Respir Res. 2021 Oct 31;22(1):282. doi: 10.1186/s12931-021-01879-6.

ABSTRACT

BACKGROUND: The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria.

METHODS: Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial.

RESULTS: The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DLCO, HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes.

CONCLUSIONS: Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.

PMID:34719401 | DOI:10.1186/s12931-021-01879-6

Gastroenterol Clin North Am. 2021 Dec;50(4):919-934. doi: 10.1016/j.gtc.2021.08.006. Epub 2021 Oct 7.

ABSTRACT

The aim of this review is to explore the relationship between esophageal syndromes and pulmonary diseases considering the most recent data available. Prior studies have shown a close relationship between lung diseases such as asthma, chronic obstructive pulmonary disorders (COPD), Idiopathic pulmonary fibrosis (IPF), and lung transplant rejection and esophageal dysfunction. Although the association has long been demonstrated, the exact relationship remains unclear. Clinical experience has shown a bidirectional relationship where esophageal disease may influence the outcomes of pulmonary disease and vice versa. The impact of esophageal dysfunction on pulmonary disorders may also be related to 2 different mechanisms: the reflux pathway leading to microaspiration and the reflex pathway triggering vagally mediated airway reactions. The aim of this review is to further explore these relationships and pathophysiologic mechanisms. Specifically, we discuss the proposed hypotheses for the relationship between the 2 diseases, as well as the pathophysiology and new developments in clinical management.

PMID:34717879 | DOI:10.1016/j.gtc.2021.08.006

Eur J Med Res. 2021 Oct 30;26(1):129. doi: 10.1186/s40001-021-00601-y.

ABSTRACT

BACKGROUND: It is necessary to systematically evaluate the efficacy and adverse reactions of pirfenidone in the treatment of patients with idiopathic pulmonary fibrosis (IPF).

METHODS: Pubmed et al. databases were searched up to March 15, 2021 for randomized controlled trials (RCT) of pirfenidone in the treatment of IPF. Two authors collected and compared the indicators including progression-free survival (PFS), vital capacity (VC), forced vital capacity (FVC), and adverse reactions. RevMan 5.3 software and Stata 15.0 software were used for meta-analysis.

RESULTS: A total of 8 reports with 9 RCTs involving 1824 IPF patients were included. Meta-analysis results showed that compared with the control group, pirfenidone could prolong the PFS phase of IPF patients (HR = 0.65, 95% CI 0.55 ~ 0.76, P < 0.001), slow down the VC of IPF patients (SMD = 0.43, 95% CI 0.21 ~ 0.66, P < 0.001), and decrease FVC (SMD = 0.31, 95% CI 0.14 ~ 0.48, P < 0.001). The main adverse reactions of pirfenidone were gastrointestinal reactions, photosensitivity and skin rashes.

CONCLUSION: Pirfenidone is beneficial to prolong the PFS of IPF patients, improve lung function, and it is safe for clinical use. However, more high-quality RCTs are still needed to provide reliable evidence for the treatment of IPF.

PMID:34717762 | DOI:10.1186/s40001-021-00601-y

BMJ Case Rep. 2021 Oct 29;14(10):e246119. doi: 10.1136/bcr-2021-246119.

ABSTRACT

Acute COVID-19 usually lasts 4 weeks from the onset of symptoms. We report two cases of COVID-19-associated organising pneumonia (OP) occurring beyond 4 weeks from the acute onset of symptoms. Both tested positive for SARS reverse transcription-PCR 2 months before presentation with a resolution of respiratory symptoms. The first case presented with residual fatigue and worsening exertional dyspnoea. Chest CT revealed an OP pattern. The second case presented with worsening cough and new-onset pleuritic chest pain with persistent radiological consolidation. A transbronchial lung biopsy confirmed OP. Both patients responded well to 12 weeks of steroid therapy. This case illustrates the rare presentation of OP as a late sequela of COVID-19 and the good response to steroid therapy.

PMID:34716149 | DOI:10.1136/bcr-2021-246119

Eur Radiol. 2021 Oct 30. doi: 10.1007/s00330-021-08338-2. Online ahead of print.

