Int Immunopharmacol. 2022 Feb 1;105:108576. doi: 10.1016/j.intimp.2022.108576. Online ahead of print.

ABSTRACT

INTRODUCTION: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common sleep disorder that causes severe physiological disturbance. Evidence showed that OSAHS is an important associated comorbidity that can affect the survival of patients with pulmonary fibrosis. Until now, the potential mechanisms by which OSAHS accelerates the progression of lung fibrosis remain unclear. By constructing a pathological model of chronic intermittent hypoxia (CIH), the present study aimed to explore the pathological progress and potential mechanism of lung injury caused by OSAHS. Meanwhile, SMND-309 was given for treatment to evaluate its potential therapeutic role in CIH-induced lung injury.

METHODS: Mice were randomly divided into (C57BL/6 wild-type) WT+(room air) RA, WT + CIH, SMND-309 + RA, and SMND-309 + CIH groups. The WT + CIH and SMND-309 + CIH groups were exposed to CIH condition for 12 weeks, while the other groups were processed in normal oxygen at the same time. The SMND-309 + RA and SMND-309 + CIH groups were intraperitoneally injected with SMND-309 at the last week of the modeling period. After 12 weeks of treatment, three mice from each group were perfused through the heart. Lung tissues were isolated, fixed, sectioned, and stained with H&E, Masson, and immunofluorescence stain. The rest of the lung tissues were harvested for Western blot and ELISA assays.

RESULTS: CIH treatment increased the expression of pro-inflammatory factors (TNF-α and IL-6), resulting in lung tissue structure disorder, inflammatory cell infiltration, increased pulmonary capillary permeability, and pulmonary edema. The activation of the NF-κB signaling pathway played a crucial role in the process of inflammation. Noticeably, we observed M2 macrophage accumulation in the lung after CIH exposure, which promoted epithelial-mesenchymal transition (EMT) and pulmonary tissue fibrosis. ELISA assays showed the increased expression of TGF-β, IL-10, and IL-4 in the CIH group. SMND-309 inhibited pulmonary inflammation, reduced the accumulation of M2 macrophage, alleviated collagen deposition andlung damage.

CONCLUSION: CIH could induce chronic lung inflammation, promote the activation of M2 macrophages, trigger the occurrence of EMT, and accelerate the deposition of lung collagen, eventually leading to lung tissue damage. This study presents a possible explanation by which interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF) with OSAHS, are usually associated with fast progress and poor prognosis. SMND-309 showed a good protective effect on CIH-induced lung damage.

PMID:35121224 | DOI:10.1016/j.intimp.2022.108576

Histol Histopathol. 2022 Feb 4:18428. doi: 10.14670/HH-18-428. Online ahead of print.

ABSTRACT

Sphingosine 1-phosphate (S1P) is a bioactive metabolite of sphingomyelin. S1P activates a series of signaling cascades by acting on its receptors S1PR1-3 on endothelial cells (ECs), which plays an important role in endothelial barrier maintenance, anti-inflammation, antioxidant and angiogenesis, and thus is considered as a potential therapeutic biomarker for ischemic stroke, sepsis, idiopathic pulmonary fibrosis, cancers, type 2 diabetes and cardiovascular diseases. We presently review the levels of S1P in those vascular and vascular-related diseases. Plasma S1P levels were reduced in various inflammation-related diseases such as atherosclerosis and sepsis, but were increased in other diseases including type 2 diabetes, neurodegeneration, cerebrovascular damages such as acute ischemic stroke, Alzheimer's disease, vascular dementia, angina, heart failure, idiopathic pulmonary fibrosis, community-acquired pneumonia, and hepatocellular carcinoma. Then, we highlighted the molecular mechanism by which S1P regulated EC biology including vascular development and angiogenesis, inflammation, permeability, and production of reactive oxygen species (ROS), nitric oxide (NO) and hydrogen sulfide (H2S), which might provide new ways for exploring the pathogenesis and implementing individualized therapy strategies for those diseases.

PMID:35118637 | DOI:10.14670/HH-18-428

Sarcoidosis Vasc Diffuse Lung Dis. 2022;38(4):e2021042. doi: 10.36141/svdld.v38i4.11465. Epub 2022 Jan 13.

