Heliyon. 2023 Dec 11;10(1):e23543. doi: 10.1016/j.heliyon.2023.e23543. eCollection 2024 Jan 15.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial disease that cannot be cured, and treatment options for IPF are very limited. Early diagnosis, close monitoring of disease progression, and timely treatment are therefore the best options for patients due to the irreversibility of IPF. Effective markers help doctors judge the development and prognosis of disease. Recent research on traditional biomarkers (KL-6, SP-D, MMP-7, TIMPs, CCL18) has provided novel ideas for predicting disease progression and prognosis. Some emerging biomarkers (HE4, GDF15, PRDX4, inflammatory cells, G-CSF) also provide more possibilities for disease prediction. In addition to markers in serum and bronchoalveolar lavage fluid (BALF), some improvements related to the GAP model and chest HRCT also show good predictive ability for disease prognosis.

PMID:38173501 | PMC:PMC10761784 | DOI:10.1016/j.heliyon.2023.e23543

Diabetes Metab J. 2024 Jan 3. doi: 10.4093/dmj.2022.0367. Online ahead of print.

ABSTRACT

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression.

METHODS: Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture.

RESULTS: DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor β (TGFβ)-induced pro-fibrotic gene expression by suppressing TGFβ receptor 1 (TGFβR1)/Smad2/3 and TGFβR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis.

CONCLUSION: Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

PMID:38173372 | DOI:10.4093/dmj.2022.0367

Eur Heart J Cardiovasc Imaging. 2024 Jan 3:jeae001. doi: 10.1093/ehjci/jeae001. Online ahead of print.

ABSTRACT

BACKGROUND: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, SSc-PAH patients demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relation between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy in SSc-PAH patients is evaluated, and compared to idiopathic PAH (IPAH) patients.

METHODS: SSc-PAH and IPAH patients underwent CMR, echocardiography, and nailfold capillaromicroscopy with post-occlusive reactivity hyperaemia (PORH)-testing on the same day. CMR imaging included T2- (oedema), native and postcontrast T1-mapping to measure the extracellular volume fraction (ECV, fibrosis), and adenosine-stress perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis and myocardial perfusion.

RESULTS: SSc-PAH patients (n=20) had higher T2, and a trend towards a higher ECV, compared to IPAH patients (n=5), and lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV, and T2 (r=-0.443, and -0.464, respectively, p<0.05 for all), and with markers of diastolic dysfunction on echocardiography. PORH-testing, but not NCD, correlated with the relative myocardial upslope (r=0.421, p<0.05).

CONCLUSIONS: SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared to IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

PMID:38170546 | DOI:10.1093/ehjci/jeae001

Sci Rep. 2024 Jan 2;14(1):240. doi: 10.1038/s41598-023-50618-y.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a devastating form of respiratory disease with a life expectancy of 3-4 years. Inflammation, epithelial injury and myofibroblast proliferation have been implicated in disease initiation and, recently, epithelial-fibroblastic crosstalk has been identified as a central driver. However, the ability to interrogate this crosstalk is limited due to the absence of in vitro models that mimic physiological conditions. To investigate IPF dysregulated cross-talk, primary normal human bronchial epithelial (NHBE) cells and primary normal human lung fibroblasts (NHLF) or diseased human lung fibroblasts (DHLF) from IPF patients, were co-cultured in direct contact at the air-liquid interface (ALI). Intercellular crosstalk was assessed by comparing cellular phenotypes of co-cultures to respective monocultures, through optical, biomolecular and electrical methods. A co-culture-dependent decrease in epithelium thickness, basal cell mRNA (P63, KRT5) and an increase in transepithelial electrical resistance (TEER) was observed. This effect was significantly enhanced in DHLF co-cultures and lead to the induction of epithelial to mesenchymal transition (EMT) and increased mRNA expression of TGFβ-2, ZO-1 and DN12. When stimulated with exogenous TGFβ, NHBE and NHLF monocultures showed a significant upregulation of EMT (COL1A1, FN1, VIM, ASMA) and senescence (P21) markers, respectively. In contrast, direct NHLF/NHBE co-culture indicated a protective role of epithelial-fibroblastic cross-talk against TGFβ-induced EMT, fibroblast-to-myofibroblast transition (FMT) and inflammatory cytokine release (IL-6, IL-8, IL-13, IL-1β, TNF-α). DHLF co-cultures showed no significant phenotypic transition upon stimulation, likely due to the constitutively high expression of TGFβ isoforms prior to any exogenous stimulation. The model developed provides an alternative method to generate IPF-related bronchial epithelial phenotypes in vitro, through the direct co-culture of human lung fibroblasts with NHBEs. These findings highlight the importance of fibroblast TGFβ signaling in EMT but that monocultures give rise to differential responses compared to co-cultures, when exposed to this pro-inflammatory stimulus. This holds implications for any translation conclusions drawn from monoculture studies and is an important step in development of more biomimetic models of IPF. In summary, we believe this in vitro system to study fibroblast-epithelial crosstalk, within the context of IPF, provides a platform which will aid in the identification and validation of novel targets.

