PLoS One. 2022 Jun 15;17(6):e0270005. doi: 10.1371/journal.pone.0270005. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with no curative pharmacological treatment. The most used animal model of IPF for anti-fibrotic drug screening is bleomycin (BLM)-induced lung fibrosis. However, several issues have been reported: the balance among disease resolution, an appropriate time window for therapeutic intervention and animal welfare remain critical aspects yet to be fully elucidated. In this study, C57Bl/6 male mice were treated with BLM via oropharyngeal aspiration (OA) following either double or triple administration. The fibrosis progression was longitudinally assessed by micro-CT every 7 days for 4 weeks after BLM administration. Quantitative micro-CT measurements highlighted that triple BLM administration was the ideal dose regimen to provoke sustained lung fibrosis up to 28 days. These results were corroborated with lung histology and Bronchoalveolar Lavage Fluid cells. We have developed a mouse model with prolonged lung fibrosis enabling three weeks of a curative therapeutic window for the screening of putative anti-fibrotic drugs. Moreover, we have demonstrated the pivotal role of longitudinal micro-CT imaging in reducing the number of animals required per experiment in which each animal can be its own control. This approach permits a valuable decrease in costs and time to develop disease animal models.

PMID:35704641 | DOI:10.1371/journal.pone.0270005

Risk Manag Healthc Policy. 2022 Jun 8;15:1189-1201. doi: 10.2147/RMHP.S357606. eCollection 2022.

ABSTRACT

OBJECTIVE: This study aims to evaluate the risk of bias (ROB) and reporting quality of idiopathic pulmonary fibrosis (IPF) prediction models by assessing characteristics of these models.

METHODS: The development and/or validation of IPF prognostic models were identified via an electronic search of PubMed, Embase, and Web of Science (from inception to 12 August, 2021). Two researchers independently assessed the risk of bias (ROB) and reporting quality of IPF prediction models based on the Prediction model Risk Of Bias Assessment Tool (PROBAST) and Transparent Reporting of a multivariable prognostic model for Individual Prognosis or Diagnosis (TRIPOD) checklist.

RESULTS: Twenty prognostic model studies for IPF were included, including 7 (35%) model development and external validation studies, 8 (40%) development studies, and 5 (25%) external validation studies. According to PROBAST, all studies were appraised with high ROB, because of deficient reporting in the domains of participants (45.0%) and analysis (67.3%), and at least 55% studies were susceptible to 4 of 20 sources of bias. For the reporting quality, none of them completely adhered to the TRIPOD checklist, with the lowest mean reporting score for the methods and results domains (46.6% and 44.7%). For specific items, eight sub-items had a reporting rate ≥80% and adhered to the TRIPOD checklist, and nine sub-items had a very poor reporting rate, less than 30%.

CONCLUSION: Studies adhering to PROBAST and TRIPOD checklists are recommended in the future. The reproducibility and transparency can be improved when studies completely adhere to PROBAST and TRIPOD checklists.

PMID:35702399 | PMC:PMC9188804 | DOI:10.2147/RMHP.S357606

Hum Genomics. 2022 Jun 13;16(1):20. doi: 10.1186/s40246-022-00393-0.

ABSTRACT

The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions of multiple tissues and organs. In the study of parenchymal lung disease, single-cell RNA-sequencing has better delineated known cell populations and identified novel cells and changes in cellular phenotypes and gene expression patterns associated with disease. In this review, we aim to highlight the advances and insights that have been made possible by applying these technologies to two seemingly very different lung diseases: fibrotic interstitial lung diseases, a group of relentlessly progressive lung diseases leading to pulmonary fibrosis, and COVID-19 pneumonia, an acute viral disease with life-threatening complications, including pulmonary fibrosis. We discuss changes in cell populations and gene expression, highlighting potential common features, such as alveolar cell epithelial injury and aberrant repair and monocyte-derived macrophage populations, as well as relevance and implications to mechanisms of disease and future directions.

PMID:35698166 | DOI:10.1186/s40246-022-00393-0

Arch Bronconeumol. 2022 May 26:S0300-2896(22)00389-1. doi: 10.1016/j.arbres.2022.05.005. Online ahead of print.

ABSTRACT

We present the case of a patient diagnosed with Idiopathic Pulmonary Fibrosis who experienced a hypersensitivity reaction to both pirfenidone and nintedanib. Given the lack of alternative treatment for the patient's condition and of standard antifibrotic desensitization protocols, we designed a protocol for desensitization to pirfenidone. The patient now tolerates pirfenidone, with functional and radiologic stability of the disease.