ABSTRACT

BACKGROUND: Secondary spontaneous pneumothorax (SSP) in interstitial lung disease (ILD) may influence prognosis of any ILD, and SSP onset predicts poor outcome in idiopathic pulmonary fibrosis (IPF). Recently, progressive fibrosing ILD (PF-ILD) has rapidly acquired importance.

OBJECTIVE: We hypothesized that PF-ILD would strongly influence the prognosis of patients with any ILD complicated with SSP.

METHODS: We retrospectively surveyed and collected data from patients hospitalized for SSP from January 2016 to June 2020. PF-ILD was defined as the following occurring within 24 months before SSP develops: relative decline in %forced vital capacity (FVC) ≥10% or two of the following: relative decline in %FVC between 5% and 10%, worsening respiratory symptoms, or increased extent of fibrosis on high-resolution computed tomography.

RESULTS: We analyzed 32 patients hospitalized for SSP in ILD. This study comprised 18 patients with PF-ILD and 14 patients with non-PF-ILD. PF-ILD patients had lower body mass index (BMI) and %FVC. No significant differences in survival regarding follow-up period from the time of ILD diagnosis and hospitalization for SSP were observed between the PF-ILD and non-PF-ILD patients. Older age and lower BMI were significant predictors of mortality by multivariate Cox regression analysis. ROC analysis showed BMI ≤17.8 kg/m2 to reliably predict poor prognosis.

CONCLUSIONS: Regardless of whether patients have PF-ILD, older age and lower BMI in patients with ILD places them at higher risk of developing SSP, and prognosis is poor if SSP develops. Therefore, clinical management of physique is important to improve the prognosis of ILD patients.

PMID:35115749 | PMC:PMC8787380 | DOI:10.36141/svdld.v38i4.11465

Eur Respir J. 2022 Feb 3:2200024. doi: 10.1183/13993003.00024-2022. Online ahead of print.

NO ABSTRACT

PMID:35115340 | DOI:10.1183/13993003.00024-2022

Eur Respir J. 2022 Feb 3:2101814. doi: 10.1183/13993003.01814-2021. Online ahead of print.

ABSTRACT

Interstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis (IPF), however it is not known if ILA are associated with decreased mean telomere length (MTL).Telomere length was measured with quantitative polymerase chain reaction in COPDGene and AGES-Reykjavik, and southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality.In all three cohorts ILA were associated with decreased MTL. In COPDGene and AGES-Reykjavik, after adjustment there was greater than two-fold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (odds ratio [OR]=2.2, 95% confidence interval [CI] 1.5-3.4, p=0.0001 and OR=2.6, 95% CI 1.4-4.9, p=0.003), respectively. In the FHS, those with ILA had shorter telomeres compared to those without ILA (-767 bp, 95% CI 76-1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR=1.3, 95% confidence interval [CI] 1.1-1.6, p=0.01) in COPDGene the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death, when comparing the shortest quartile of telomere length (hazard ratio [HR]=0.82, 95% CI 0.4-1.7, p=0.6 and HR=1.2, 95% CI 0.6-2.2, p=0.5) in COPDGene and AGES-Reykjavik respectively.ILA are associated with decreased mean telomere length when compared to those without ILA.

PMID:35115336 | DOI:10.1183/13993003.01814-2021

J Surg Res. 2022 Jan 31;274:9-15. doi: 10.1016/j.jss.2021.12.025. Online ahead of print.

ABSTRACT

INTRODUCTION: Currently, standard practice is to use the continuous suturing technique on the bronchial anastomosis during lung transplantation. This study used a large cohort to investigate and contrast continuous and interrupted suturing techniques, comparing survival outcomes and occurrence of postoperative bronchial complications to examine if utilization of interrupted suturing has merit.

METHODS: Survival outcomes of 740 single-center lung transplant recipients over 8 y (February 2012-March 2020) were compared by suturing techniques: either continuous or interrupted at the bronchial anastomosis. Clinical parameters and demographics were compared between two suturing groups, with P values < 0.05 considered significant. The groups were compared for postoperative morbidity, including need for bronchial interventions. Survival was compared using Kaplan-Meier curves and log-rank tests. Cox regression analysis was run with statistically significant variables to study association with survival.

