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Polysulfated Hyaluronan GlycoMira-1111 Inhibits Elastase and Improves Rheology in Cystic Fibrosis Sputum Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Apparao B. Kummarapurugu; Shuo Zheng; Abigail Pulsipher; Justin R. Savage; Jonathan Ma; Bruce K. Rubin; Thomas P. Kennedy; Judith A. Voynow
Cystic fibrosis (CF) lung disease is marked by high concentrations of neutrophil elastase (NE) and DNA polymers; both factors contribute to airway disease. Although inhaled recombinant human dornase alfa reduces the frequency of CF pulmonary exacerbations, it also increases free NE activity in the sputum. There are no approved anti-NE therapies for patients with CF. We investigated whether synthetic
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CD44v3-Positive Intermediate Progenitor Cells Contribute to Airway Goblet Cell Hyperplasia Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Sang-Nam Lee; Su-Jin Kim; Seol Ah Yoon; Ji Min Song; Ji-Suk Ahn; Hyung Chul Kim; Augustine M. K. Choi; Joo-Heon Yoon
In allergic airway diseases, intermediate progenitor cells (IPCs) increase in number in the surface epithelium. IPCs arise from basal cells, the origin of hallmark pathological changes, including goblet cell hyperplasia and mucus hypersecretion. Thus, targeting IPCs will benefit future treatment of allergic airway diseases. However, the lack of adequate cell surface markers for IPCs limits their identification
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FK506-Binding Protein 13 Expression Is Upregulated in Interstitial Lung Disease and Correlated with Clinical Severity. A Potentially Protective Role Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Victor Tat; Ehab A. Ayaub; Anmar Ayoub; Megan Vierhout; Safaa Naiel; Manreet K. Padwal; Soumeya Abed; Olivia Mekhael; Karun Tandon; Spencer D. Revill; Tamana Yousof; Pierre-Simon Bellaye; Philipp S. Kolb; Anna Dvorkin-Gheva; Asghar Naqvi; Jean-Claude Cutz; Nathan Hambly; Jiro Kato; Martha Vaughan; Joel Moss; Martin R. J. Kolb; Kjetil Ask
Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. We sought to investigate the role of FKBP13 (13-kD FK506-binding protein), an endoplasmic reticulum–resident molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy specimens from
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BK Channels Regulate LPS-induced CCL-2 Release from Human Pulmonary Endothelial Cells Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Tatiana Zyrianova; Benjamin Lopez; Andy Liao; Charles Gu; Leanne Wong; Michela Ottolia; Riccardo Olcese; Andreas Schwingshackl
We recently established a role for the stretch-activated two-pore-domain K+ (K2P) channel TREK-1 (K2P2.1) in inflammatory cytokine secretion using models of hyperoxia-, mechanical stretch–, and TNF-α–induced acute lung injury. We have now discovered the expression of large conductance, Ca2+-activated K+ (BK) channels in human pulmonary microvascular endothelial cells and primary human alveolar epithelial
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Olfactomedin 4–Positive Neutrophils Are Upregulated after Hemorrhagic Shock Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Al-Faraaz Kassam; Nick C. Levinsky; Jaya P. Mallela; Kira Angel; Amy Opoka; Patrick Lahni; Rashmi D. Sahay; Lin Fei; Vanessa Nomellini; Hector R. Wong; Matthew N. Alder
Neutrophils are vital to both the inflammatory cascade and tissue repair after an injury. Neutrophil heterogeneity is well established but there is less evidence for significant, different functional roles for neutrophil subsets. OLFM4 (Olfactomedin-4) is expressed by a subset of neutrophils, and high expression of OLFM4 is associated with worse outcomes in patients with sepsis and acute respiratory
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Role of Dual Oxidases in Ventilator-induced Lung Injury Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Laura Cagle; Angela Linderholm; Lisa Franzi; Sabrina Hoehne; Jerold Last; Nicholas Kenyon; Beate Illek; Richart Harper
Positive-pressure ventilation results in ventilator-induced lung injury, and few therapeutic modalities have been successful at limiting the degree of injury to the lungs. Understanding the primary drivers of ventilator-induced lung injury will aid in the development of specific treatments to ameliorate the progression of this syndrome. There are conflicting data for the role of neutrophils in acute
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MicroRNA-574-5p Attenuates Acute Respiratory Distress Syndrome by Targeting HMGB1 Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Binchan He; Wei Zhou; Yuwen Rui; Lulu Liu; Bilin Chen; Xin Su
Acute respiratory distress syndrome (ARDS) is a critical condition with high mortality. HMGB1 (high-mobility group protein B1) is one of the key proinflammatory factors in the ARDS “inflammatory storm.” According to previous studies, some microRNAs (miRNAs) play important roles in this process. We aimed to determine the contributing miRNAs targeting the expression and release of HMGB1. miRNA expression