ABSTRACT

OBJECTIVES: In patients with IPF, this study aimed (i) to examine the relationship between serial change in CT parameters of lung volume and lung function, (ii) to identify the prognostic value of serial change in CT parameters of lung volume, and (iii) to define a threshold for serial change in CT markers of lung volume that optimally captures disease progression.

METHODS: Serial CTs were analysed for progressive volume loss or fibrosis progression in 81 IPF patients (66 males, median age = 67 years) with concurrent forced vital capacity (FVC) (median follow-up 12 months, range 6-23 months). Serial CT measurements of volume loss comprised oblique fissure posterior retraction distance (OFPRD), aortosternal distance (ASD), lung height corrected for body habitus (LH), and automated CT-derived total lung volumes (ALV) (measured using commercially available software). Fibrosis progression was scored visually. Serial changes in CT markers and FVC were compared using regression analysis, and evaluated against mortality using Cox proportional hazards.

RESULTS: There were 58 deaths (72%, median survival = 17 months). Annual % change in ALV was most significantly related to annual % change in FVC (R2 = 0.26, p < 0.0001). On multivariate analysis, annual % change in ASD predicted mortality (HR = 0.97, p < 0.001), whereas change in FVC did not. A 25% decline in annual % change in ASD best predicted mortality, superior to 10% decline in FVC and fibrosis progression.

CONCLUSION: In IPF, serial decline in CT markers of lung volume and, specifically, annualised 25% reduction in aortosternal distance provides evidence of disease progression, not always identified by FVC trends or changes in fibrosis extent.

KEY POINTS: • Serial decline in automated and surrogate markers of lung volume on CT corresponds to changes in FVC. • Annualised reductions in the distance between ascending aorta and posterior border of the sternum on CT predict mortality beyond annualised percentage change in FVC.

PMID:34716781 | DOI:10.1007/s00330-021-08338-2

Lung. 2021 Oct 29. doi: 10.1007/s00408-021-00488-w. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease, in which inflammation is thought to only play a secondary role. Several factors associated with acute exacerbations of IPF (AE-IPF) have been identified, including infections. This study investigated whether humoral immunodeficiency or increased inflammatory markers at diagnosis were associated with AE-IPF and survival.

METHODS: Four-hundred-and-nine patients diagnosed with IPF between 2011 and 2017 were retrospectively included. Immune status investigations at diagnosis included measurement of serum immunoglobulins (available in 38%), leukocyte and lymphocyte subsets in blood and bronchoalveolar lavage (BAL) fluid (available in 58%), as well as response to pneumococcal vaccination (available in 64%).

RESULTS: Serum immunoglobulins or IgG subclass levels were below the lower limit of normal in 6%. The response to pneumococcal vaccination was severely impaired in 1%. Thirteen percent of patients developed an AE-IPF (4.7% per year). AE-IPF were associated with elevated lymphocytes in BAL fluid at diagnosis (p = 0.03). Higher serum IgA and IgG at diagnosis were associated with worse survival (p = 0.01; and p = 0.04), as were an increased BAL lymphocyte percentage (p = 0.005), and higher blood leukocytes and neutrophils (p = 0.01; and p = 0.0005). In a multivariate model, only BAL lymphocyte count retained statistical significance (p = 0.007).

CONCLUSION: The prevalence of humoral immunodeficiencies was low in patients with IPF and not associated with AE-IPF or survival. Elevated lymphocytes in BAL were associated with the development of AE-IPF and worse survival. Higher serum immunoglobulins and immune cells in blood were also associated with worse survival. The local immune response in the lungs may be a target for future therapies.

PMID:34714393 | DOI:10.1007/s00408-021-00488-w

Front Public Health. 2021 Oct 6;9:729162. doi: 10.3389/fpubh.2021.729162. eCollection 2021.