PMID:35697567 | DOI:10.1016/j.arbres.2022.05.005

Respirology. 2022 Jun 13. doi: 10.1111/resp.14310. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) has poor prognosis, and the multidisciplinary diagnostic agreement is low. Moreover, surgical lung biopsies pose comorbidity risks. Therefore, using data from non-invasive tests usually employed to assess interstitial lung diseases (ILDs), we aimed to develop an automated algorithm combining deep learning and machine learning that would be capable of detecting and differentiating IPF from other ILDs.

METHODS: We retrospectively analysed consecutive patients presenting with ILD between April 2007 and July 2017. Deep learning was used for semantic image segmentation of HRCT based on the corresponding labelled images. A diagnostic algorithm was then trained using the semantic results and non-invasive findings. Diagnostic accuracy was assessed using five-fold cross-validation.

RESULTS: In total, 646,800 HRCT images and the corresponding labelled images were acquired from 1068 patients with ILD, of whom 42.7% had IPF. The average segmentation accuracy was 96.1%. The machine learning algorithm had an average diagnostic accuracy of 83.6%, with high sensitivity, specificity and kappa coefficient values (80.7%, 85.8% and 0.665, respectively). Using Cox hazard analysis, IPF diagnosed using this algorithm was a significant prognostic factor (hazard ratio, 2.593; 95% CI, 2.069-3.250; p < 0.001). Diagnostic accuracy was good even in patients with usual interstitial pneumonia patterns on HRCT and those with surgical lung biopsies.

CONCLUSION: Using data from non-invasive examinations, the combined deep learning and machine learning algorithm accurately, easily and quickly diagnosed IPF in a population with various ILDs.

PMID:35697345 | DOI:10.1111/resp.14310

J Clin Rheumatol. 2022 Jun 13. doi: 10.1097/RHU.0000000000001847. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVE: Patients classified as interstitial pneumonia with autoimmune features (IPAF) have interstitial lung disease (ILD) and features of autoimmunity but do not fulfill criteria for connective tissue diseases (CTDs). Our goal was to identify patients classifiable as IPAF, CTD-ILD, and idiopathic pulmonary fibrosis (IPF) from a preexisting pulmonary cohort and evaluate the prognosis of patients with IPAF.

METHODS: We reviewed the medical records of 456 patients from a single-center pulmonary ILD cohort whose diagnoses were previously established by a multidisciplinary panel that did not include rheumatologists. We reclassified patients as IPAF, CTD-ILD, or IPF. We compared transplant-free survival using Kaplan-Meier methods and identified prognostic factors using Cox models.

RESULTS: We identified 60 patients with IPAF, 113 with CTD-ILD, and 126 with IPF. Transplant-free survival of IPAF was not statistically significantly different from that of CTD-ILD or IPF. Among IPAF patients, male sex (hazard ratio, 4.58 [1.77-11.87]) was independently associated with worse transplant-free survival. During follow-up, only 10% of IPAF patients were diagnosed with CTD-ILD, most commonly antisynthetase syndrome.

CONCLUSION: Despite similar clinical characteristics, most patients with IPAF did not progress to CTD-ILD; those who did often developed antisynthetase syndrome, highlighting the critical importance of comprehensive myositis autoantibody testing in this population. As in other types of ILD, male sex may portend a worse prognosis in IPAF. The routine engagement of rheumatologists in the multidisciplinary evaluation of ILD will help ensure the accurate classification of these patients and help clarify prognostic factors.

PMID:35697042 | DOI:10.1097/RHU.0000000000001847

Respir Med. 2022 Jun 4;200:106898. doi: 10.1016/j.rmed.2022.106898. Online ahead of print.

ABSTRACT

BACKGROUND: Several studies have reported that acute exacerbation (AE), which occurs during the clinical course of idiopathic pulmonary fibrosis (IPF), also occurs in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the incidence, clinical features, and risk factors for AE, a major cause of death of RA-ILD patients, and the differences in clinical aspects of AE between RA-ILD and IPF have yet to be fully understood.

METHODS: We retrospectively reviewed data on 149 RA-ILD patients and 305 IPF patients. We investigated the frequency of AE and compared the clinical data between RA-ILD with and without AE to clarify the risk factor for AE. We also compared the post-AE prognosis and cause of death between RA-ILD and IPF patients.