PMID:38168149 | DOI:10.1038/s41598-023-50618-y

BMC Pulm Med. 2024 Jan 2;24(1):10. doi: 10.1186/s12890-023-02776-y.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival.

METHODS: We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan-Meier method and the log-rank test.

RESULTS: Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at - 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs.

CONCLUSIONS: In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

PMID:38167026 | DOI:10.1186/s12890-023-02776-y

J Nanobiotechnology. 2024 Jan 3;22(1):14. doi: 10.1186/s12951-023-02251-0.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a highly debilitating and fatal chronic lung disease that is difficult to cure clinically. IPF is characterized by a gradual decline in lung function, which leads to respiratory failure and severely affects patient quality of life and survival. Oxidative stress and chronic inflammation are believed to be important pathological mechanisms underlying the onset and progression of IPF, and the vicious cycle of NOX4-derived ROS, NLRP3 inflammasome activation, and p38 MAPK in pulmonary fibrogenesis explains the ineffectiveness of single-target or single-drug interventions. In this study, we combined astragaloside IV (AS-IV) and ligustrazine (LIG) based on the fundamental theory of traditional Chinese medicine (TCM) of "tonifying qi and activating blood" and loaded these drugs onto nanoparticles (AS_LIG@PPGC NPs) that were inhalable and could penetrate the mucosal barrier. Our results suggested that inhalation of AS_LIG@PPGC NPs significantly improved bleomycin-induced lung injury and fibrosis by regulating the NOX4-ROS-p38 MAPK and NOX4-NLRP3 pathways to treat and prevent IPF. This study not only demonstrated the superiority, feasibility, and safety of inhalation therapy for IPF intervention but also confirmed that breaking the vicious cycle of ROS and the NLRP3 inflammasome is a promising strategy for the successful treatment of IPF. Moreover, this successful nanoplatform is a good example of the integration of TCM and modern medicine.

PMID:38166847 | DOI:10.1186/s12951-023-02251-0

2024 Oct 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–.

ABSTRACT

The diffusing capacity of the lungs for carbon monoxide (DLCO), also known as the transfer factor for carbon monoxide (TLCO), measures the amount of carbon monoxide (CO) transferred per minute from alveolar gas to red blood cells (RBCs). This test provides critical insights into the lungs' ability to transfer oxygen from inhaled air to the bloodstream, making it essential for diagnosing and monitoring various pulmonary conditions. Expressed in mL/min/mm Hg or mmol/min/kPa, the DLCO represents the volume of CO (in mL) transferred per minute for each unit of pressure difference (in mm Hg) across the total available functioning gas exchange surface in the lungs.

Clinicians use inhaled CO for this test because of its strong affinity for hemoglobin (Hgb). Oxygen is not preferred due to its weaker interaction with Hgb. Cardiac output and overall body consumption also limit oxygen uptake. Due to CO's strong binding to Hgb, this gas' absorption is primarily limited by changes to the alveolar-capillary membrane rather than blood flow, enabling clinicians to evaluate the membrane's integrity.

The DLCO helps evaluate patients with dyspnea, hypoxemia, emphysema, and interstitial lung disease (ILD) and serves as an early indicator for conditions like idiopathic pulmonary fibrosis (IPF) before spirometric changes are detectable. Additionally, DLCO determination helps clinicians monitor disease progression and therapy response and predict mortality. Any condition that reduces oxygen uptake will produce a similar decrease in CO uptake. Overlooking a low DLCO may be a missed opportunity for early intervention.