ABSTRACT

Background: Through collection and sorting of rare disease projects funded by the National Natural Science Foundation of China, an understanding was gained of the categories of projects funded by the foundation in the field of rare diseases, types of diseases, categories of disease systems, regional distribution, distribution of supporting institutions, and their dynamic changes, followed by an analysis of focuses and influences of relevant state policies. This will help improve the rare disease-relating policies of the state in supporting the key fields, thus promoting healthy and sustainable development in the field of rare diseases. Method: Through the website of inquiry of projects funded by the National Natural Science Foundation of China, a retrieval was made concerning the projects funded by the foundation in the field of rare diseases during the period from 1986 to 2019, followed by descriptive analysis of fund input of rare disease projects, number of projects, temporal and regional distribution, and the analysis of the law of their dynamic changes. Result: As of the end of 2019, there were 57 rare diseases and 678 related projects funded by the National Natural Science Foundation of China, with accumulated total funding of ¥ 253,525,000. Among the categories of projects, the most-funded projects were general (¥ 150,145,000, 59.22%), followed by Youth Foundation projects (¥ 53,719,000, 21.19%) and key projects (¥ 15,870,000, 6.26%); among the categories of disease systems, the most funded disease system was the nervous system (¥ 93,186,000, 37.76%), followed by the respiratory system (¥ 35,444,000, 13.98%); the most funded diseases were multiple sclerosis (¥ 34,870,000, 13.75%), idiopathic pulmonary fibrosis (¥ 29,854,000, 11.78%), and retinitis pigmentosa (¥ 27,005,000, 10.65%); the most funded regions were East China (¥ 106,987,000, 42.20%) and North China (¥ 71,844,000, 28.34%), while the least funded region was Northwest China (¥ 7,295,000, 2.88%); among the supporting institutions, the most funded institutions were Peking University (¥ 24,720,000, 9.75%), and Sun Yat-sen University (¥ 14,505,000, 5.72%). Conclusion: With the promulgation of more policies on encouragement of innovation and accelerated approval procedures, etc., the National Natural Science Foundation of China has been increasing its funding to rare diseases, covering increasingly more categories of funded projects, more types of diseases, and wider regions. Nonetheless, the support for scientific research in China is still relatively weak. Therefore, it is proposed that the healthy and sustainable development in the course of rare diseases should be promoted through the improvement of relevant rare disease policies, encouragement of R&D of medicine for rare diseases, the establishment of special funds for rare diseases, acceleration of fund circulation, and combination of balanced development and preferential funding to key regions and major diseases.

PMID:34712637 | PMC:PMC8547256 | DOI:10.3389/fpubh.2021.729162

Front Pharmacol. 2021 Oct 12;12:754851. doi: 10.3389/fphar.2021.754851. eCollection 2021.

ABSTRACT

Background: Progressive fibrosing interstitial lung disease (PF-ILD) and idiopathic pulmonary fibrosis (IPF) share similar progression phenotype but with different pathophysiological mechanism. The purpose of this study was to assess clinical characteristics and outcomes of patients with PF-ILD in a single-center cohort. Methods: Patients with PF-ILD treated in Shanghai Pulmonary Hospital from Jan. 2013 to Dec. 2014 were retrospectively analyzed. Baseline characteristics and clinical outcomes were collected for survival analysis to identifying clinical predictors of mortality. Results: Among 608 patients with ILD, 132 patients met the diagnostic criteria for PF-ILD. In this single-center cohort, there were 51 (38.6%) cases with connective tissue disease-associated interstitial lung disease (CTD-ILD) and 45 (34.1%) with unclassifiable ILDs. During follow-up, 83 patients (62.9%) either died (N = 79, 59.8%) or underwent lung transplantations (N = 4, 3.0%) with a median duration follow-up time of 53.7 months. Kaplan-Meier survival curves revealed that the 1, 3 and 5-years survival of PF-ILD were 90.9, 58.8 and 48.1%, respectively. In addition, the prognosis of patients with PF-ILD was similar to those with IPF, while it was worse than non-PF-ILD ones. Multivariate Cox regression analysis demonstrated that high-resolution computed tomography (HRCT) scores (HR 1.684, 95% CI 1.017-2.788, p = 0.043) and systolic pulmonary artery pressure (SPAP) > 36.5 mmHg (HR 3.619, 95%CI 1.170-11.194, p = 0.026) were independent risk factors for the mortality of PF-ILD. Conclusion: Extent of fibrotic changes on HRCT and pulmonary hypertension were predictors of mortality in patients with PF-ILD.