RESULTS: Twenty-seven (18.1%) RA-ILD patients and 84 (27.5%) IPF patients developed AE. The median survival time (MST) after AE of RA-ILD and IPF was 277 days and 60 days, respectively (log rank, p = 0.038). In a multivariate analysis, hypoalbuminemia [odds ratio (O.R.) 0.090 (95%CI 0.011-0.733), p = 0.012] and % carbon monoxide diffusion capacity (%DLCO) [O.R. 0.810 (95%CI 0.814-0.964), p < 0.01] were independent risk factors for AE. AE was the most frequent cause of death of RA-ILD and IPF.

CONCLUSION: RA-ILD patients could develop AE, and AE was not uncommon in RA-ILD or IPF. %DLCO and hypoalbuminemia were predictive factors of AE in RA-ILD. The prognosis after AE of RA-ILD was significantly better than that of IPF. The most frequent cause of death in RA-ILD and IPF was AE.

PMID:35696743 | DOI:10.1016/j.rmed.2022.106898

Am J Respir Cell Mol Biol. 2022 Jun 13. doi: 10.1165/rcmb.2021-0445OC. Online ahead of print.

ABSTRACT

As shown in our previous studies, the intratracheal-administration of stanniocalcin-1 (STC1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin (BLM)-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetyl-CoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a BLM-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from idiopathic pulmonary fibrosis patients, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal-administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.

PMID:35696344 | DOI:10.1165/rcmb.2021-0445OC

Am J Respir Crit Care Med. 2022 Jun 13. doi: 10.1164/rccm.202112-2684OC. Online ahead of print.

ABSTRACT

RATIONALE Reliable outcome prediction in patients with fibrotic lung disease using baseline high-resolution computed tomography (HRCT) data remains challenging. OBJECTIVES To evaluate the prognostic accuracy of a deep learning algorithm (SOFIA), trained and validated in the identification of UIP-like features on HRCT (UIP probability), in a large cohort of well characterised patients with progressive fibrotic lung disease, drawn from a national registry. METHODS SOFIA and radiologist-UIP probabilities were converted to PIOPED-based UIP probability categories (UIP not included in the differential: 0-4%, low probability of UIP: 5-29%, intermediate probability of UIP: 30-69%, high probability of UIP: 70-94%, and pathognomonic for UIP:95-100%) and their prognostic utility assessed using Cox proportional hazards modelling. MEASUREMENTS AND MAIN RESULTS On multivariable analysis adjusting for age, gender, guideline based radiologic diagnosis and disease severity (using total ILD extent on HRCT, %predicted FVC, DLco or the CPI), only SOFIA-UIP probability PIOPED categories predicted survival. SOFIA-PIOPED UIP probability categories remained prognostically significant in patients considered indeterminate (n=83) by expert radiologist consensus (HR1.73, p<0.0001, 95%CI 1.40-2.14). In patients undergoing surgical lung biopsy (SLB) (n=86), after adjusting for guideline-based histologic pattern and total ILD extent on HRCT, only SOFIA-PIOPED probabilities were predictive of mortality (HR1.75, p<0.0001, 95%CI 1.37-2.25). CONCLUSIONS Deep learning-based UIP probability on HRCT provides enhanced outcome prediction in patients with progressive fibrotic lung disease when compared to expert radiologist evaluation or guideline-based histologic pattern. In principle this tool may be useful in multidisciplinary characterisation of fibrotic lung disease. The utility of this technology as a decision support system when ILD expertise is unavailable requires further investigation.

PMID:35696341 | DOI:10.1164/rccm.202112-2684OC

Expert Rev Respir Med. 2022 Jun 13. doi: 10.1080/17476348.2022.2089116. Online ahead of print.

ABSTRACT

INTRODUCTION: Rheumatoid arthritis (RA) is the most common inflammatory autoimmune disease, characterised by symmetric destructive arthritis and synovitis. Lung involvement is frequent, including in the form of interstitial lung disease (ILD). RA-ILD often presents with a radiologic and pathologic pattern of usual interstitial pneumonia, similar to idiopathic pulmonary fibrosis, highlighting the similarities between the two diseases, but other patterns and pathological associations are described.

AREAS COVERED: This article reviews the pathogenesis of pulmonary fibrosis in the setting of rheumatoid arthritis as well as the current and future therapeutic options.