The Fick equation for gas diffusion helps explain the physiologic factors that affect the DLCO. The respiratory membrane forms the diffusing barrier and separates air within the alveoli from blood flowing in the pulmonary capillaries. The membrane consists of the alveolar epithelium, interstitium, and capillary endothelium. The DLCO results from 2 main measurements: alveolar volume accessible during a 10-second breath hold (Va) and the rate of alveolar capillary blood CO uptake (Kco).

The Fick equation is:

Vg=[k*(A)(ΔP)] / T ,

where V is the volume of gas transferred per unit of time, K is the diffusion coefficient of the gas, A is the surface area for gas exchange, ΔP is the partial pressure difference of gas, and T is the membrane thickness. The Fick equation demonstrates that factors that influence the movement of gas molecules across the capillary membrane include the membrane's surface area and thickness, as well as the driving pressure or pressure gradient across the capillary membrane.

Alterations in respiratory membrane properties, Hgb levels, and capillary blood volume contribute to DLCO variations. Gas diffusion across the alveolar membrane increases when the membrane surface area, alveolar pressure gradient, or gas solubility increases or when the membrane becomes thinner. Conversely, membrane thickening or a decrease in the membrane surface area, alveolar pressure gradient, or gas solubility reduces gas diffusion across the alveolar membrane.

Blood in the airways can also bind CO, and the DLCO may rise in the presence of hemoptysis and pulmonary hemorrhage. In contrast, anemia can decrease the DLCO. Measuring the DLCO is relatively simple and carries minimal risk, yet it provides critical insights into lung function, facilitating early detection and management of abnormalities. Incorporating DLCO testing into routine pulmonary evaluations can significantly improve patient outcomes and quality of care.

PMID:32310609 | Bookshelf:NBK556149

2024 Aug 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–.

ABSTRACT

Nintedanib is a small molecule tyrosine kinase inhibitor that binds to growth factor receptors, inhibiting the proliferation of fibroblasts. This action reduces ongoing fibrotic processes and delays the progression to long-lasting damage. Nintedanib is indicated for treating idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and progressive phenotype interstitial lung disease. This activity reviews the indications, contraindications, and adverse events associated with nintedanib therapy. The activity also covers the administration, pharmacokinetics, and relevant interactions of nintedanib, providing knowledge crucial for tailoring treatment to individual patient needs.

PMID:36251827 | Bookshelf:NBK585049

Heliyon. 2023 Dec 3;10(1):e23233. doi: 10.1016/j.heliyon.2023.e23233. eCollection 2024 Jan 15.

ABSTRACT

Long noncoding RNAs (lncRNAs) play a critical role in idiopathic pulmonary fibrosis (IPF); however, the underlying molecular mechanisms are unclear. Our study demonstrated that lncRNA small nucleolar RNA host gene 8 (SNHG8) was increased in bleomycin (BLM)-induced A549 cells. LncRNA SNHG8 overexpression further elevated fibrosis-related factors monocyte chemotactic protein 1 (MCP1), CC motif chemokine ligand 18 (CCL18), and α-smooth muscle actin (α-SMA), as well as increased collagen type I alpha-1 chain (COL1A1) and collagen type III alpha-1 chain (COL3A1). Meanwhile, lncRNA SNHG8 knockdown exhibited an opposite role in reducing BLM-induced pulmonary fibrosis. With regard to the mechanism, SNHG8 was then revealed to act as a competing endogenous RNA (ceRNA) for microRNA (miR)-4701-5p in regulating Mucin 5B (MUC5B) expression. Furthermore, the interactions between SNHG8 and miR-4701-5p, between miR-4701-5p and MUC5B, and between SNHG8 and MUC5B on the influence of fibrosis-related indicators were confirmed, respectively. In addition, SNHG8 overexpression enhanced the levels of transforming growth factor (TGF)-β1 and phosphorylation Smad2/3 (p-Smad2/3), which was suppressed by SNHG8 knockdown in BLM-induced A549 cells. Moreover, miR-4701-5p inhibitor-induced elevation of TGF-β1 and p-Smad2/3 was significantly suppressed by SNHG8 knockdown. In conclusion, SNHG8 knockdown attenuated pulmonary fibrosis progression by regulating miR-4701-5p/MUC5B axis, which might be associated with the modulation of TGF-β1/Smad2/3 signaling. These findings reveal that lncRNA SNHG8 may become a potential target for the treatment of IPF.