RESULTS: Of the 740 patients, 462 received the continuous suturing technique and 278 received the interrupted suturing technique. Most demographic and clinical data were not statistically significant between the two groups, and those that were significant were not associated with worse survival outcomes, with the exception of the variable diagnosis. Bronchial complications were comparable between the continuous and interrupted groups (12.6% versus 10.4%, P = 0.382). Extracorporeal membrane oxygenation (ECMO) use did not differ significantly between the two groups (P = 0.12). The Kaplan-Meier curve showed comparable survival between groups (P = 0.98), and Cox regression analysis showed that only diagnosis, bronchial complications, and ECMO utilization were associated with different survival outcomes. Chronic obstructive pulmonary disorder was shown to be associated with more favorable survival outcomes as opposed to idiopathic pulmonary fibrosis and the category "other". The need for ECMO and the occurrence of a bronchial complication were also associated with worse survival outcomes.

CONCLUSIONS: Both techniques showed reasonable post-transplant outcomes, as our study demonstrated similar survival outcomes and bronchial complication rates.

PMID:35114484 | DOI:10.1016/j.jss.2021.12.025

PLoS One. 2022 Feb 3;17(2):e0262795. doi: 10.1371/journal.pone.0262795. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a fibrosing interstitial lung disease, predominantly affects the elderly and is associated with a high mortality risk. Nintedanib, a tyrosine kinase inhibitor, significantly reduces IPF progression. However, data on the tolerability and efficacy of nintedanib in the elderly with IPF are limited. Therefore, this study aimed to examine the tolerability and efficacy of nintedanib in the elderly with IPF in a real-world setting. Medical records of 19 elderly IPF patients (≥ 75 years) and 46 non-elderly IPF patients (< 75 years) newly administered nintedanib were retrospectively analyzed. We compared the forced vital capacity (FVC) level, incidence and severity of adverse events, and continuation rates of nintedanib between the two groups. FVC and percent predicted diffusing capacity of the lung for carbon monoxide (DLco) were lower in the elderly IPF group at baseline. Although the elderly IPF patients had a significantly higher incidence of adverse events, such as diarrhea, nausea, and elevation of hepatic enzymes, the rate of discontinuation of nintedanib owing to adverse events was not different between the groups. The continuation rates of nintedanib treatment at 6 months and 1 year in the elderly IPF group were equivalent. Furthermore, there was a similar trend in the reduction of the annual FVC decline after nintedanib initiation between the groups. Our study demonstrated that nintedanib was tolerable in both the IPF patient groups in a real-world setting. Proper management of adverse events in the elderly with IPF would lead to a better clinical outcome.

PMID:35113907 | DOI:10.1371/journal.pone.0262795

Aging Dis. 2022 Feb 1;13(1):73-86. doi: 10.14336/AD.2021.0730. eCollection 2022 Feb.

ABSTRACT

Pulmonary fibrosis, a kind of terminal pathological changes in the lung, is caused by aberrant wound healing, deposition of extracellular matrix (ECM), and eventually replacement of lung parenchyma by ECM. Pulmonary fibrosis induced by acute lung injury and some diseases is reversible under treatment. While idiopathic pulmonary fibrosis is persistent and irreversible even after treatment. Currently, the pathogenesis of irreversible pulmonary fibrosis is not fully elucidated. The known factors associated with the development of irreversible fibrosis include apoptosis resistance of (myo)fibroblasts, dysfunction of pulmonary vessel, cell mitochondria and autophagy, aberrant epithelia hyperplasia and lipid metabolism disorder. In this review, other than a brief introduction of reversible pulmonary fibrosis, we focus on the underlying pathogenesis of irreversible pulmonary fibrosis from the above aspects as well as preclinical disease models, and also suggest directions for future studies.

PMID:35111363 | PMC:PMC8782547 | DOI:10.14336/AD.2021.0730

Trials. 2022 Feb 2;23(1):103. doi: 10.1186/s13063-022-06026-0.

ABSTRACT

BACKGROUND: At present, there is short of effective treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). The treatment of IPF with traditional Chinese medicine (TCM) has some advantages. However, the evidence is unclear whether TCM can be recommended as an effective therapy to treat AE-IPF. The purpose of the study is to explore the efficacy and safety of TCM for patients with AE-IPF.

METHODS: A randomized, double-blind, placebo-controlled, exploratory clinical trial will be performed. A total of 80 patients diagnosed with AE-IPF will be randomized into the intervention or control group. In addition to conventional treatment, the intervention group will be treated with Kangxianhuanji granule, and the control group will be given a placebo granule. The administration frequency is 10 g each time and two times daily. After 4 weeks of treatment, the patients were followed up for 12 weeks. The primary outcomes are treatment failure rate and all-cause mortality. Secondary outcome measures will include the length of hospitalization, overall survival, acute exacerbation rate, intubation rate, Modified British Medical Research Council (mMRC) score, the St George's Respiratory Questionnaire idiopathic pulmonary fibrosis (SGRQ-I) score, and arterial blood gas analysis.