EXPERT OPINION: Pulmonary fibrosis in the setting of RA-ILD is an example of genotype-environment interaction and involves multiple mechanisms including autoimmunity, inflammation and fibrogenesis. Despite that ILD conveys most of the exceeding mortality in RA patients, there are no official guidelines for the management of RA-ILD. Attention should be paid to potential lung toxicity of RA treatment even though some of them might help stabilise the ILD. Current standard of care is often composed of glucocorticoids that may be associated with immunosuppressive therapy. Following the approval of antifibrotic therapy for ILDs with a progressive fibrosing phenotype, current works are evaluating the benefit of such treatment in RA-ILD.

PMID:35695895 | DOI:10.1080/17476348.2022.2089116

RSC Med Chem. 2022 Apr 1;13(5):610-621. doi: 10.1039/d1md00403d. eCollection 2022 May 25.

ABSTRACT

Pirfenidone (PFD) was the first approved drug by FDA for the treatment of idiopathic pulmonary fibrosis (IPF). However, the rapid metabolism of 5-methyl of PFD increases the risk of side effects in clinics. Thus, in this paper, a common practice that a stable amide bond linking various groups used to replace 5-methyl of PFD in medicinal chemistry was applied, and total 18 PFD derivatives were synthesized. All compounds were investigated for their antiproliferation activities against NIH3T3 cells and the structure-activity relationships of the target compounds were also discussed. Among them, YZQ17 possessed potent antiproliferation activity compared to PFD and better potency in inhibiting TGF-β-induced migration of NIH3T3 cells at a much lower concentration than that of PFD. In addition, YZQ17 dramatically inhibited the expression levels of fibrotic markers α-SMA, collagen I, and fibronectin. Moreover, further mechanistic studies confirmed that YZQ17 exhibited this considerable anti-fibrosis activity via the TGF-β/Smad2/3 dependent pathway. Finally, the results of human and rat liver microsomes assay in vitro and pharmacokinetic assay in rats confirmed that YZQ17 showed better pharmacokinetics than that of PFD. Collectively, the preliminary study of PFD derivatives modified by the amide group indicated that YZQ17 could be regarded as a lead compound for further investigation and optimization.

PMID:35694690 | PMC:PMC9132227 | DOI:10.1039/d1md00403d

J Thorac Dis. 2022 May;14(5):1450-1465. doi: 10.21037/jtd-21-1830.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal heterogeneous disease with a varied clinical course that is difficult to predict. Accurate predictive models are urgently needed to identify individuals with poor survival for the optimal timing of referral for transplantation and provide some clues for mechanistic research on disease progression.

METHODS: We obtained the gene expression profiles of bronchoalveolar lavage fluid (BALF) from the Gene Expression Omnibus. Individuals from the GPL14550 platform were assigned to the derivation cohort (n=112) and individuals from the GPL17077 platform to the validation cohort (n=64). Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were applied to select candidate genes for overall survival. A nomogram model was constructed based on Cox hazard regression analysis. The model was assessed by C-statistic, calibration curve, and decision curve analysis (DCA) and was externally validated.

RESULTS: A nomogram model comprising seven genes was constructed. Excellent discrimination and calibration were observed in the derivation (C-index 0.815) and validation (C-index 0.812) cohorts. The AUCs for predicting 1-, 2- and 3-year survival were 0.857, 0.918, 0.930 in the derivation cohort and 0.850, 0.880, 0.925 in the validation cohort, respectively. DCA confirmed the clinical applicability of the model. A risk score based on the model was an independent prognostic predictor and could divide patients into high- and low-risk groups. The Kaplan-Meier analysis displayed that high-risk patients exhibited significantly poorer survival compared with low-risk patients. Gene Set Enrichment Analysis (GSEA) showed that high-risk patients were primarily enriched in inflammatory hallmarks, and single sample GSEA (ssGSEA) indicated that the high-risk group is closely correlated with the immune process. These lead to increased insight into mechanisms associated with IPF progression that inflammation mediated by immune response might be involved in the disease progression.

CONCLUSIONS: The novel BALF seven-gene model performed well in risk stratification and individualized survival prediction for patients with IPF, facilitating personalized management of IPF patients. It deepened the understanding of the role of inflammation in IPF progression, which needs to be further studied.

