, the relationships between baseline clinical parameters, including age, sex, CCIS, ILD diagnosis, pulmonary function test results, and disease outcomes, were retrospectively assessed, and the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPC models, respectively.

RESULTS: A total of 185 patients (mean age, 71.9 years), all of whom underwent pulmonary function testing, including percentage predicted diffusion capacity for carbon monoxide, were assessed. ILD diagnosis consisted of IPF in 57 cases, iNSIP and CVD-IP in 117 cases, CHP in 6 cases, and UC-ILD in 5 cases. The ILD-GAPC provided a greater area under the receiver operating characteristic curve (0.758) for predicting 3-year ILD-related events than the ILD-GAP (0.721). In addition, log-rank tests showed that the Kaplan-Meier curves differed significantly among low, middle, and high ILD-GAPC scores (P < 0.001), unlike ILD-GAP scores (P = 0.083).

CONCLUSIONS: The ILD-GAPC model could provide more accurate information for predicting prognosis in patients with ILD than the ILD-GAP model.

PMID:36817552 | PMC:PMC9931459 | DOI:10.1155/2023/5088207

Front Pharmacol. 2023 Feb 3;14:1089812. doi: 10.3389/fphar.2023.1089812. eCollection 2023.

ABSTRACT

Fibroblasts activation is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis pathogenesis, and transforming growth factor (TGF)-β1 plays a key regulatory role in fibroblast activation. It has been reported that metformin (MET) alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) by regulating TGF-β1-induced fibroblasts activation, but the underlying mechanisms still deserve further investigations. In this study, MET blocked α-smooth muscle actin (α-SMA) accumulation in vivo accompanied with S100A4 expression and STAT3 phosphorylation inhibition, resulting in attenuating the progression of lung fibrosis after BLM administration. We determined that S100A4 plays critical roles in fibroblasts activation in vitro, evidenced by siRNA knockdown of S100A4 expression downregulated TGF-β1 induced α-SMA production in Human fetal lung fibroblast (HFL1) cells. Importantly, we found for the first time that the expression of S100A4 in fibroblasts was regulated by STAT3. Stattic, an effective small molecule inhibitor of STAT3 phosphorylation, reduced S100A4 level in TGF-β1- treated HFL1 cells accompanied with less α-SMA production. We further found that MET, which inhibits STAT3 phosphorylation by AMPK activation, also inhibits fibroblasts activation by targeting S100A4 in vitro. Together all these results, we conclude that S100A4 contributes to TGF-β1- induced pro-fibrogenic function in fibroblasts activation, and MET was able to protect against TGF-β1-induced fibroblasts activation and BLM-induced PF by down-regulating S100A4 expression through AMPK-STAT3 axis. These results provide a useful clue for a clinical strategy to prevent PF.

PMID:36817136 | PMC:PMC9936158 | DOI:10.3389/fphar.2023.1089812

Pharm Biol. 2023 Dec;61(1):288-297. doi: 10.1080/13880209.2022.2160767.

ABSTRACT

CONTEXT: Fibroblast senescence was reported to contribute to the pathological development of idiopathic pulmonary fibrosis (IPF), and baicalein is reported to attenuate IPF.

OBJECTIVE: This study explores whether baicalein attenuates lung fibrosis by regulating lung fibroblast senescence.

MATERIALS AND METHODS: Institute of Cancer Research (ICR) mice were randomly assigned to control, bleomycin (BLM), baicalein and BLM + baicalein groups. Lung fibrosis was established by a single intratracheal dose of BLM (3 mg/kg). The baicalein group received baicalein orally (100 mg/kg/day). Sirtuin 3 (Sirt3) siRNA (50 μg) was injected through the tail vein once a week for 2 weeks to explore its effect on the anti-pulmonary fibrosis of baicalein.