PMID:38163156 | PMC:PMC10756985 | DOI:10.1016/j.heliyon.2023.e23233

Mymensingh Med J. 2024 Jan;33(1):298-302.

ABSTRACT

We diagnosed and treated a case of Primary SjoGren's Syndrome with Idiopathic Pulmonary Fibrosis (IPF) in a 65 years old woman who presented with dyspnoea and multiple joint pains for 5 years and remained undiagnosed. She had variable presentation and was initially established as a case of mixed connective tissue disease which consists of Systemic Lupus Erythematosus (SLE), Systemic Sclerosis and Dermatomyositis. She complained of xerostomia, xerophthalmia, difficulty in opening mouth, progressive dysphagia with solid foods and raynaud's phenomenon. In addition to this she noticed photosensitive rash, oral ulcers and difficulty in raising arms above head especially while combing hair. Examination revealed bi basal fine end inspiratory crepitations unaltered while coughing, bed side 6 minutes walking test showed exertional desaturation of SpO2 from 92.0% to 84.0%. Grade 2 tenderness was noted in wrists, knees, elbows and small joints of hands and feet except DIP. However, no oral lesions or dental carries were found. Unstimulated salivary flow rate was 1.0 ml in 15 minutes and sublingual salivary pool was significantly reduced. Schirmer's test was positive. HRCT lung revealed reticulonodular shadowing, honey combing and traction bronchiectasis in basal segments of both lobes, suggestive of usual interstitial pneumonia in both lungs. Auto antibody tests revealed ANA, RA, anti CCP and anti ds DNA negative, CPK was 63U/L. ENA (Extractable Nuclear Antigen) profile demonstrated positive Anti SS- A antibody while it remained insignificant for anti SS-B, anti RNP, anti Sm antibody, anti Scl-7o, anti Jo-1. According to the American-European Consensus Criteria for SjoGren's Syndrome, it meets all the criteria to be diagnosed as Primary Sjogren's Syndrome. We finally diagnosed a case of Primary SjoGren's syndrome with IPF and the patient was treated with pirfenidone, prednisolone, artificial tears and vaccination against Haemophilus influenzae and Streptococcal pneumoniae. The 10 year survival rate for such patients is nearly 80.0%.

PMID:38163807

Arch Bronconeumol. 2023 Dec 18:S0300-2896(23)00403-9. doi: 10.1016/j.arbres.2023.12.002. Online ahead of print.

ABSTRACT

INTRODUCTION: Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE).

METHODS: The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF - "lack of efficacy" (LE) and "intolerance" (INT).

RESULTS: While 263 (43%) of 612 patients received no second AF ("non-switched"), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: -98ml/y in switched and -172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001).

CONCLUSION: The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy.

PMID:38160169 | DOI:10.1016/j.arbres.2023.12.002

BMJ Open Respir Res. 2023 Dec 30;10(1):e002008. doi: 10.1136/bmjresp-2023-002008.

ABSTRACT

OBJECTIVES: We aimed to assess the available evidence for corticosteroids in fibrotic interstitial lung disease (fILD) to inform the randomised embedded multifactorial adaptive platform ILD.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES: We searched Embase, Medline, Cochrane CENTRAL and Web of Science databases from inception to April 17 2023.

ELIGIBILITY CRITERIA: We included studies that compared corticosteroids with standard care, placebo or no treatment in adult patients with fILD.

DATA EXTRACTION AND SYNTHESIS: We report on the change in forced vital capacity (FVC) and mortality. We used random-effects meta-analysis to estimate relative risk (RR) for dichotomous outcomes, and mean difference (MD) and standardised MDs for continuous outcomes, with 95% CIs.