PMID:35693599 | PMC:PMC9186233 | DOI:10.21037/jtd-21-1830

Thorax. 2022 Jun 10:thoraxjnl-2021-218577. doi: 10.1136/thoraxjnl-2021-218577. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk genome-wide association studies. We used the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR (mammalian target of rapamycin) signalling, telomere maintenance and spindle assembly genes in IPF risk.

PMID:35688625 | DOI:10.1136/thoraxjnl-2021-218577

Thorax. 2022 Jun 10:thoraxjnl-2021-218055. doi: 10.1136/thoraxjnl-2021-218055. Online ahead of print.

ABSTRACT

BACKGROUND: Interstitial lung abnormalities (ILAs) are associated with the risk of lung cancer and its mortality. However, the impact of ILA on treatment-related complications and survival in patients who underwent curative surgery is still unknown.

RESEARCH QUESTION: This study aimed to evaluate the significance of the presence of computed tomography-diagnosed ILA and histopathologically matched interstitial abnormalities on postoperative pulmonary complications (PPCs) and the long-term survival of patients who underwent surgical treatment for lung cancer.

STUDY DESIGN AND METHODS: A matched case-control study was designed to compare PPCs and mortality among 50 patients with ILA, 50 patients with idiopathic pulmonary fibrosis (IPF) and 200 controls. Cases and controls were matched by sex, age, smoking history, tumour location, the extent of surgery, tumour histology and pathological TNM stage.

RESULTS: Compared with the control group, the OR of the prevalence of PPCs increased to 9.56 (95% CI 2.85 to 32.1, p<0.001) in the ILA group and 56.50 (95% CI 17.92 to 178.1, p<0.001) in the IPF group. The 5-year overall survival (OS) rates of the control, ILA and IPF groups were 76% (95% CI 71% to 83%), 52% (95% CI 37% to 74%) and 32% (95% CI 19% to 53%), respectively (log-rank p<0.001). Patients with ILA had better 5-year OS than those with IPF (log-rank p=0.046) but had worse 5-year OS than those in the control group (log-rank p=0.002).

CONCLUSIONS: The presence of radiological and pathological features of ILA in patients with lung cancer undergoing curative surgery was associated with frequent complications and decreased survival.

PMID:35688622 | DOI:10.1136/thoraxjnl-2021-218055

J Med Chem. 2022 Jun 10. doi: 10.1021/acs.jmedchem.2c00613. Online ahead of print.

ABSTRACT

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase that plays important roles in the degradation of extracellular matrix proteins. MMP2 is considered to be an attractive target for the treatment of various diseases such as cancer, arthritis, and fibrosis. In this study, we have developed a novel class of MMP2-selective inhibitors by hybridizing the peptide that binds to a zinc ion and S2-S5 pockets with small molecules that bind to the S1' pocket. Structural modifications based on X-ray crystallography revealed that the introduction of 2,4-diaminobutanoic acid (Dab) at position 4 dramatically enhanced MMP2 selectivity by forming an electrostatic interaction with Glu130. After improving the metabolic and chemical stability, TP0556351 (9) was identified. It exhibited potent MMP2 inhibitory activity (IC50 = 0.20 nM) and extremely high selectivity. It suppressed the accumulation of collagen in a bleomycin-induced idiopathic pulmonary fibrosis model in mice, demonstrating the efficacy of MMP2-selective inhibitors for fibrosis.

PMID:35687819 | DOI:10.1021/acs.jmedchem.2c00613

Am J Respir Crit Care Med. 2022 Jun 6. doi: 10.1164/rccm.202109-2151OC. Online ahead of print.

ABSTRACT

RATIONALE: A prevailing paradigm recognizes idiopathic pulmonary fibrosis (IPF) originating from various alveolar epithelial cell (AEC) injuries, and there is a growing appreciation of AEC aging as a key driver of the pathogenesis. However, it is incompletely understood what main factor(s) contributes to the worsened alveolar epithelial aging in lung fibrosis. It remains a challenge how to dampen AEC aging, and thereby mitigating the disease progression.

OBJECTIVES: To determine the role of AEC CD38 in promoting cellular aging and lung fibrosis.

METHODS: scRNA-seq and animal models were used.