PMID:34712141 | PMC:PMC8546258 | DOI:10.3389/fphar.2021.754851

Front Pharmacol. 2021 Oct 12;12:679388. doi: 10.3389/fphar.2021.679388. eCollection 2021.

ABSTRACT

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,-4,-13,-14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and -13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.

PMID:34712131 | PMC:PMC8546112 | DOI:10.3389/fphar.2021.679388

BMJ Open Respir Res. 2021 Oct;8(1):e001039. doi: 10.1136/bmjresp-2021-001039.

ABSTRACT

INTRODUCTION: Bioelectrical impedance analysis (BIA) can be used to estimate Fat-Free Mass Index (FFMI). However, the use of directly measured BIA variables, such as phase angle (PhA), has gained attention. The frequency of low FFMI and PhA and its associations with exercise capacity and health-related quality of life (HRQL) in patients with idiopathic pulmonary fibrosis (IPF) have been scarcely studied.

OBJECTIVES: To investigate the frequency of low FFMI and PhA and their associations with exercise capacity and HRQL in patients with IPF.

METHODS: Patients underwent assessment of lung function, body composition, exercise capacity by the 6 min walk distance (6MWD), and HRQL by the Medical Outcomes Study Short-Form 36-item Questionnaire (SF-36). Patients were classified as presenting normal or low PhA or FFMI, accordingly to the 10th percentiles of age-sex-body mass index (BMI)-specific reference values.

RESULTS: 98 patients (84 males, age: 68±8 years, forced vital capacity: 64%±18%predicted) were included. 24 patients presented low PhA. They were characterised by worse lung function, exercise capacity and HRQL compared with patients with normal PhA. 10 patients presented low FFMI, but despite differences in body composition, no differences were found between these patients and patients with normal FFMI. In a single regression analysis, age, lung function and body composition variables (except FFMI) were related to 6MWD and SF-36 Physical Summary Score (R²=0.06-0.36, p<0.05). None of the variables were related to SF-36 Mental Summary Score.

CONCLUSION: One-fourth of the patients with IPF with normal to obese BMI present abnormally low PhA. Patients classified as low PhA presented worse lung function, exercise capacity and HRQL.

PMID:34711642 | DOI:10.1136/bmjresp-2021-001039

Respir Res. 2021 Oct 28;22(1):278. doi: 10.1186/s12931-021-01866-x.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment.

METHODS: AEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments.

RESULTS: AEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs.

CONCLUSIONS: These results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.

PMID:34711218 | DOI:10.1186/s12931-021-01866-x

J Pharm Pract. 2021 Oct 28:8971900211053286. doi: 10.1177/08971900211053286. Online ahead of print.

ABSTRACT

PURPOSE: This article is an in-depth review of the complex classification, diagnosis, and treatment of idiopathic interstitial pneumonias (IIP), as well as emergence of new treatment options.

SUMMARY: Idiopathic interstitial pneumonias consist of various subgroup classifications that require expert analysis of imaging and histology to accurately diagnose this broad group of patients. Timely and accurate assessment of these patients is key in developing an appropriate pharmacological plan. The pathophysiology of IIP is not well understood but has been linked to an immune response resulting in inflammation, fibrosis, or proliferation of lung tissue which reduces lung function. Lung transplantation is currently the only curative option for treatment, but many new antiproliferative and immunosuppressive agents are being used to effectively slow the progression of lung dysfunction.

CONCLUSION: An often mixed radiological and histological pattern along with the invasive nature of biopsy for gold standard diagnosis create a challenge for the accurate identification of IIP. Further understanding of these idiopathic interstitial pneumonias will pave the way forward to the emergence of new treatment options and updates to standards of care.