RESULTS: Of the 13 229 unique citations identified, we included 10 observational studies comprising 1639 patients. Corticosteroids had an uncertain effect on mortality compared with no treatment (RR 1.03 (95% CI 0.85 to 1.25); very low certainty evidence). The effect of corticosteroids on the rate of decline in FVC (% predicted) was uncertain when compared with no treatment (MD 4.29% (95% CI -8.26% to 16.83%); very low certainty evidence). However, corticosteroids might reduce the rate of decline in FVC in patients with non-idiopathic pulmonary fibrosis (IPF) fILD (MD 10.89% (95% CI 5.25% to 16.53%); low certainty evidence), while an uncertain effect was observed in patients with IPF (MD -3.80% (95% CI -8.94% to 1.34%); very low certainty evidence).

CONCLUSIONS: The current evidence on the efficacy and safety of corticosteroids in fILD is limited and of low certainty. Randomised trials are needed to address this significant research gap.

PMID:38160015 | DOI:10.1136/bmjresp-2023-002008

Int Immunopharmacol. 2023 Dec 29;127:111456. doi: 10.1016/j.intimp.2023.111456. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related inflammatory disease with no cure up till now.It is accompanied by neutrophils infiltration as the main responders to inflammation and fibrosis. Importantly, neutrophils release neutrophil extracellular traps (NETs) through NETosis process. The function of microRNAs during inflammation became of great biological attention. Owing to microRNAs' central role in immune system, microRNA-155-5p (miR-155-5p) is intensely involved in the inflammatory response. Capsaicin (Cap) is a bioactive compound that exhibits antioxidative and anti-inflammatory functions. Recent studies have shown its role in regulation of certain microRNAs' expressions. Accordingly, the present study aims to investigate the effect of miR-155-5p regulation in suppressing NETs production via ameliorating its target inflammatory cytokines, IL-1ß, TNF-α and TGF-ß1, in bleomycin (BLM)-induced pulmonary fibrosis rat model treated by Cap. The obtained results demonstrated that miR-155-5p downregulation was associated with significant decrease in IL-1ß, TNF-α, TGF-β1, which consequently, reduced hydroxyproline (HYP), NETs activity markers as NE and PAD-4, and alleviated CTGF levels in lung tissues of animals treated by Cap. Furthermore, NETosis ultrastructure examination by transmission electron microscope (TEM), MPO immunohistochemical staining and histopathological studies confirmed an abolishment in NETs formation and an improvement in lung tissue architecture in Cap-treated rats. This study concluded that Cap quenched the inflammatory response through interrupting IL-1β, TNF-α and TGF-β1 pathway via modulating miR-155-5p expression. In addition, Cap was able to alleviate pulmonary NETosis markers by restraining NETs activity markers. These findings provide novel insight into the application of Cap-based treatment in ameliorating pulmonary damage in IPF.

PMID:38159555 | DOI:10.1016/j.intimp.2023.111456

Expert Rev Respir Med. 2023 Dec 30:1-14. doi: 10.1080/17476348.2023.2299751. Online ahead of print.

ABSTRACT

INTRODUCTION: Many patients with interstitial lung diseases (ILDs), especially fibrotic ILDs, experience chronic cough. It negatively impacts both physical and psychological well-being. Effective treatment options are limited.

AREAS COVERED: The pathophysiology of chronic cough in IPF is complex and involves multiple mechanisms, including mechanical distortion of airways, parenchyma, and nerve fibers. The pathophysiology of cough in other fibrosing ILDs is poorly understood and involves various pathways. The purpose of this review is to highlight mechanisms of chronic cough and to present therapeutic evidence for its management in the most commonly occurring diffuse fibrosing lung diseases including idiopathic pulmonary fibrosis (IPF), connective tissue disease-related interstitial lung disease (CTD-ILD), sarcoidosis-related ILD (Sc-ILD), chronic hypersensitivity pneumonitis-related ILD (CHP-ILD), and post-COVID-19-related interstitial lung disease (PC-ILD).

EXPERT OPINION: This review guides the management of chronic cough in fibrosing ILDs. In this era of precision medicine, chronic cough management should be individualized in each interstitial lung disease.

