Idiopathic Pulmonary Fibrosis
A novel seven-gene risk profile in BALF to identify high-risk patients with idiopathic pulmonary fibrosis
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
Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis
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
Impact of interstitial lung abnormalities on postoperative pulmonary complications and survival of lung cancer
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
Discovery of Aryloxyphenyl-Heptapeptide Hybrids as Potent and Selective Matrix Metalloproteinase-2 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis
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
CD38 Mediates Lung Fibrosis by Promoting Alveolar Epithelial Cell Aging
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
Catalpol Attenuates Pulmonary Fibrosis by Inhibiting Ang II/AT<sub>1</sub> and TGF-β/Smad-Mediated Epithelial Mesenchymal Transition
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
Classification and Pathological Diagnosis of Idiopathic Interstitial Pneumonia
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
Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis
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
Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge
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
Alveolar Basal Cells Differentiate towards Secretory Epithelial- and Aberrant Basaloid-like Cells In Vitro
Cells. 2022 Jun 2;11(11):1820. doi: 10.3390/cells11111820.
ABSTRACT
In idiopathic pulmonary fibrosis (IPF), keratin (KRT)17+/KRT5+ basal and KRT17+/KRT5- aberrant basaloid cells are atypically present within the alveolar space. We previously described the fibrosis-enriched outgrowth of alveolar basal cells from peripheral fibrotic lung tissue. Using single cell RNA sequencing (scRNA-seq), we here characterize the transcriptome of these cultured alveolar basal cells under different culture conditions.
METHODS: Fibrotic peripheral lung tissue pieces were placed in DMEM growth medium. Outgrown cells were analysed by scRNA-seq, TaqMan-PCR or immunofluorescence (IF) either directly or after medium change to an epithelial cell specific medium (Cnt-PR-A).
RESULTS: A fraction of alveolar basal cells cultured in DMEM growth medium showed close transcriptomic similarities to IPF basal cells. However, although they expressed KRT5, the transcriptome of the majority of cells matched best to the transcriptome of recently described KRT17+/KRT5- aberrant basaloid cells, co-expressing the canonical basal cell marker KRT17 and mesenchymal cell marker (VIM, FN1). A smaller fraction of cells matched best to secretory epithelial cells. Two differentiation gradients from basal to aberrant basaloid-like cells and basal to secretory epithelial-like cells were apparent. Interestingly, these differentiation paths seemed reversed when the cell culture medium was changed to Cnt-PR-A.
CONCLUSIONS: Our results suggest that cultured alveolar basal cells have the capacity to differentiate towards secretory epithelial-like cells and to aberrant basaloid-like cells. However, due to the persistent expression of KRT5, a complete differentiation towards aberrant basaloid cells did not seem to be achieved in our culture conditions. Importantly, differentiation seemed reversible by changing the cells microenvironment. Determining specific factors influencing these differentiation paths may help to define novel drug targets for IPF therapy.
PMID:35681516 | DOI:10.3390/cells11111820
Cellular Senescence in Aging Lungs and Diseases
Cells. 2022 May 29;11(11):1781. doi: 10.3390/cells11111781.
ABSTRACT
Cellular senescence represents a state of irreversible cell cycle arrest occurring naturally or in response to exogenous stressors. Following the initial arrest, progressive phenotypic changes define conditions of cellular senescence. Understanding molecular mechanisms that drive senescence can help to recognize the importance of such pathways in lung health and disease. There is increasing interest in the role of cellular senescence in conditions such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) in the context of understanding pathophysiology and identification of novel therapies. Herein, we discuss the current knowledge of molecular mechanisms and mitochondrial dysfunction regulating different aspects of cellular senescence-related to chronic lung diseases to develop rational strategies for modulating the senescent cell phenotype in the lung for therapeutic benefit.
PMID:35681476 | DOI:10.3390/cells11111781
Immunity, Ciliated Epithelium, and Mortality: Are We Ready to Identify Idiopathic Pulmonary Fibrosis Endotypes With Prognostic Significance?
Chest. 2022 Jun;161(6):1440-1441. doi: 10.1016/j.chest.2022.02.018.