PMID:34708667 | DOI:10.1177/08971900211053286

Oxid Med Cell Longev. 2021 Oct 18;2021:9932442. doi: 10.1155/2021/9932442. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a condition which affects mainly older adults, that suggests mitochondrial dysfunction and oxidative stress, which follow cells senescence, and might contribute to the disease onset. We have assumed pathogenesis associated with crosstalk between the extracellular matrix (ECM) and mitochondria, mainly based on mitochondrial equilibrium impairment consisting of (1) tyrosine kinases and serine-threonine kinase (TKs and ST-Ks) activation via cytokines, (2) mitochondrial electron transport chain dysfunction and in consequence electrons leak with lower ATP synthesis, (3) the activation of latent TGF-β via αVβ6 integrin, (4) tensions transduction via α2β1 integrin, (5) inefficient mitophagy, and (6) stress inhibited biogenesis. Mitochondria dysfunction influences ECM composition and vice versa. Damaged mitochondria release mitochondrial reactive oxygen species (mtROS) and the mitochondrial DNA (mtDNA) to the microenvironment. Therefore, airway epithelial cells (AECs) undergo transition and secrete cytokines. Described factors initiate an inflammatory process with immunological enhancement. In consequence, local fibroblasts exposed to harmful conditions transform into myofibroblasts, produce ECM, and induce progression of fibrosis. In our review, we summarize numerous aspects of mitochondrial pathobiology, which seem to be involved in the pathogenesis of lung fibrosis. In addition, an increasing body of evidence suggests considering crosstalk between the ECM and mitochondria in this context. Moreover, mitochondria and ECM seem to be important players in the antifibrotic treatment of IPF.

PMID:34707784 | PMC:PMC8545566 | DOI:10.1155/2021/9932442

Aust Health Rev. 2021 Oct 28. doi: 10.1071/AH20337. Online ahead of print.

ABSTRACT

ObjectivesIdiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease presenting in people aged ≥50 years. There is currently no cure for IPF, but two medications (pirfenidone and nintedanib) have been shown to slow the functional decline of the lungs. In 2017, these two medications were listed on the Pharmaceutical Benefits Scheme (PBS) for subsidisation in Australia. This study evaluated local trends in the use of these two medications.MethodsPrescription data for this analysis were obtained from the PBS Item Reports for the period May 2017-May 2020. Population data were extracted from the Australian Bureau of Statistics data cubes. A descriptive approach was used to conduct and report the analysis to illustrate trends in the use of these two medications and associated costs.ResultsThere were 44 010 prescriptions processed for the treatment for IPF in the 3-year period. Nintedanib use was higher than pirfenidone use, accounting for 54% of prescriptions. New South Wales accounted for 35% of the total prescriptions but, when standardised against population size, the Australian Capital Territory accounted for the highest proportion of prescriptions (24%). Prescriptions for nintedanib and pirfenidone were associated with a total cost of A$131 377 951 over the period 2017-20.ConclusionThis study provides initial information on prescription rates, practices and expenditure for pirfenidone and nintedanib. In addition, we provide some insight into possible pharmacological and epidemiological trends based on jurisdictional differences. Together, the results from this study provide a platform for future research given the dearth of information on IPF in Australia.What is known about the topic?Data regarding trends in the utilisation of antifibrotics for the treatment of IPF in Australia are currently limited.What does this paper add?This study demonstrated that nintedanib use was slightly higher than pirfenidone use, and that there were variations in jurisdictional prescribing practices. The highest number of prescriptions and costs were attributable to New South Wales but, when standardised against population size, the Australian Capital Territory had the highest number of prescriptions and costs.What are the implications for practitioners?This study provides some insights into the use of pirfenidone and nintedanib, as well as pharmacoepidemiological trends, in Australia, which is useful for economic evaluation and modelling future health expenditure.

