Growth factors in lung development and disease: friends or foe?

Growth factors mediate tissue interactions and regulate a variety of cellular functions that are critical for normal lung development and homeostasis. Besides their involvement in lung pattern formation, growth and cell differentiation during organogenesis, these factors have been also implicated in modulating injury-repair responses of the adult lung. Altered expression of growth factors, such as transforming growth factor β1, vascular endothelial growth factor and epidermal growth factor, and/or their receptors, has been found in a number of pathological lung conditions. In this paper, we discuss the dual role of these molecules in mediating beneficial feedback responses or responses that can further damage lung integrity; we shall also discuss the basis for their prospective use as therapeutic agents

A case of pulmonary hemorrhage and renal failure

Background: Alveolar hemorrhage can be seen in many vasculitic disorders. However, granulomatosis polyangiitis (formerly Wegener’s granulomatosis) uncommonly presents with life threatening alveolar hemorrhage and has only been discussed in a few case reports [1]. Case Presentation: A 53 year old Caucasian male presented with hemoptysis and profound anemia. Two weeks prior, he had presented with abdominal pain with normal renal function and numerous pulmonary nodules. During the current admission, the patient was hypoxic with acute renal failure requiring hemodialysis. Urine sediment demonstrated dysmorphic red blood cells. A bronchoscopy revealed diffuse alveolar hemorrhage. The diagnosis of pulmonary-renal syndrome was made and therapeutic plasma exchange was initiated. Laboratory studies were significant for a c-ANCA titer positive at 1:640 FIU and anti-proteinase (PR)-3 antibody titer positive with 78.3 U/ml. Renal biopsy demonstrated necrotizing crescentic glomerulonephritis. A diagnosis of granulomatosis vasculitis was determined. Conclusion: Alveolar hemorrhage is rare to be the presenting symptom of granulomatosis vasculitis where the common presenting features are recurrent sinusitis, epistaxis, chronic otitis media or rhinitis. Physicians should consider granulomatosis vasculitis in the differential diagnosis of pulmonary-renal syndrome presenting with hemoptysis

Synthesis, characterization, molecular docking studies and biological activity ofcoumarin linked 2-pyridone heterocycles

In the present paper, the synthesis, characterization, antimicrobial activity and in silico molecular docking study of6-((arylidene)amino)-4-(4-chlorophenyl)-2-oxo-1-((1-(2-oxo-2H-chromen-3-yl)ethylidene)amino)-1,2-dihydropyridine-3,5-dicarbonitriles 4a-o have been reported. Compounds 4d, 4g, 4j, 4k, 4m and 4o show significant activity. Structuredetermination of the synthesized compounds has been done by the standard spectroscopic techniques. It is observed thatbiological activity is influenced by electronic environment of the molecules. Electron withdrawing group at para positionplays a major role for enhancing the biological activity for antibacterial activity and the electron donating group at paraposition for antifungal activity. Compounds 4a-o have been further evaluated for cytotoxicity on HeLa cells. From thecytotoxicity results, compounds have been found to possess low cytotoxicity with potent antimicrobial activity

Synthesis, characterization, molecular docking studies and biological activity of coumarin linked 2-pyridone heterocycles

231-237In the present paper, the synthesis, characterization, antimicrobial activity and in silico molecular docking study of 6-((arylidene)amino)-4-(4-chlorophenyl)-2-oxo-1-((1-(2-oxo-2H-chromen-3-yl)ethylidene)amino)-1,2-dihydropyridine-3,5-dicarbonitriles 4a-o have been reported. Compounds 4d, 4g, 4j, 4k, 4m and 4o show significant activity. Structure determination of the synthesized compounds has been done by the standard spectroscopic techniques. It is observed that biological activity is influenced by electronic environment of the molecules. Electron withdrawing group at para position plays a major role for enhancing the biological activity for antibacterial activity and the electron donating group at para position for antifungal activity. Compounds 4a-o have been further evaluated for cytotoxicity on HeLa cells. From the cytotoxicity results, compounds have been found to possess low cytotoxicity with potent antimicrobial activity

Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease

Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2. In the context of MV-O2, attenuated PDGF signal

Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis.

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer's safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6

An integrated cell atlas of the lung in health and disease

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas

Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate investigation of pathologies including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. We generated long-term feeder-free, chemically defined culture of distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids exhibited AT1 transdifferentiation potential while basal cell organoids developed lumens lined by differentiated club and ciliated cells. Single cell analysis of basal organoid KRT5+ cells revealed a distinct ITGA6+ITGB4+ mitotic population whose proliferation further segregated to a TNFRSF12Ahi subfraction comprising ~10% of KRT5+ basal cells, residing in clusters within terminal bronchioles and exhibiting enriched clonogenic organoid growth activity. Distal lung organoids were created with apical-out polarity to display ACE2 on the exposed external surface, facilitating SARS-CoV-2 infection of AT2 and basal cultures and identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and establishes a facile in vitro organoid model for human distal lung infections including COVID-19-associated pneumonia

The human body at cellular resolution: the NIH Human Biomolecular Atlas Program

Abstract: Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions

Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019 : a systematic analysis for the Global Burden of Disease Study 2020, Release 1

Background Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. Methods For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dosespecific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in countryreported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. Findings By 2019, global coverage of third-dose DTP (DTP3; 81.6% [95% uncertainty interval 80.4-82 .7]) more than doubled from levels estimated in 1980 (39.9% [37.5-42.1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38.5% [35.4-41.3] in 1980 to 83.6% [82.3-84.8] in 2019). Third- dose polio vaccine (Pol3) coverage also increased, from 42.6% (41.4-44.1) in 1980 to 79.8% (78.4-81.1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56.8 million (52.6-60. 9) to 14.5 million (13.4-15.9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. Interpretation After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe