BMC Pulm Med. 2021 Jun 2;21(1):187. doi: 10.1186/s12890-021-01556-w.

ABSTRACT

BACKGROUND: Previous studies suggest that transient receptor potential (TRP) channels and neurogenic inflammation may be involved in idiopathic pulmonary fibrosis (IPF)-related high cough sensitivity, although the details of mechanism are largely unknown. Here, we aimed to further explore the potential mechanism involved in IPF-related high cough sensitivity to capsaicin challenge in a guinea pig model of pulmonary fibrosis induced by bleomycin.

METHODS: Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were employed to measure the expression of TRP channel subfamily A, member 1 (TRPA1) and TRP vanilloid 1 (TRPV1), which may be involved in the cough reflex pathway. Immunohistochemical analysis and RT-qPCR were used to detect the expression of neuropeptides substance P (SP), Neurokinin-1 receptor (NK1R), and calcitonin gene-related peptide (CGRP) in lung tissues. Concentrations of nerve growth factor (NGF), SP, neurokinin A (NKA), neurokinin B (NKB), and brain-derived neurotrophic factor (BDNF) in lung tissue homogenates were measured by ELISA.

RESULTS: Cough sensitivity to capsaicin was significantly higher in the model group than that of the sham group. RT-qPCR and immunohistochemical analysis showed that the expression of TRPA1 and TRPV1 in the jugular ganglion and nodal ganglion, and SP, NK1R, and CGRP in lung tissue was significantly higher in the model group than the control group. In addition, expression of TRP and neurogenic factors was positively correlated with cough sensitivity of the experimental animals.

CONCLUSION: Up-regulated expression of TRPA1 and TRPV1 in the cough reflex pathway and neurogenic inflammation might contribute to the IPF-related high cough sensitivity in guinea pig model.

PMID:34078339 | DOI:10.1186/s12890-021-01556-w

Am J Respir Crit Care Med. 2021 Jun 2. doi: 10.1164/rccm.202012-4418LE. Online ahead of print.

NO ABSTRACT

PMID:34077698 | DOI:10.1164/rccm.202012-4418LE

Ann Am Thorac Soc. 2021 Jun 2. doi: 10.1513/AnnalsATS.202102-197OC. Online ahead of print.

ABSTRACT

RATIONALE: Usual interstitial pneumonia (UIP) is the histopathologic hallmark of idiopathic pulmonary fibrosis (IPF), the prototypical interstitial lung disease (ILD). Diagnosis of IPF requires a typical UIP pattern identified by high-resolution chest CT or lung sampling. A genomic classifier for UIP has been developed to predict histopathologic UIP using lung samples obtained by bronchoscopy.

OBJECTIVE: Perform a systematic review to evaluate genomic classifier testing in the detection of histopathologic UIP to inform new American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Asociación Latinoamericana del Tórax (ALAT) guidelines.

METHODS: Medline, Embase and Cochrane Central Register of Controlled Trials were searched through June 2020. Studies that enrolled patients with ILD and reported the use of genomic classifier testing were selected for inclusion. Data were extracted and pooled across studies via meta-analysis. The quality of the evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.

RESULTS: Genomic classifier testing had a sensitivity of 68% (95% CI 55-73%) and a specificity of 92% (95% CI 81-95%) in predicting the UIP pattern in ILD. Confidence in an IPF diagnosis increased from 43% to 93% in one cohort and from 59% to 89% in another cohort. Agreement in categorical IPF and non-IPF diagnoses measured using a concordance coefficient was 0.75 and 0.64 in the two cohorts. The quality of evidence was moderate for test characteristics and very low for both confidence and agreement.

CONCLUSION: Genomic classifier testing predicts histopathologic UIP in patients with ILD with a specificity of 92% and improves diagnostic confidence; however, sensitivity is only 68% and testing is not widely available.

PMID:34077697 | DOI:10.1513/AnnalsATS.202102-197OC

J Bras Pneumol. 2021 May 31;47(3):e20200096. doi: 10.36416/1806-3756/e20200096. eCollection 2021.