NO ABSTRACT
PMID:35680308 | DOI:10.1016/j.chest.2022.02.018
Dehydroepiandrosterone in fibrotic interstitial lung disease: a translational study
Respir Res. 2022 Jun 8;23(1):149. doi: 10.1186/s12931-022-02076-9.
ABSTRACT
BACKGROUND: Dehydroepiandrosterone (DHEA) is a precursor sex hormone with antifibrotic properties. The aims of this study were to investigate antifibrotic mechanisms of DHEA, and to determine the relationship between DHEA-sulfate (DHEAS) plasma levels, disease severity and survival in patients with fibrotic interstitial lung diseases (ILDs).
METHODS: Human precision cut lung slices (PCLS) and normal human lung fibroblasts were treated with DHEA and/or transforming growth factor (TGF)-β1 before analysis of pro-fibrotic genes and signal proteins. Cell proliferation, cytotoxicity, cell cycle and glucose-6-phosphate dehydrogenase (G6PD) activity were assessed. DHEAS plasma levels were correlated with pulmonary function, the composite physiologic index (CPI), and time to death or lung transplantation in a derivation cohort of 31 men with idiopathic pulmonary fibrosis (IPF) and in an independent validation cohort of 238 men and women with fibrotic ILDs.
RESULTS: DHEA decreased the expression of pro-fibrotic markers in-vitro and ex-vivo. There was no cytotoxic effect for the applied concentrations, but DHEA interfered in proliferation by modulating the cell cycle through reduction of G6PD activity. In men with IPF (derivation cohort) DHEAS plasma levels in the lowest quartile were associated with poor lung function and higher CPI (adjusted OR 1.15 [95% CI 1.03-1.38], p = 0.04), which was confirmed in the fibrotic ILD validation cohort (adjusted OR 1.03 [95% CI 1.00-1.06], p = 0.01). In both cohorts the risk of early mortality was higher in patients with low DHEAS levels, after accounting for potential confounding by age in men with IPF (HR 3.84, 95% CI 1.25-11.7, p = 0.02), and for age, sex, IPF diagnosis and prednisone treatment in men and women with fibrotic ILDs (HR 3.17, 95% CI 1.35-7.44, p = 0.008).
CONCLUSIONS: DHEA reduces lung fibrosis and cell proliferation by inducing cell cycle arrest and inhibition of G6PD activity. The association between low DHEAS levels and disease severity suggests a potential prognostic and therapeutic role of DHEAS in fibrotic ILD.
PMID:35676709 | DOI:10.1186/s12931-022-02076-9
Insights from Transcriptomics: CD163+ Profibrotic Lung Macrophages in COVID-19
Am J Respir Cell Mol Biol. 2022 Jun 8. doi: 10.1165/rcmb.2022-0107TR. Online ahead of print.
ABSTRACT
COVID19 begins with upper airway symptoms but proceeds in a significant proportion of patients to life-threatening infection of the lower respiratory tract, where an exuberant inflammatory response, edema, and adverse parenchymal remodeling impair gas exchange. Respiratory failure is caused initially by flooding of the airspaces with plasma exudate, sloughed epithelium, and inflammatory cells. For many patients with COVID19, this acute phase has been observed to give way to a prolonged course of acute respiratory distress syndrome (ARDS), and a significant proportion of patients go on to develop fibroproliferative remodeling of the lung parenchyma, which lengthens the duration of respiratory impairment and mechanical ventilation. Monocyte-derived macrophages have previously been implicated in the fibrotic phase of lung injury in multiple models. From several recent studies that employed single cell genomic techniques, a profile of the transcriptomic state of COVID19 lung macrophages has emerged. Linkages have been made between these macrophages, which are monocyte-derived and CD163+, and profibrotic macrophages found in other contexts, including animal models of fibrosis and Idiopathic Pulmonary Fibrosis. Here, emerging concepts of macrophage profibrotic function in COVID19 are highlighted, with a focus on gaps in knowledge to be addressed by future research. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
PMID:35675555 | DOI:10.1165/rcmb.2022-0107TR
Preferential PDE4B Inhibition - A Step toward a New Treatment for Idiopathic Pulmonary Fibrosis
N Engl J Med. 2022 Jun 9;386(23):2235-2236. doi: 10.1056/NEJMe2205411.