PMID:34706811 | DOI:10.1071/AH20337

Am J Respir Cell Mol Biol. 2021 Oct 27. doi: 10.1165/rcmb.2021-0257OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease with high mortality and morbidity. Asporin (ASPN), a member of the small leucine-rich proteoglycan (SLRP) family, plays crucial roles in tissue injury and regeneration. However, the precise pathophysiological role of ASPN and its molecular mechanisms in IPF remain unknown. We sought to investigate the role of ASPN during the development of pulmonary fibrosis and the therapeutic potential of targeting ASPN-related signaling pathways. In our study, three microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were screened out by bioinformatic analysis. Hub genes were selected from the protein-protein interaction network. ASPN was examined in lung tissues from pulmonary fibrosis mouse models and the role of ASPN in TGF-β/Smad signaling was determined by transfection with ASPN shRNA vectors in vitro. Biotinylation assays were conducted to measure plasma membrane TβRI and TβRI recycling after ASPN knockdown. The results showed ASPN expression was increased in the lungs of pulmonary fibrosis mouse models, and ASPN was primarily localized in α-SMA+ myofibroblasts. In vitro experiments proved that ASPN knockdown inhibited TGF-β/Smad signaling and myofibroblast differentiation by regulating the stability of TβRI. Further molecular mechanisms revealed that ASPN knockdown inhibited TGF-β/Smad signaling by suppressing recycling of TβRI to the cell surface in a Rab11-dependent manner and facilitated lysosome-mediated degradation of TβRI. In conclusion, our findings provide important evidence for the use of ASPN as a novel pharmacological target for treating pulmonary fibrosis.

PMID:34705621 | DOI:10.1165/rcmb.2021-0257OC

Surg Case Rep. 2021 Oct 26;7(1):231. doi: 10.1186/s40792-021-01321-5.

ABSTRACT

BACKGROUND: Non-intubated video-assisted thoracic surgery is a therapeutic option for intractable secondary spontaneous pneumothorax in patients who are poor candidates for surgery with endotracheal intubation under general anesthesia. However, intraoperative respiratory management in this surgery is often challenging because of hypoxia caused by surgical pneumothorax.

CASE PRESENTATION: A 75-year-old man with idiopathic pulmonary fibrosis who had been on home oxygen therapy underwent non-intubated uniportal video-assisted thoracic surgery for intractable spontaneous pneumothorax. During the operation, oxygen was administered using a high-flow nasal cannula at a high flow rate. An air-locking port for single-incision surgery was used to minimize the inflow of air into the pleural cavity. The intrapleural air was continuously suctioned through the chest tube. The air-leak point was easily identified and closed using ligation. Oxygenation was satisfactory throughout the operation.

CONCLUSIONS: Non-intubated uniportal video-assisted thoracic surgery for secondary spontaneous pneumothorax with an air-locking port, continuous pleural suction, and high-flow nasal cannula may achieve satisfactory intraoperative oxygenation in patients with respiratory dysfunction. The intrapleural space can be feasible for surgical manipulation without surgical pneumothorax in non-intubated video-assisted thoracic surgery even when supplied with oxygen at a high flow rate using a high-flow nasal cannula.

PMID:34704179 | DOI:10.1186/s40792-021-01321-5

Sci Rep. 2021 Oct 26;11(1):21114. doi: 10.1038/s41598-021-00717-5.

ABSTRACT

Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis. Periostin is an extracellular matrix protein highly expressed in the lung tissues of IPF. This study aimed to investigate the possibility that periostin secreted by fibroblasts derived from IPF lung might affect proliferation of NSCLC cells. Periostin was more highly expressed and secreted by fibroblasts from diseased human lung with IPF (DIPF) than by normal human lung fibroblasts (NHLF). Cocultivation of NSCLC cells with conditioned media (CM) from DIPF increased proliferation of NSCLC cells through pErk signaling, with this proliferation attenuated by periostin-neutralizing antibodies. Knockdown of integrin β3, a subunit of the periostin receptor, in NSCLC cells suppressed proliferation of NSCLC cells promoted by recombinant human periostin and CM of DIPF. On in vivo examination, DIPF promoted tumor progression more than NHLF, and knockdown of integrin β3 in NSCLC cells suppressed tumor progression promoted by DIPF. Fibroblasts derived from surgical specimens from IPF patients also increased secretion of periostin compared to those from non-IPF patients. Periostin secreted from IPF-activated fibroblasts plays critical roles in the proliferation of NSCLC cells. The present study provides a solid basis for considering periostin-targeted therapy for NSCLC patients with IPF.