DISCUSSION: TCM may be beneficial in IPF. However, it has never been evaluated in patients with AE-IPF, who are incredibly prone to respiratory failure and have a high mortality rate. It is the first clinical trial to explore the efficacy and safety of TCM in the treatment of AE-IPF. This result will provide a basis for further study, which provides a high-quality evidence for the treatment of AE-IPF with TCM.

TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900026289 . Registered on 29 September 2019.

PMID:35109889 | DOI:10.1186/s13063-022-06026-0

Eur Heart J Case Rep. 2022 Jan 19;6(1):ytac023. doi: 10.1093/ehjcr/ytac023. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Ephedra and ephedrine alkaloids were commonly used in herbal supplements before being prohibited by the European Commission and US Food and Drug Administration. However, ongoing, unknowing use by consumers can lead to potential adverse cardiovascular effects, such as arrhythmias.

CASE SUMMARY: A 65-year-old-man with a history of idiopathic pulmonary fibrosis status post-right single lung transplant was admitted for dizziness and resting tachycardia. Electrocardiogram showed a narrow complex, long R-P tachycardia with upright P-waves in lead V 1. An initial workup suggested an arrhythmia associated with the consumption of an herbal supplement containing heart-leaf sida, a banned botanical ephedrine alkaloid. After the supplement was discontinued, the patient's heart rate abruptly decreased without other intervention. Electrocardiogram showed a change in P-wave morphology in lead V 1 from upright to biphasic (+/-) after conversion to normal sinus rhythm. Thus, a diagnosis of atrial tachycardia originating at or near the donor right superior pulmonary vein was favoured.

DISCUSSION: Atrial tachycardia can be precipitated by the proarrhythmic effects of ephedrine alkaloids, especially in patients with underlying risk factors and susceptible atrial anatomical substrate post-lung transplantation. Despite being banned by the European Union and the USA, ephedrine alkaloids continue to be used in over-the-counter herbal supplements and may go undetected by consumers. Ongoing vigilance for ephedrine alkaloids, more rigorous regulation, and active patient education can help reduce potential cardiovascular adverse events.

PMID:35106447 | PMC:PMC8801050 | DOI:10.1093/ehjcr/ytac023

Respir Med Case Rep. 2022 Jan 19;36:101588. doi: 10.1016/j.rmcr.2022.101588. eCollection 2022.

ABSTRACT

Herein, we report an autopsy case of idiopathic pulmonary fibrosis (IPF) in which remarkable honeycomb cyst expansion appeared in the clinical course. Radiological findings initially showed subpleural predominant reticulation that had progressed to usual interstitial pneumonia with honeycomb cysts, along with a restrictive pattern in the pulmonary function tests. The diameter of honeycomb cysts had gradually increased, and some cysts had abruptly expanded at the end stage. Based on pathological findings of autopsy specimens, bronchiectasis, alveolar collapse due to inflammation, and check-valve mechanism caused by a slit-like orifice of the cysts could have contributed to honeycomb cyst expansion.

PMID:35106280 | PMC:PMC8784337 | DOI:10.1016/j.rmcr.2022.101588

Comput Intell Neurosci. 2022 Jan 28;2022:2832400. doi: 10.1155/2022/2832400. eCollection 2022.

ABSTRACT

Pulmonary fibrosis is a severe chronic lung disease that causes irreversible scarring in the tissues of the lungs, which results in the loss of lung capacity. The Forced Vital Capacity (FVC) of the patient is an interesting measure to investigate this disease to have the prognosis of the disease. This paper proposes a deep learning-based FVC-Net architecture to predict the progression of the disease from the patient's computed tomography (CT) scan and the patient's metadata. The input to the model combines the image score generated based on the degree of honeycombing for a patient identified based on segmented lung images and the metadata. This input is then fed to a 3-layer net to obtain the final output. The performance of the proposed FVC-Net model is compared with various contemporary state-of-the-art deep learning-based models, which are available on a cohort from the pulmonary fibrosis progression dataset. The model showcased significant improvement in the performance over other models for modified Laplace Log-Likelihood (-6.64). Finally, the paper concludes with some prospects to be explored in the proposed study.

PMID:35103054 | PMC:PMC8799953 | DOI:10.1155/2022/2832400

Int J Cardiovasc Imaging. 2022 Feb 1. doi: 10.1007/s10554-022-02541-y. Online ahead of print.

ABSTRACT

Previous reports suggested that poor pulmonary function was associated with increased arterial elastance (Ea) in patients with chronic obstructive pulmonary disease and systemic sclerosis. The mechanisms connecting pulmonary function and Ea have not yet been accurately studied in patients with idiopathic pulmonary fibrosis (IPF). The present study was designed to assess Ea in IPF patients without chronic severe pulmonary hypertension and to determine its prognostic role over a medium-term follow-up. This retrospective study included 60 consecutive patients with mild-to-moderate IPF (73.8 ± 6.6 years, 75% males) and 60 controls matched by age, sex and cardiovascular risk factors. All patients underwent physical examination, spirometry, blood tests, modified Haller index (MHI, chest transverse diameter over the distance between sternum and spine) assessment, conventional transthoracic echocardiography implemented with speckle tracking analysis of left atrial positive global strain (LA-GSA+ ) and finally carotid Doppler ultrasonography, at basal evaluation. The effective arterial elastance index (EaI) was calculated as the ratio of end-systolic pressure to stroke volume index. During follow-up period, we evaluated the composite endpoint of (1) pulmonary or cardiovascular hospitalizations; (2) all-cause mortality. At baseline, EaI was significantly higher in IPF patients than controls (4.1 ± 1.3 vs 3.5 ± 1.0 mmHg/ml/m2, p = 0.01). EaI was strongly correlated to the following variables: C-reactive protein (CRP) (r = 0.86), forced vital capacity (FVC) (r = - 0.91), E/e' ratio (r = 0.91), LA-GSA+ (r = - 0.92), common carotid artery-cross sectional area (CCA-CSA) (r = 0.89) and MHI (r = 0.86), in IPF patients. Mean follow-up time was 2.4 ± 1.3 years. During follow-up, 12 patients died and 17 were hospitalized due to major adverse clinical events. At univariate Cox analysis, CRP (HR 1.51, 95% CI 1.25-1.82), FVC (HR 0.88, 95% CI 0.85-0.91), LA-GSA+ (HR 0.85, 95% CI 0.77-0.94), CCA-CSA (HR 1.12, 95% CI 1.03-1.22) and EaI (HR 2.43, 95% CI 1.75-3.37) were significantly associated with outcome. At multivariate Cox analysis, only EaI (HR 1.60, 95% CI 1.03-2.50) retained statistical significance. An EaI ≥ 4 mmHg/ml/m2 showed 100% sensitivity and 99.4% specificity for predicting outcome (AUC = 0.98). In patients with mild-to-moderate IPF, an EaI ≥ 4 mmHg/ml/m2 is a negative prognostic factor over a medium-term follow-up.

PMID:35103898 | DOI:10.1007/s10554-022-02541-y

Ann Am Thorac Soc. 2022 Feb;19(2):161-162. doi: 10.1513/AnnalsATS.202108-972ED.

NO ABSTRACT

PMID:35103565 | DOI:10.1513/AnnalsATS.202108-972ED

Am J Respir Cell Mol Biol. 2022 Feb;66(2):235-237. doi: 10.1165/rcmb.2021-0224LE.

NO ABSTRACT

PMID:35103555 | DOI:10.1165/rcmb.2021-0224LE

Stem Cell Res Ther. 2022 Jan 31;13(1):45. doi: 10.1186/s13287-021-02692-0.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disease characterized by aberrant tissue remodeling, formation of scar tissue within the lungs and continuous loss of lung function. The areas of fibrosis seen in lungs of IPF patients share many features with normal aging lung including cellular senescence. The contribution of the immune system to the etiology of IPF remains poorly understood. Evidence obtained from animal models and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. Currently, there is only modest effective pharmacotherapy for IPF. Mesenchymal stem cells (MSCs)-based therapies have emerged as a potential option treatment of IPF. This study characterizes the functionality of autologous MSCs for use as an IPF therapy and presents an attempt to determine whether the disease occurring in the lungs is associated with an alterated immune system.

METHODS: Comprehensive characterization of autologous adipose-derived MSCs (aMSCs) from 5 IPF patient and 5 age- and gender-matched healthy controls (HC) was done using flow cytometry, PCR (ddPCR), multiplex Luminex xMAP technology, confocal microscopy self-renewal capacity and osteogenic differentiation. Additionally, multi-parameter quantitative flow cytometry of unmanipulated whole blood of 15 IPF patients and 87 (30 age- and gender-matched) HC was used to analyze 110 peripheral phenotypes to determine disease-associated changes in the immune system.

RESULTS: There are no differences between autologous aMSCs from IPF patients and HC in their stem cell properties, self-renewal capacity, osteogenic differentiation, secretome content, cell cycle inhibitor marker levels and mitochondrial health. IPF patients had altered peripheral blood immunophenotype including reduced B cells subsets, increased T cell subsets and increased granulocytes demonstrating disease-associated alterations in the immune system.

CONCLUSIONS: Our results indicate that there are no differences in aMSC properties from IPF patients and HC, suggesting that autologous aMSCs may be an acceptable option for IPF therapy. The altered immune system of IPF patients may be a valuable biomarker for disease burden and monitoring therapeutic response.

PMID:35101101 | DOI:10.1186/s13287-021-02692-0

J Cell Physiol. 2022 Jan 30. doi: 10.1002/jcp.30687. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few effective treatment options. We found a highly significant correlation between pregnancy-associated plasma protein (PAPP)-A expression in IPF lung tissue and disease severity as measured by various pulmonary and physical function tests. PAPP-A is a metalloproteinase that enhances local insulin-like growth factor (IGF) activity. We used primary cultures of normal adult human lung fibroblasts (NHLF) to test the hypothesis that PAPP-A plays an important role in the development of pulmonary fibrosis. Treatment of NHLF with pro-fibrotic transforming growth factor (TGF)-β stimulated marked increases in IGF-I mRNA expression (>20-fold) and measurable IGF-I levels in 72-h conditioned medium (CM). TGF-β treatment also increased PAPP-A levels in CM fourfold (p = 0.004) and proteolytic activity ~2-fold. There was an indirect effect of TGF-β to stimulate signaling through the PI3K/Akt pathway, which was significantly inhibited by both IGF-I-inactivating and PAPP-A inhibitory antibodies. Induction of senescence in NHLF increased PAPP-A levels in CM 10-fold (p = 0.006) with attendant increased proteolytic activity. Thus, PAPP-A is a novel component of the senescent lung fibroblast secretome. In addition, NHLF secreted extracellular vehicles (EVs) with surface-bound active PAPP-A that were increased fivefold with senescence. Regulation of PAPP-A and IGF signaling by TGF-β and cell senescence suggests an interactive cellular mechanism underlying the resistance to apoptosis and the progression of fibrosis in IPF. Furthermore, PAPP-A-associated EVs may be a means of pro-fibrotic, pro-senescent communication with other cells in the lung and, thus, a potential therapeutic target for IPF.

PMID:35098542 | DOI:10.1002/jcp.30687

Front Genome Ed. 2022 Jan 14;3:785829. doi: 10.3389/fgeed.2021.785829. eCollection 2021.

ABSTRACT

Pulmonary surfactant is critically important to prevent atelectasis by lowering the surface tension of the alveolar lining liquid. While respiratory distress syndrome (RDS) is common in premature infants, severe RDS in term and late preterm infants suggests an underlying genetic etiology. Pathogenic variants in the genes encoding key components of pulmonary surfactant including surfactant protein B (SP-B, SFTPB gene), surfactant protein C (SP-C, SFTPC gene), and the ATP-Binding Cassette transporter A3 (ABCA3, ABCA3 gene) result in severe neonatal RDS or childhood interstitial lung disease (chILD). These proteins play essential roles in pulmonary surfactant biogenesis and are expressed in alveolar epithelial type II cells (AEC2), the progenitor cell of the alveolar epithelium. SP-B deficiency most commonly presents in the neonatal period with severe RDS and requires lung transplantation for survival. SFTPC mutations act in an autosomal dominant fashion and more commonly presents with chILD or idiopathic pulmonary fibrosis than neonatal RDS. ABCA3 deficiency often presents as neonatal RDS or chILD. Gene therapy is a promising option to treat monogenic lung diseases. Successes and challenges in developing gene therapies for genetic disorders of surfactant dysfunction include viral vector design and tropism for target cell types. In this review, we explore adeno-associated virus (AAV), lentiviral, and adenoviral (Ad)-based vectors as delivery vehicles. Both gene addition and gene editing strategies are compared to best design treatments for lung diseases resulting from pathogenic variants in the SFTPB, SFTPC, and ABCA3 genes.

PMID:35098209 | PMC:PMC8798122 | DOI:10.3389/fgeed.2021.785829

Front Med (Lausanne). 2022 Jan 14;8:723635. doi: 10.3389/fmed.2021.723635. eCollection 2021.

ABSTRACT

OBJECTIVE: Lung microbiota is increasingly implicated in multiple types of respiratory diseases. However, no study has drawn a consistent conclusion regarding the relationship between changes in the microbial community and lung diseases. This study verifies the association between microbiota level and lung diseases by performing a meta-analysis.

METHODS: Literature databases, including PubMed, ISI Web of Science, Embase, Google Scholar, PMC, and CNKI, were used to collect related articles published before March 20, 2021. The standard mean deviation (SMD) and related 95% confidence intervals (CIs) were calculated using a random-effects model. Subgroup, sensitivity, and publication bias analyses were also conducted.

RESULTS: Six studies, comprising 695 patients with lung diseases and 176 healthy individuals, were included in this meta-analysis. The results indicated that the microbiota level was higher in patients with lung diseases than in healthy individuals (SMD = 0.39, 95% CI = 0.22-0.55, I 2 = 91.5%, P < 0.01). Subgroup analysis based on country demonstrated that the microbiota level was significantly higher in Chinese (SMD = 1.90, 95% CI = 0.87-2.93, I 2 = 62.3%, P < 0.01) and Korean (SMD = 0.24, 95% CI = 0.13-0.35, I 2 = 78.7%, P < 0.01) patients with lung diseases. The microbiota level of patients with idiopathic pulmonary fibrosis (IPF) (SMD = 1.40, 95% CI = 0.42-2.38, I 2 = 97.3%, P = 0.005), chronic obstructive pulmonary disease (COPD) (SMD = 0.30, 95% CI = 0.09-0.50, I 2 = 83.9%, P = 0.004), and asthma (SMD = 0.19, 95% CI = 0.06-0.32, I 2 = 69.4%, P = 0.004) were significantly higher than those of the healthy group, whereas a lower microbiota level was found in patients with chronic hypersensitivity pneumonitis (CHP). The microbiota level significantly increased when the disease sample size was >50. Subgroup analysis based on different microbiota genera, indicated that Acinetobacter baumannii and Pseudomonas aeruginosa were significantly increased in COPD and asthma diseases.

CONCLUSION: We observed that patients with IPF, COPD, and asthma had a higher microbiota level, whereas patients with CHP had a lower microbiota level compared to the healthy individuals. The level of A. baumannii and P. aeruginosa were significantly higher in patients with COPD and asthma, and thus represented as potential microbiota markers in the diagnosis and treatment of lung diseases.

PMID:35096850 | PMC:PMC8795898 | DOI:10.3389/fmed.2021.723635

Oxid Med Cell Longev. 2022 Jan 20;2022:2523066. doi: 10.1155/2022/2523066. eCollection 2022.

ABSTRACT

Pneumoconiosis is one of the most common occupational diseases in the world, and specific treatment methods of pneumoconiosis are lacking at present, so it carries great social and economic burdens. Pneumoconiosis, coronavirus disease 2019, and idiopathic pulmonary fibrosis all have similar typical pathological changes-pulmonary fibrosis. Pulmonary fibrosis is a chronic lung disease characterized by excessive deposition of the extracellular matrix and remodeling of the lung tissue structure. Clarifying the pathogenesis of pneumoconiosis plays an important guiding role in its treatment. The occurrence and development of pneumoconiosis are accompanied by epigenetic factors (e.g., DNA methylation and noncoding RNA) changes, which in turn can promote or inhibit the process of pneumoconiosis. Here, we summarize epigenetic changes and functions in the several kinds of evidence classification (epidemiological investigation, in vivo, and in vitro experiments) and main types of cells (macrophages, fibroblasts, and alveolar epithelial cells) to provide some clues for finding specific therapeutic targets for pneumoconiosis and even for pulmonary fibrosis.

PMID:35096264 | PMC:PMC8794660 | DOI:10.1155/2022/2523066