NO ABSTRACT
PMID:35675182 | DOI:10.1056/NEJMe2205411
DNA methylation in pulmonary fibrosis and lung cancer
Expert Rev Respir Med. 2022 Jun 8:1-10. doi: 10.1080/17476348.2022.2085091. Online ahead of print.
ABSTRACT
INTRODUCTION: Pulmonary fibrosis is an age-related, progressive, and fatal disease with a median survival of 3-5 years after diagnosis; idiopathic pulmonary fibrosis (IPF) is the most common type. It is characterized by fibroblast proliferation and accumulation of excessive extracellular matrix. Patients with IPF are at increased risk for lung cancer. Epigenetic mechanisms are involved in lung fibrosis and cancer, and DNA methylation is critical in disease pathogenesis and progression. Therefore, studies of DNA methylation contribute to better understanding of the underlying mechanisms of these two respiratory diseases, and can offer novel diagnostic and treatment options.
AREAS COVERED: This review discusses the latest advances in our understanding of epigenetic factors related to DNA methylation that impact development of lung cancer and pulmonary fibrosis, discusses the role of DNA methylation in promoting or inhibiting these diseases, and proposes its potential clinical significance in disease diagnosis and treatment.
EXPERT OPINION: DNA methylation plays a critical role in lung cancer and fibrosis pathogenesis. DNA methylation offers a new biomarker for disease diagnosis or monitoring, and provides a new therapeutic target for treatment.
PMID:35673969 | DOI:10.1080/17476348.2022.2085091
Exploring the comorbidity mechanisms between asthma and idiopathic pulmonary fibrosis and the pharmacological mechanisms of Bu-Shen-Yi-Qi decoction therapy via network pharmacology
BMC Complement Med Ther. 2022 Jun 7;22(1):151. doi: 10.1186/s12906-022-03637-7.
ABSTRACT
BACKGROUNDS: Asthma and idiopathic pulmonary fibrosis (IPF) are common chronic diseases of the respiratory system in clinical practice. However, the relationship and molecular links remain unclear, and the current treatment's efficacy is disappointing. Bu-Shen-Yi-Qi (BSYQ) decoction has proven effective in treating various chronic airway inflammatory diseases, including asthma and IPF. But the underlying pharmacological mechanisms are still to be elucidated.
METHODS: This study searched the proteins related to asthma and IPF via TTD, CTD, and DisGeNET databases and then submitted to the STRING to establish the protein-protein interaction (PPI) network. The co-bioinformatics analysis was conducted by Metascape. The active ingredients of BSYQ decoction were screened from TCMSP, ETCM, BATMAN-TCM databases, and HPLC/MS experiment. The corresponding targets were predicted based on TCMSP, ETCM, and BATMAN-TCM databases. The shared targets for asthma and IPF treatment were recognized, and further GO and KEGG analyses were conducted with the DAVID platform. Finally, molecule docking via Autodock Vina was employed to predict the potential binding mode between core potential compounds and targets.
RESULTS: Finally, 1333 asthma-related targets and 404 IPF-related proteins were retrieved, 120 were overlapped between them, and many of the asthma-related proteins fall into the same statistically significant GO terms with IPF. Moreover, 116 active ingredients of BSYQ decoction were acquired, and 1535 corresponding targets were retrieved. Eighty-three potential compounds and 56 potential targets were recognized for both asthma and IPF treatment. GO and KEGG analysis indicated that the inflammation response, cytokine production, leukocyte differentiation, oxygen level response, etc., were the common pathological processes in asthma and IPF, which were regulated by BSYQ decoction. Molecule docking further predicted the potential binding modes between the core potential compounds and targets.
CONCLUSION: The current study successfully clarified the complex molecule links between asthma and IPF and found the potential common targets. Then we demonstrated the efficacy of BSYQ decoction for asthma and IPF treatment from the angle of network pharmacology, which may provide valuable references for further studies and clinical use.
PMID:35672815 | DOI:10.1186/s12906-022-03637-7
Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival
Respir Res. 2022 Jun 7;23(1):147. doi: 10.1186/s12931-022-02067-w.
ABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with increased expression of cyclin-dependent kinase inhibitors such as p16 and p21, and subsequent induction of cell cycle arrest, cellular senescence, and pro-fibrotic gene expression. We sought to link p16-expression with a diagnosis of IPF or other fibrotic interstitial lung diseases (ILDs), radiographic pattern, senescent foci-specific gene expression, antifibrotic therapy response, and lung transplant (LTx)-free survival.
METHODS: Eighty-six cases of fibrosing ILD were identified with surgical lung biopsy. Immunohistochemistry for p16 was performed on sections with the most active fibrosis. p16-positive foci (loose collection of p16-positive fibroblasts with overlying p16-positive epithelium) were identified on digital slides and quantified. Cases were scored as p16-low (≤ 2.1 foci per 100 mm2) or p16-high (> 2.1 foci per 100 mm2). Twenty-four areas including senescent foci, fibrotic and normal areas were characterized using in situ RNA expression analysis with digital spatial profiling (DSP) in selected cases.
RESULTS: The presence of p16-positive foci was specific for the diagnosis of IPF, where 50% of cases expressed any level of p16 and 26% were p16-high. There was no relationship between radiographic pattern and p16 expression. However, there was increased expression of cyclin-dependent kinase inhibitors, collagens and matrix remodeling genes within p16-positive foci, and cases with high p16 expression had shorter LTx-free survival. On the other hand, antifibrotic therapy was significantly protective. DSP demonstrated that fibroblastic foci exhibit transcriptional features clearly distinct from that of normal-looking and even fibrotic areas.
CONCLUSIONS: We demonstrated the potential clinical applicability of a standardized quantification of p16-positive fibroblastic foci. This method identifies an IPF phenotype associated with foci-specific upregulation of senescence-associated and matrix remodeling gene expression. While these patients have reduced LTx-free survival, good response to antifibrotic therapies was observed in those who were treated.
PMID:35672770 | DOI:10.1186/s12931-022-02067-w
Mannan-Binding Lectin Reduces Epithelial-Mesenchymal Transition in Pulmonary Fibrosis via Inactivating the Store-Operated Calcium Entry Machinery
J Innate Immun. 2022 Jun 7:1-13. doi: 10.1159/000524693. Online ahead of print.
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a type of idiopathic interstitial pneumonia with a poor clinical prognosis. Increasing evidence has demonstrated that epithelial-mesenchymal transition (EMT) contributes to the production of pathogenic myofibroblasts and plays a pivotal role in the development of pulmonary fibrosis. Mannan-binding lectin (MBL) is a soluble calcium-dependent complement molecule. Several studies have reported associations between serum MBL levels and lung diseases; however, the effect of MBL on IPF remains unknown. The present study observed aggravated pulmonary fibrosis in bleomycin-treated MBL-/- mice compared with their wild-type counterparts. Lung tissues from bleomycin-treated MBL-/- mice displayed a more severe EMT phenotype. In vitro studies determined that MBL inhibited the EMT process through attenuating store-operated calcium entry (SOCE) signaling. It was further demonstrated that MBL promoted the ubiquitination of Orai1, an essential component of SOCE, via pyruvate dehydrogenase kinase 1 (PDK1)-serum glucocorticoid-regulated kinase 1 signaling. PDK1 inhibition abolished the MBL-mediated regulation of SOCE activity and the EMT process. Notably, biochemical analysis showed that MBL interacted with PDK1 and contributed to PDK1 ubiquitination. In summary, the present findings suggested that MBL limited the EMT phenotype in human alveolar epithelial cells through regulation of SOCE, and MBL could be recognized as a potential therapeutic target for IPF.
PMID:35671705 | DOI:10.1159/000524693
Reply to: Idiopathic Pulmonary Fibrosis Update. Reconciliation with Hypersensitivity Pneumonitis Guidelines Required?
Am J Respir Crit Care Med. 2022 Jun 7. doi: 10.1164/rccm.202206-1058LE. Online ahead of print.
NO ABSTRACT
PMID:35671482 | DOI:10.1164/rccm.202206-1058LE