ABSTRACT

Many conditions result in chronic interstitial lung disease (ILD), being classified as fibrosing ILDs, including idiopathic pulmonary fibrosis, connective tissue diseases, sarcoidosis, and fibrotic hypersensitivity pneumonitis. HRCT plays an important role in the clinical evaluation of fibrosing ILDs. Current treatment perspectives are encouraging and reinforce the need for HRCT scans of adequate technical quality for early detection of fibrosing ILD. Despite efforts in this regard, the significance and management of imaging findings of early interstitial lung abnormalities have yet to be clarified. After identification of CT findings consistent with fibrosing ILD, radiologists must be able to identify characteristic morphological patterns and, in some cases, features of specific clinical entities. In cases in which HRCT features are not sufficiently specific for a definitive diagnosis, HRCT can aid in selecting the best site for surgical lung biopsy. CT follow-up is useful for identifying progressive fibrosing ILDs and detecting complications unrelated to the underlying disease, including infections, acute exacerbations, and neoplasms. Automated quantification tools have clinical applicability and are likely to be available for use in imaging analysis in the near future. In addition, incorporation of CT evaluation into scoring systems based on clinical and functional parameters for staging fibrosing disease is likely to become valuable in determining prognosis. Knowledge of the clinical applications of CT evaluation is essential for specialists managing patients with fibrosing ILD and can have a positive impact on the clinical course of the disease.

PMID:34076172 | DOI:10.36416/1806-3756/e20200096

Am J Gastroenterol. 2021 Jun 1;116(6):1189-1200. doi: 10.14309/ajg.0000000000001202.

ABSTRACT

INTRODUCTION: Gastroesophageal reflux plays a significant role in idiopathic pulmonary fibrosis (IPF). Given the morbidity and mortality associated with IPF, understanding the mechanisms responsible for reflux is essential if patients are to receive optimal treatment and management, especially given the lack of clear benefit of antireflux therapies. Our aim was to understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux-a prerequisite of aspiration), and pulmonary function in patients with IPF.

METHODS: We prospectively recruited 35 patients with IPF (aged 53-75 years; 27 men) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment.

RESULTS: Twenty-two patients (63%) exhibited dysmotility, 16 (73%) exhibited ineffective esophageal motility (IEM), and 6 (27%) exhibited esophagogastric junction outflow obstruction. Patients with IEM had more severe pulmonary disease (% forced vital capacity: P = 0.032) and more proximal reflux (P = 0.074) than patients with normal motility. In patients with IEM, intrathoracic pressure inversely correlated with the number of proximal events (r = -0.429; P = 0.098). Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus (r = 0.583; P = 0.018), whereas in patients with normal motility, it inversely correlated with the bolus exposure time (r = -0.478; P = 0.098) and number of proximal events (r = -0.542; P = 0.056). % forced vital capacity in patients with IEM inversely correlated with the percentage of reflux events reaching the proximal esophagus (r = -0.520; P = 0.039) and inspiratory LESP (r = -0.477; P = 0.062) and positively correlated with intrathoracic pressure (r = 0.633; P = 0.008).

DISCUSSION: We have shown that pulmonary function is worse in patients with IEM which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs.

PMID:34074825 | DOI:10.14309/ajg.0000000000001202

BMC Pulm Med. 2021 Jun 1;21(1):184. doi: 10.1186/s12890-021-01522-6.

ABSTRACT

BACKGROUND: Current interstitial lung disease (ILD) diagnostic guidelines assess criteria across clinical, radiologic and pathologic domains. Significant interobserver variation in histopathologic evaluation has previously been shown but the specific source of these discrepancies is poorly documented. We sought to document specific areas of difficulty and develop improved criteria that would reduce overall interobserver variation.

METHODS: Using an internet-based approach, we reviewed selected images of specific diagnostic features of ILD histopathology and whole slide images of fibrotic ILD. After an initial round of review, we confirmed the presence of interobserver variation among our group. We then developed refined criteria and reviewed a second set of cases.

RESULTS: The initial round reproduced the existing literature on interobserver variation in diagnosis of ILD. Cases which were pre-selected as inconsistent with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) were confirmed as such by multi-observer review. Cases which were thought to be in the spectrum of chronic fibrotic ILD for which UIP/IPF were in the differential showed marked variation in nearly all aspects of ILD evaluation including extent of inflammation and extent and pattern of fibrosis. A proposed set of more explicit criteria had only modest effects on this outcome. While we were only modestly successful in reducing interobserver variation, we did identify specific reasons that current histopathologic criteria of fibrotic ILD are not well defined in practice.