PMID:34702952 | DOI:10.1038/s41598-021-00717-5

BMC Bioinformatics. 2021 Oct 26;22(1):524. doi: 10.1186/s12859-021-04412-0.

ABSTRACT

BACKGROUND: Recent development of single cell sequencing technologies has made it possible to identify genes with different expression (DE) levels at the cell type level between different groups of samples. In this article, we propose to borrow information through known biological networks to increase statistical power to identify differentially expressed genes (DEGs).

RESULTS: We develop MRFscRNAseq, which is based on a Markov random field (MRF) model to appropriately accommodate gene network information as well as dependencies among cell types to identify cell-type specific DEGs. We implement an Expectation-Maximization (EM) algorithm with mean field-like approximation to estimate model parameters and a Gibbs sampler to infer DE status. Simulation study shows that our method has better power to detect cell-type specific DEGs than conventional methods while appropriately controlling type I error rate. The usefulness of our method is demonstrated through its application to study the pathogenesis and biological processes of idiopathic pulmonary fibrosis (IPF) using a single-cell RNA-sequencing (scRNA-seq) data set, which contains 18,150 protein-coding genes across 38 cell types on lung tissues from 32 IPF patients and 28 normal controls.

CONCLUSIONS: The proposed MRF model is implemented in the R package MRFscRNAseq available on GitHub. By utilizing gene-gene and cell-cell networks, our method increases statistical power to detect differentially expressed genes from scRNA-seq data.

PMID:34702190 | DOI:10.1186/s12859-021-04412-0

Mech Ageing Dev. 2021 Oct 23:111591. doi: 10.1016/j.mad.2021.111591. Online ahead of print.

ABSTRACT

Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.

PMID:34699859 | DOI:10.1016/j.mad.2021.111591

Chest. 2021 Oct 23:S0012-3692(21)04208-2. doi: 10.1016/j.chest.2021.10.021. Online ahead of print.

ABSTRACT

BACKGROUND: The adherence to and clinical efficacy of pulmonary rehabilitation in idiopathic pulmonary fibrosis (IPF), particularly in comparison to people with chronic obstructive pulmonary disease (COPD), remains uncertain. The objectives of this real-world study were to compare the responses of patients with IPF with a matched group of patients with COPD undergoing the same supervised, outpatient pulmonary rehabilitation program, and to determine whether pulmonary rehabilitation is associated with survival in IPF.

RESEARCH QUESTION: Do people with IPF improve to the same extent with pulmonary rehabilitation as a matched group of individuals with COPD, and are non-completion of and/or non-response to pulmonary rehabilitation associated with one-year all-cause mortality in IPF?

STUDY DESIGN AND METHODS: Using propensity score matching, 163 patients with IPF were matched 1:1 with a control group of 163 patients with COPD referred to pulmonary rehabilitation. We compared between-group pulmonary rehabilitation completion rates and response. Survival status in the IPF cohort was recorded over one-year following pulmonary rehabilitation discharge. Cox proportional-hazards regression explored the association between pulmonary rehabilitation status and all-cause mortality.

RESULTS: Similar pulmonary rehabilitation completion rates (IPF: 69%; COPD: 63%; p=0.24) and improvements in exercise response were observed in both groups with no significant mean (95% confidence interval (CI)) between-group differences in incremental shuttle walk (ISW) change (2 (-18 to 22) meters). Pulmonary rehabilitation non-completion (hazard ratio (HR) (95%CI) 5.62 (2.24 to 14.08)) and non-response (HR (95%CI) 3.91 (1.54 to 9.93)) were independently associated with increased one-year all-cause mortality in IPF.

INTERPRETATION: Compared with a matched group of patients with COPD, this real-word study demonstrates that patients with IPF have similar completion rates and magnitude of response to pulmonary rehabilitation. In IPF, non-completion of and non-response to pulmonary rehabilitation were associated with increased all-cause mortality. These data reinforce the benefits of pulmonary rehabilitation in patients with IPF.

PMID:34699771 | DOI:10.1016/j.chest.2021.10.021