PMID:38159067 | DOI:10.1080/17476348.2023.2299751

J Cell Mol Med. 2023 Dec 30. doi: 10.1111/jcmm.18098. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is considered as a chronic, fibrosing interstitial pneumonia with unknown mechanism. The present work aimed to explore the function, biogenesis and regulatory mechanism of circELP2 in pulmonary fibrosis and evaluate the value of blocking circELP2-medicated signal pathway for IPF treatment. The results showed that heterogeneous nuclear ribonucleoprotein L initiated reverse splicing of circELP2 resulting in the increase of circELP2 generation. The biogenetic circELP2 activated the abnormal proliferation and migration of fibroblast and extracellular matrix deposition to promote pulmonary fibrogenesis. Mechanistic studies demonstrated that cytoplasmic circELP2 sponged miR-630 to increase transcriptional co-activators Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ). Then, YAP1/TAZ bound to the promoter regions of their target genes, such as mTOR, Raptor and mLST8, which in turn activated or inhibited the genes expression in mitochondrial quality control pathway. Finally, the overexpressed circELP2 and miR-630 mimic were packaged into adenovirus vector for spraying into the mice lung to evaluate therapeutic effect of blocking circELP2-miR-630-YAP1/TAZ-mitochondrial quality control pathway in vivo. In conclusion, blocking circELP2-medicated pathway can alleviate pulmonary fibrosis, and circELP2 may be a potential target to treat lung fibrosis.

PMID:38159063 | DOI:10.1111/jcmm.18098

Eur J Pharmacol. 2023 Dec 27;964:176293. doi: 10.1016/j.ejphar.2023.176293. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with no cure. Bufotalin (BT), an active component extracted from Venenum Bufonis, has been prescribed as a treatment for chronic inflammatory diseases. However, whether BT has antifibrotic properties has never been investigated. In this study, we report on the potential therapeutic effect and mechanism of BT on IPF. BT was shown to attenuate lung injury, inflammation, and fibrosis as well as preserve pulmonary function in bleomycin (BLM)-induced pulmonary fibrosis model. We next confirmed BT's ability to inhibit TGF-β1-induced epithelial-mesenchymal transition (EMT) and myofibroblast activation (including differentiation, proliferation, migration, and extracellular matrix production) in vitro. Furthermore, transcriptional profile analysis indicated the Wnt signaling pathway as a potential target of BT. Mechanistically, BT effectively prevented β-catenin from translocating into the nucleus to activate transcription of profibrotic genes. This was achieved by blunting TGF-β1-induced increases in phosphorylated Akt Ser437 (p-Akt S437) and phosphorylated glycogen synthase kinase (GSK)-3β Ser9 (p-GSK-3β S9), thereby reactivating GSK-3β. Additionally, the antifibrotic effects of BT were further validated in another in vivo model of radiation-induced pulmonary fibrosis. Collectively, these data demonstrated the potent antifibrotic actions of BT through inhibition of Akt/GSK-3β/β-catenin axis downstream of TGF-β1. Thus, BT could be a potential option to be further explored in IPF treatment.

PMID:38158113 | DOI:10.1016/j.ejphar.2023.176293

Cell Mol Life Sci. 2023 Dec 29;81(1):13. doi: 10.1007/s00018-023-05080-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial-mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of β-catenin. We concluded that the miR-29b‒TRIOBP-TRIO-β-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis.

PMID:38157020 | DOI:10.1007/s00018-023-05080-4

Respir Med. 2023 Dec 26:107515. doi: 10.1016/j.rmed.2023.107515. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) increases mortality risk, but which factors increase mortality is unknown. We aimed to perform a prognostic review of factors associated with mortality in patients with IPF.

STUDY DESIGN: and methods: We searched MEDLINE, EMBASE, and CINAHL for studies that reported on the association between any prognostic factor and AE-IPF. We assessed risk of bias using the QUIPS tool. We conduced pairwise meta-analyses using REML heterogeneity estimator, and GRADE approach to assess the certainty of the evidence.

RESULTS: We included 35 studies in our analysis. We found that long-term supplemental oxygen at baseline (aHR 2.52 [95 % CI 1.68 to 3.80]; moderate certainty) and a diagnosis of IPF compared to non-IPF ILD (aHR 2.19 [95 % CI 1.22 to 3.92]; moderate certainty) is associated with a higher risk of death in patients with AE-IPF. A diffuse pattern on high resolution computed tomography (HRCT) compared to a non-diffuse pattern (aHR 2.61 [95 % CI 1.32 to 2.90]; moderate certainty) is associated with a higher risk of death in patients with AE-IPF. We found that using corticosteroids prior to hospital admission (aHR 2.19 [95 % CI 1.26 to 3.82]; moderate certainty) and those with increased neutrophils (by % increase) in bronchoalveolar lavage (BAL) during the exacerbation is associated with a higher risk of death (aHR 1.02 [1.01 to 1.04]; moderate certainty).