RESULTS: BLM-treated mice exhibited obvious lung fibrosis and fibroblast senescence by showing increased levels of collagen deposition (27.29% vs. 4.14%), hydroxyproline (208.05 vs. 40.16 ng/mg), collagen I (25.18 vs. 9.15 μg/mg), p53, p21, p16, MCP-1, PAI-1, TNF-α, MMP-10 and MMP-12 in lung tissues, which were attenuated by baicalein. Baicalein also mitigated BLM-mediated activation of TGF-β1/Smad signalling pathway. Baicalein restored the BLM-induced downregulation of Sirt3 expression in lung tissues and silencing of Sirt3 abolished the inhibitory role of baicalein against BLM-induced lung fibrosis, fibroblast senescence and activation of TGF-β1/Smad signalling pathway.

CONCLUSIONS: Baicalein preserved the BLM-induced downregulation of lung Sirt3 expression, and thus the suppression of TGF-β1/Smad signalling pathway and lung fibrosis, which might provide an experimental basis for treatment of IPF.

PMID:36815239 | DOI:10.1080/13880209.2022.2160767

Eur Respir Rev. 2023 Feb 21;32(167):220206. doi: 10.1183/16000617.0206-2022. Print 2023 Mar 31.

ABSTRACT

Patients with interstitial lung disease can develop a progressive fibrosing phenotype characterised by an irreversible, progressive decline in lung function despite treatment. Current therapies slow, but do not reverse or stop, disease progression and are associated with side-effects that can cause treatment delay or discontinuation. Most crucially, mortality remains high. There is an unmet need for more efficacious and better-tolerated and -targeted treatments for pulmonary fibrosis. Pan-phosphodiesterase 4 (PDE4) inhibitors have been investigated in respiratory conditions. However, the use of oral inhibitors can be complicated due to class-related systemic adverse events, including diarrhoea and headaches. The PDE4B subtype, which has an important role in inflammation and fibrosis, has been identified in the lungs. Preferentially targeting PDE4B has the potential to drive anti-inflammatory and antifibrotic effects via a subsequent increase in cAMP, but with improved tolerability. Phase I and II trials of a novel PDE4B inhibitor in patients with idiopathic pulmonary fibrosis have shown promising results, stabilising pulmonary function measured by change in forced vital capacity from baseline, while maintaining an acceptable safety profile. Further research into the efficacy and safety of PDE4B inhibitors in larger patient populations and for a longer treatment period is needed.

PMID:36813290 | DOI:10.1183/16000617.0206-2022

Respir Med Res. 2023 Jan 20;83:100996. doi: 10.1016/j.resmer.2023.100996. Online ahead of print.

ABSTRACT

BACKGROUND: Diagnosing interstitial lung disease (ILD) remains challenging. Guidelines recommend utilizing a multidisciplinary discussion (MDD) to review clinical and radiographic data and if diagnostic uncertainty persists, then to obtain histopathology. Surgical lung biopsy and transbronchial lung cryobiopsy (TBLC) are acceptable methods, but risks of complications may be prohibitive. The Envisia genomic classifier (EGC) represents another option to determine a molecular usual interstitial pneumonia (UIP) signature to facilitate an ILD diagnosis at MDD with high sensitivity and specificity. We evaluated the concordance between TBLC and EGC at MDD and the safety of this procedure.

METHODS: Demographic data, pulmonary function values, chest imaging pattern, procedural information, and MDD diagnosis were recorded. Concordance was defined as agreement between the molecular EGC results and histopathology from TBLC in the context of the patient's High Resolution CT pattern.

RESULTS: 49 patients were enrolled. Imaging demonstrated a probable (n = 14) or indeterminate (n = 7) UIP pattern in 43% and an alternative pattern in 57% (n = 28). EGC results were positive for UIP in 37% (n = 18) and negative in 63% (n = 31). MDD diagnosis was obtained in 94% (n = 46) with fibrotic hypersensitivity pneumonitis (n = 17, 35%) and IPF (n = 13, 27%) most common. The concordance between EGC and TBLC at MDD was 76% (37/49) with discordant results seen in 24% (12/49) of patients.

CONCLUSIONS: There appears to be reasonable concordance between EGC and TBLC results at MDD. Efforts clarifying the contributions of these tools to an ILD diagnosis may help identify specific patient populations that may benefit from a tailored diagnostic approach.

PMID:36812772 | DOI:10.1016/j.resmer.2023.100996