CONCLUSIONS: Any additional classification scheme must address interobserver variation in histopathologic diagnosis of fibrotic ILD order to remain clinically relevant. Improvements to tissue-based diagnostics may require substantial resources such as larger datasets or novel technologies to improve reproducibility. Benchmarks should be established for expected outcomes among clinically defined subgroups as a quality metric.

PMID:34074264 | DOI:10.1186/s12890-021-01522-6

Tissue Eng Part C Methods. 2021 Jun 2. doi: 10.1089/ten.TEC.2020.0365. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe health problem characterized by progressive fibroblast proliferation and aberrant vascular remodeling. However, the lack of a suitable in-vitro model that replicates cell-specific changes in IPF tissue is a crucial issue. Three-dimensional (3D) cell cultures allow the mimicking of cell specific functions, facilitating development of novel anti-fibrosis drugs. We have established a layer-by-layer (LbL) cell coating technique that enables the construction of 3D tissue and also vascularized 3D tissue. The present study evaluated whether this technique is beneficial for constructing an in-vitro IPF-3D model using human lung fibroblasts and microvascular endothelial cells. We fabricated an in-vitro IPF-3D model to provide IPF-derived fibroblasts specific function and aberrant microvascular structure using the LbL cell coating technique. We also found that this in-vitro IPF-3D model showed drug responsiveness to two anti-fibrosis drugs that have recently been approved worldwide. This in-vitro IPF-3D model constructed by a LbL cell coating technique would help in the understanding of fibroblast function and the microvascular environment in IPF and could also be used to predict the efficacy of novel anti-fibrosis drugs. .

PMID:34074128 | DOI:10.1089/ten.TEC.2020.0365

Cells. 2021 May 26;10(6):1321. doi: 10.3390/cells10061321.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton's tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.

PMID:34073225 | DOI:10.3390/cells10061321

Int J Mol Sci. 2021 May 31;22(11):5909. doi: 10.3390/ijms22115909.

ABSTRACT

We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male-female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-β (TGF-β) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-β and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.

PMID:34072833 | DOI:10.3390/ijms22115909

Int J Mol Sci. 2021 May 27;22(11):5696. doi: 10.3390/ijms22115696.

ABSTRACT

In the longtime challenge of identifying specific, easily detectable and reliable biomarkers of IPF, BALF proteomics is providing interesting new insights into its pathogenesis. To the best of our knowledge, the present study is the first shotgun proteomic investigation of EVs isolated from BALF of IPF patients. Our main aim was to characterize the proteome of the vesicular component of BALF and to explore its individual impact on the pathogenesis of IPF. To this purpose, ultracentrifugation was chosen as the EVs isolation technique, and their purification was assessed by TEM, 2DE and LC-MS/MS. Our 2DE data and scatter plots showed considerable differences between the proteome of EVs and that of whole BALF and of its fluid component. Analysis of protein content and protein functions evidenced that EV proteins are predominantly involved in cytoskeleton remodeling, adenosine signaling, adrenergic signaling, C-peptide signaling and lipid metabolism. Our findings may suggest a wider system involvement in the disease pathogenesis and support the importance of pre-fractioning of complex samples, such as BALF, in order to let low-abundant proteins-mediated pathways emerge.

PMID:34071777 | DOI:10.3390/ijms22115696

Int J Mol Sci. 2021 May 25;22(11):5599. doi: 10.3390/ijms22115599.

ABSTRACT

Concentration of hyaluronic acid (HA) in the lungs increases in idiopathic pulmonary fibrosis (IPF). HA is involved in the organization of fibrin, fibronectin, and collagen. HA has been proposed to be a biomarker of fibrosis and a potential target for antifibrotic therapy. Hyaluronidase (HD) breaks down HA into fragments, but is a subject of rapid hydrolysis. A conjugate of poloxamer hyaluronidase (pHD) was prepared using protein immobilization with ionizing radiation. In a model of bleomycin-induced pulmonary fibrosis, pHD decreased the level of tissue IL-1β and TGF-β, prevented the infiltration of the lung parenchyma by CD16+ cells, and reduced perivascular and peribronchial inflammation. Simultaneously, a decrease in the concentrations of HA, hydroxyproline, collagen 1, total soluble collagen, and the area of connective tissue in the lungs was observed. The effects of pHD were significantly stronger compared to native HD which can be attributed to the higher stability of pHD. Additional spiperone administration increased the anti-inflammatory and antifibrotic effects of pHD and accelerated the regeneration of the damaged lung. The potentiating effects of spiperone can be explained by the disruption of the dopamine-induced mobilization and migration of fibroblast progenitor cells into the lungs and differentiation of lung mesenchymal stem cells (MSC) into cells of stromal lines. Thus, a combination of pHD and spiperone may represent a promising approach for the treatment of IPF and lung regeneration.