INTERPRETATION: Our results have implications for healthcare providers in making treatment decisions and prognosticating the clinical trajectory of patients, for researchers to design future interventions to improve patient trajectory, and for guideline developers in making decisions about resource allocation.

PMID:38154738 | DOI:10.1016/j.rmed.2023.107515

Environ Res. 2023 Dec 26:117984. doi: 10.1016/j.envres.2023.117984. Online ahead of print.

ABSTRACT

BACKGROUND: The impact of residential greenness on incident idiopathic pulmonary fibrosis (IPF) is unknown. We aimed to assess the association between residential greenness and incident IPF, identify underlying pathways, and further evaluate the effect among different genetic subgroups.

METHODS: 469,348 participants in the UK Biobank were included and followed until December 2020. Normalized difference vegetation index (NDVI) within 300-, 500-, 1000-, and 1500-m buffers (NDVI300m, NDVI500m, NDVI1000m, and NDVI1500m) was employed as indicators of greenness. The polygenic risk score (PRS) was constructed based on 13 independent SNPs. Cox models were fitted to assess the association of residential greenness with incident IPF. Casual mediation analyses were applied to evaluate potential mediators.

FINDINGS: After a median follow-up of 11.85 years, 1574 IPF cases were identified. We found residential greenness inversely associated with incident IPF. The HRs (95%CIs) for each interquartile increase of NDVI300m, NDVI500m, NDVI1000m, NDVI1500m were 0.93 (0.87, 0.99), 0.92 (0.86, 0.98), 0.89 (0.83, 0.95), and 0.89 (0.83, 0.95), respectively. The association was stronger among individuals with intermediate or high genetic risk. In mediation analyses, the main mediators identified were PM2.5 and NO2, with proportion mediated estimated to be 31.92% and 40.61% respectively for NDVI300m.

INTERPRETATION: Residential greenness was associated with reduced risk of incident IPF.

PMID:38154569 | DOI:10.1016/j.envres.2023.117984

Int J Gen Med. 2023 Dec 23;16:6099-6113. doi: 10.2147/IJGM.S438297. eCollection 2023.

ABSTRACT

OBJECTIVE: To summarize the contents and assess the methodological quality and measurement properties of the patient-reported outcome (PRO) scales featured with Traditional Chinese Medicine (TCM) for respiratory diseases based on the guideline of COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN).

METHODS: PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP, and China Biology Medicine (CBM) were searched for studies on PRO scales featured with TCM for respiratory diseases from their inception until December 2022. The characteristics of the PRO scales were qualitatively summarized. Following the COSMIN guideline, the risk of bias was assessed according to the checklist, and different measurement properties (content validity, structural validity, internal consistency, reliability, criterion validity, and responsiveness) were evaluated. Finally, the evidence's overall quality was assessed, and the recommendation was formulated using the modified GRADE approach.

RESULTS: A total of 13 scales were included, with 6 for chronic obstructive pulmonary disease (COPD), 3 for lung cancer, 2 for idiopathic pulmonary fibrosis (IPF), 1 for community-acquired pneumonia (CAP), and 1 for bronchiectasis. All 13 scales are disease-specific scales and were developed based on Chinese cultural background to measure the efficacy of TCM. The study did not provide information on measurement error, cross-cultural validity, and hypothesis testing for the construct validity of these measures. No scale was rated as sufficient in content validity and responsiveness. Two scales showed sufficient structural validity, while 11 scales exhibited sufficient internal consistency. Three scales demonstrated sufficient reliability, and 7 scales showed sufficient criterion validity. All 13 scales have a recommendation level of B.

CONCLUSION: The 13 scales could reflect the clinical efficacy of TCM and are suitable for the Chinese population. Nevertheless, the validation of these scales was not comprehensive enough, and the methodological quality of their studies needs to be further strengthened.

PMID:38152077 | PMC:PMC10752031 | DOI:10.2147/IJGM.S438297