MEASUREMENTS AND MAIN RESULTS: We discovered a pivotal role of CD38, a cardinal nicotinamide adenine dinucleotide (NAD) hydrolase, in AEC aging and its promotion of lung fibrosis. We found increased CD38 expression in idiopathic pulmonary fibrosis (IPF) lungs that inversely correlated with the lung function of patients. CD38 was primarily located in the AECs of human lung parenchyma and was markedly induced in IPF AECs. Similarly, CD38 expression was elevated in the AECs of fibrotic lungs of young mice and further augmented in those of old mice, which was in accordance with worsened AEC aging phenotype and aggravated lung fibrosis in the old animals. We found that CD38 elevation downregulated intracellular NAD, which likely led to the aging promoting impairment of the NAD-dependent cellular and molecular activities. Furthermore, we demonstrated that genetic and pharmacological inactivation of CD38 improved these NAD dependent events and ameliorated bleomycin induced lung fibrosis.

CONCLUSIONS: Our study suggests targeting alveolar CD38 as a novel and effective therapeutic strategy to treat this pathology.

PMID:35687485 | DOI:10.1164/rccm.202109-2151OC

Front Med (Lausanne). 2022 May 24;9:878601. doi: 10.3389/fmed.2022.878601. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating chronic lung condition affecting over 3 million people worldwide with a high mortality rate and there are no effective drugs. Angiotensin II (Ang II), as a major effector peptide of the renin angiotensin aldosterone system, has been shown to act in tandem with the transforming growth factor-β (TGF-β) signaling pathway to promote the infiltration of inflammatory cells, production of reactive oxygen species (ROS) and profibrotic factors after lung injury, and to participate in the process of epithelial mesenchymal transition (EMT). Catalpol (CAT) has been shown to have anti-inflammatory and antifibrotic effects. However, the effects and mechanisms of CAT on pulmonary fibrosis are not clear.

PURPOSE: To assess the effects and mechanisms of catalpol on bleomycin-induced pulmonary fibrosis in mice.

METHODS: We used bleomycin-induced mouse model of pulmonary fibrosis to evaluate the alleviation effect of CAT at 7, 14, 28d, respectively. Next, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, immunofluorescence, Masson trichrome staining and western blotting were used to study the underlying mechanism of CAT on bleomycin-induced pulmonary fibrosis.

RESULTS: It's demonstrated that CAT exerted a potent anti-fibrotic function in BLM-induced mice pulmonary fibrosis via alleviating inflammatory, ameliorating collagen deposition, reducing the level of Ang II and HYP and alleviating the degree of EMT. Moreover, CAT attenuate BLM-induced fibrosis by targeting Ang II/AT1 and TGF-β/Smad signaling in vivo.

CONCLUSION: CAT may serve as a novel therapeutic candidate for the simultaneous blockade of Ang II and TGF-β pathway to attenuate pulmonary fibrosis.

PMID:35685407 | PMC:PMC9171363 | DOI:10.3389/fmed.2022.878601

Comput Intell Neurosci. 2022 May 31;2022:1198581. doi: 10.1155/2022/1198581. eCollection 2022.

ABSTRACT

Idiopathic interstitial pneumonia (IIP) is a group of progressive lower respiratory tract diseases of unknown origin characterized by diffuse alveolitis and alveolar structural disorders leading to pulmonary fibrillation and hypertension, pulmonary heart disease, and right heart failure due to pulmonary fibrosis, and more than half of them die from respiratory failure. To address these problems of overly complex prediction methods and large data sets involved in the prediction process of interstitial pneumonia, this paper proposes a prediction model for interstitial pneumonia which is based on the Gaussian Parsimonious Bayes algorithm. Three usual tests of pneumonia, specifically from various patients, were collected as the sample set. These samples are divided into training and testing sets. Additionally, a cross-validation strategy was used to avoid the overfitting problem. The results showed that the prediction model based on the Gaussian Parsimonious Bayes algorithm predicted 92% accuracy on the test set, and the Parsimonious Bayes method could directly predict the final detection of interstitial pneumonia based on the usual pneumonia test pneumonia. In addition, it was found that the closer the data distribution of the sample set was to a normal distribution, the higher the prediction accuracy was, and then, after excluding pneumonia from the test below 60 points, the prediction accuracy reached 96%.

PMID:35685144 | PMC:PMC9173946 | DOI:10.1155/2022/1198581

Molecules. 2022 May 26;27(11):3452. doi: 10.3390/molecules27113452.

ABSTRACT

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.

PMID:35684390 | DOI:10.3390/molecules27113452

Int J Mol Sci. 2022 May 28;23(11):6064. doi: 10.3390/ijms23116064.

ABSTRACT

CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.

PMID:35682743 | DOI:10.3390/ijms23116064