PMID:34070506 | DOI:10.3390/ijms22115599

J Clin Med. 2021 May 25;10(11):2285. doi: 10.3390/jcm10112285.

ABSTRACT

Progressive fibrosing interstitial lung disease (PF-ILD) describes a phenotypic subset of interstitial lung diseases characterized by progressive, intractable lung fibrosis. PF-ILD is separate from, but has radiographic, histopathologic, and clinical similarities to idiopathic pulmonary fibrosis. Two antifibrotic medications, nintedanib and pirfenidone, have been approved for use in patients with idiopathic pulmonary fibrosis. Recently completed randomized controlled trials have demonstrated the clinical efficacy of antifibrotic therapy in patients with PF-ILD. The validation of efficacy of antifibrotic therapy in PF-ILD has changed the treatment landscape for all of the fibrotic lung diseases, providing a new treatment pathway and opening the door for combined antifibrotic and immunosuppressant drug therapy to address both the fibrotic and inflammatory components of ILD characterized by mixed pathophysiologic pathways.

PMID:34070297 | DOI:10.3390/jcm10112285

Molecules. 2021 May 10;26(9):2820. doi: 10.3390/molecules26092820.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease characterized by the proliferation of myofibroblasts and deposition of extracellular matrix that results in irreversible distortion of the lung structure and the formation of focal fibrosis. The molecular mechanism of IPF is not fully understood, and there is no satisfactory treatment. However, most studies suggest that abnormal activation of transforming growth factor-β1 (TGF-β1) can promote fibroblast activation and epithelial to mesenchymal transition (EMT) to induce pulmonary fibrosis. Deglycosylated azithromycin (Deg-AZM) is a compound we previously obtained by removing glycosyls from azithromycin; it was demonstrated to exert little or no antibacterial effects. Here, we discovered a new function of Deg-AZM in pulmonary fibrosis. In vivo experiments showed that Deg-AZM could significantly reduce bleomycin-induced pulmonary fibrosis and restore respiratory function. Further study revealed the anti-inflammatory and antioxidant effects of Deg-AZM in vivo. In vitro experiments showed that Deg-AZM inhibited TGF-β1 signaling, weakened the activation and differentiation of lung fibroblasts, and inhibited TGF-β1-induced EMT in alveolar epithelial cells. In conclusion, our findings show that Deg-AZM exerts antifibrotic effects by inhibiting TGF-β1-induced myofibroblast activation and EMT.

PMID:34068694 | DOI:10.3390/molecules26092820

Cell Biochem Biophys. 2021 May 31. doi: 10.1007/s12013-021-01002-y. Online ahead of print.

ABSTRACT

An overview of Prof. Viswanathan Natarajan's journey in academia as a mentor, teacher, and lipid scientist for nearly 50 years is presented. As a graduate student, Dr. Natarajan interrogated biosynthesis and catabolism of phospholipids in the developing brain; however, in the last five decades, he has been investigating the role of sphingolipids and sphingolipid-metabolizing enzymes in pulmonary endothelial cells, epithelial cells, and fibroblasts under normal conditions and during various lung pathologies such as sepsis, asthma, pulmonary hypertension, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, and lung cancer. His recent work on sphingosine-1-phosphate and lysophosphatidic acid metabolism in pre-clinical animal models has identified small molecule inhibitors in the signaling pathways that could have therapeutic potential in ameliorating pulmonary fibrosis, hypoxia-induced pulmonary hypertension, lung cancer, and bronchopulmonary dysplasia. Future research in bioactive lipids in combination with OMICS should unravel the importance of various lipid mediators as modulators of cell function under normal and pathological conditions.

PMID:34060023 | DOI:10.1007/s12013-021-01002-y

Adv Ther. 2021 May 31. doi: 10.1007/s12325-021-01768-w. Online ahead of print.

ABSTRACT

INTRODUCTION: In 2015, Boehringer Ingelheim (BI) created a support program for patients with idiopathic pulmonary fibrosis (IPF) treated with nintedanib, to help patients obtain their prescription, learn about their disease and medication, and provide support in the management of their IPF. The purpose of this study was to measure the impact of the program on nintedanib persistence among patients with IPF newly treated with the medication.

METHODS: A retrospective cohort analysis of BI Pharmaceuticals, Inc.'s Specialty Pharmacy (SP) database was conducted. Patients at least 18 years of age, newly treated with nintedanib from April 1, 2015 to January 31, 2018, and with at least one diagnosis of IPF were included in the study; earliest nintedanib prescription was the index date. Patients were classified into two mutually exclusive cohorts: enrolled in the patient support program within 60 days of index or not enrolled in the program at any time. The cohorts were compared in terms of patient characteristics, time to nintedanib discontinuation (a gap of more than 60 days between refills), and proportion of persistent patients at 6, 12, 18, and 24 months after index. Time to discontinuation was compared between the cohorts using Kaplan-Meier analysis. A multivariable Cox proportional hazards model assessed the impact of program participation on time to discontinuation within the first 12 months.

RESULTS: A total of 3114 enrolled and 9388 non-enrolled patients were identified. The proportion of patients persistent on nintedanib was higher among enrolled patients throughout the post-index period (57.8% vs. 49.7% at 6 months, 34.7% vs. 28.9% at 12 months; p < 0.05). In adjusted analyses, being enrolled in the program was associated with a 21% decreased hazard of discontinuing nintedanib over the first-year post-index [hazard ratio (HR) = 0.79, 95% CI 0.75-0.83, p < 0.05).

CONCLUSION: Real-world evidence suggests a persistence benefit for patients with IPF treated with nintedanib who are enrolled in the patient support program.

PMID:34057677 | DOI:10.1007/s12325-021-01768-w

JMIR Public Health Surveill. 2021 May 31;7(5):e24199. doi: 10.2196/24199.

ABSTRACT

BACKGROUND: Patients use Facebook as a resource for medical information. We analyzed posts on idiopathic pulmonary fibrosis (IPF)-related Facebook groups and pages for the presence of guideline content, user engagement, and usefulness.

OBJECTIVE: The objective of this study was to describe and analyze posts from Facebook groups and pages that primarily focus on IPF-related content.

METHODS: Cross-sectional analysis was performed on a single date, identifying Facebook groups and pages resulting from separately searching "IPF" and "idiopathic pulmonary fibrosis." For inclusion, groups and pages needed to meet either search term and be in English, publicly available, and relevant to IPF. Every 10th post was assessed for general characteristics, source, focus, and user engagement metrics. Posts were analyzed for presence of IPF guideline content, useful scientific information (eg, scientific publications), useful support information (eg, information about support groups), and potentially harmful information.

RESULTS: Eligibility criteria were met by 12 groups and 27 pages, leading to analysis of 523 posts. Of these, 42% contained guideline content, 24% provided useful support, 20% provided useful scientific information, and 5% contained potentially harmful information. The most common post source was nonmedical users (85%). Posts most frequently focused on IPF-related news (29%). Posts containing any guideline content had fewer likes or comments and a higher likelihood of containing potentially harmful content. Posts containing useful supportive information had more likes, shares, and comments.

CONCLUSIONS: Facebook contains useful information about IPF, but posts with misinformation and less guideline content have higher user engagement, making them more visible. Identifying ways to help patients with IPF discriminate between useful and harmful information on Facebook and other social media platforms is an important task for health care professionals.

PMID:34057425 | DOI:10.2196/24199

Am J Hosp Palliat Care. 2021 May 31:10499091211018664. doi: 10.1177/10499091211018664. Online ahead of print.

ABSTRACT

OBJECTIVES: Interstitial lung disease (ILD) is a debilitating and life-limiting condition, requiring multi-disciplinary care. While guidelines recommend early specialist palliative care referral to improve symptoms and quality of life, few patients access such care towards the end-of-life. This study aimed to explore clinicians' perspectives regarding specialist palliative care and opioids to understand barriers to optimal care and guide clinical practice improvement initiatives.

METHODS: A cross-sectional, exploratory, qualitative study was undertaken with Australian respiratory clinicians caring for people with ILD (n = 17). In-depth, semi-structured interviews were audio-recorded, transcribed verbatim and coded. Thematic analysis was undertaken to extrapolate recurring ideas from the data.

RESULTS: Four themes were identified: 1) understanding how to improve patient care and support, 2) the need to dispel stigmatized beliefs and misconceptions, 3) the importance of trusted relationships and good communication and 4) the challenges of navigating the health-care system. Participants discussed the need to implement early specialist palliative care and symptom palliation to alleviate symptoms, provide emotional support and augment quality of life. Participants described challenges accessing palliative care and opioids due to stigmatized beliefs amongst patients and clinicians and difficulties navigating the health-care system. Trusted therapeutic relationships with patients and strong inter-disciplinary partnerships with collaborative education and communication were perceived to improve patients' access to symptom palliation.

CONCLUSION: Specialist palliative care and opioids were believed to improve patients' quality of life, however, many barriers can make accessing such care challenging. To address these issues, multi-disciplinary collaboration, high-quality communication and trusted therapeutic relationships are crucial throughout the ILD illness journey.

PMID:34056929 | DOI:10.1177/10499091211018664

Cureus. 2021 Apr 25;13(4):e14684. doi: 10.7759/cureus.14684.

ABSTRACT

Introduction Interstitial lung disease (ILD) is a heterogeneous group of over 200 parenchymal lung diseases with a myriad of etiologies. Interstitial lung disease registries from around the world show varying prevalence and incidence of these diseases. The aim of this study was to determine the epidemiology and characteristics of ILD in Pakistan. Methods This web-based registry, which is the first multicenter registry of ILD from Pakistan, recruited patients from 10 centers of five major cities between January 2016 and March 2019. Results A total of 744 patients were enrolled in the registry. The five most frequent ILDs were idiopathic pulmonary fibrosis (IPF) 34.4%, hypersensitivity pneumonitis (HP) - 17.7%, idiopathic nonspecific interstitial pneumonitis (iNSIP) - 16.8%, connective tissue disease-associated ILD (CTD-ILD) - 16.3%, and sarcoidosis - 9.1%. Conclusion Idiopathic pulmonary fibrosis is the most prevalent ILD in Pakistan, followed by HP and iNSIP. An ongoing prospective registry with longitudinal follow-up will help us further elaborate on the clinical characteristics, treatment, and survival outcome of patients with ILD.

PMID:34055529 | PMC:PMC8149777 | DOI:10.7759/cureus.14684

NPJ Genom Med. 2021 May 28;6(1):36. doi: 10.1038/s41525-021-00198-5.

ABSTRACT

Telomere biology disorders (TBD) are a heterogeneous group of diseases arising from germline mutations affecting genes involved in telomere maintenance. Telomeres are DNA-protein structures at chromosome ends that maintain chromosome stability; their length affects cell replicative potential and senescence. A constellation of bone marrow failure, pulmonary fibrosis, liver cirrhosis and premature greying is suggestive, however incomplete penetrance results in highly variable manifestations, with idiopathic pulmonary fibrosis as the most common presentation. Currently, the true extent of TBD burden is unknown as there is no established diagnostic criteria and the disorder often is unrecognised and underdiagnosed. There is no gold standard for measuring telomere length and not all TBD-related mutations have been identified. There is no specific cure and the only treatment is organ transplantation, which has poor outcomes. This review summarises the current literature and discusses gaps in understanding and areas of need in managing TBD.

PMID:34050178 | DOI:10.1038/s41525-021-00198-5

Eur Respir J. 2021 May 28:2100267. doi: 10.1183/13993003.00267-2021. Online ahead of print.

ABSTRACT

Alveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic-gain-of-function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation.We performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces the in vivo phenotype and validated findings in human primary alveolar organoids.We show that wild-type SFTPC takes an unexpected indirect trafficking route via the plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate.These data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development.

PMID:34049951 | DOI:10.1183/13993003.00267-2021