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ADAM17 Deficiency Protects against Pulmonary Emphysema Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Mohamed I. Saad; Louise McLeod; Christopher Hodges; Ross Vlahos; Stefan Rose-John; Saleela Ruwanpura; Brendan J. Jenkins
Pulmonary emphysema is the major debilitating component of chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality worldwide. The ADAM17 (A disintegrin and metalloproteinase 17) protease mediates inflammation via ectodomain shedding of numerous proinflammatory cytokines, cytokine receptors, and adhesion molecules; however, its role in the pathogenesis of emphysema
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IL-36 Cytokines Promote Inflammation in the Lungs of Long-Term Smokers Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Melissa A. Kovach; Karlhans Che; Bettina Brundin; Anders Andersson; Helga Asgeirsdottir; Médea Padra; Sara K. Lindén; Ingemar Qvarfordt; Michael W. Newstead; Theodore J. Standiford; Anders Lindén
Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers
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The Interplay of the Genetic Architecture, Aging, and Environmental Factors in the Pathogenesis of Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-02-01 Annie Pardo; Moisés Selman
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease of indeterminate etiology and limited therapeutic options. The initiation, development, and progression of IPF are influenced by genetic predisposition, aging, and host and environmental factors, but the magnitude of the contribution of each of them and the sequence of the pathogenic events are uncertain. Current evidence indicates
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Electronic-Cigarette Use Alters Nasal Mucosal Immune Response to Live-attenuated Influenza Virus. A Clinical Trial Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Meghan E. Rebuli; Ellen Glista-Baker; Jessica R. Hoffman; Parker F. Duffney; Carole Robinette; Adam M. Speen; Erica A. Pawlak; Radhika Dhingra; Terry L. Noah; Ilona Jaspers
Inhalation of tobacco smoke has been linked to increased risk of viral infection, such as influenza. Inhalation of electronic-cigarette (e-cigarette) aerosol has also recently been linked to immune suppression within the respiratory tract, specifically the nasal mucosa. We propose that changes in the nasal mucosal immune response modify antiviral host-defense responses in e-cigarette users. Nonsmokers
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Lung Myofibroblasts Promote Macrophage Profibrotic Activity through Lactate-induced Histone Lactylation Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Huachun Cui; Na Xie; Sami Banerjee; Jing Ge; Dingyuan Jiang; Tapan Dey; Qiana L. Matthews; Rui-Ming Liu; Gang Liu
Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a
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Targeting Jak–Stat Signaling in Experimental Pulmonary Hypertension Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Dinesh Yerabolu; Astrid Weiss; Baktybek Kojonazarov; Mario Boehm; Beate Christiane Schlueter; Clemens Ruppert; Andreas Günther; Danny Jonigk; Friedrich Grimminger; Hossein-Ardeschir Ghofrani; Werner Seeger; Norbert Weissmann; Ralph Theo Schermuly
In pulmonary arterial hypertension (PAH), progressive structural remodeling accounts for the pulmonary vasculopathy including the obliteration of the lung vasculature that causes an increase in vascular resistance and mean blood pressure in the pulmonary arteries ultimately leading to right heart failure–mediated death. Deciphering the molecular details of aberrant signaling of pulmonary vascular cells
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Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which Is Associated with Increased Severity of Murine Acute Respiratory Distress Syndrome Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Zhenguo Zeng; Weiguo Chen; Alexander Moshensky; Zaid Shakir; Raheel Khan; Laura E. Crotty Alexander; Lorraine B. Ware; C. M. Aldaz; Jeffrey R. Jacobson; Steven M. Dudek; Viswanathan Natarajan; Roberto F. Machado; Sunit Singla
A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease.
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Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Kun Han; Robert V. Blair; Naoki Iwanaga; Fengming Liu; Kasi E. Russell-Lodrigue; Zhongnan Qin; Cecily C. Midkiff; Nadia A. Golden; Lara A. Doyle-Meyers; Mohammad E. Kabir; Kristin E. Chandler; Kellie L. Cutrera; Mi Ren; Christopher J. Monjure; Gabrielle Lehmicke; Tracy Fischer; Brandon Beddingfield; Alanna G. Wanek; Angela Birnbaum; Nicholas J. Maness; Chad J. Roy; Prasun K. Datta; Jay Rappaport; Jay
Preclinical mouse models that recapitulate some characteristics of coronavirus disease (COVID-19) will facilitate focused study of pathogenesis and virus–host responses. Human agniotensin-converting enzyme 2 (hACE2) serves as an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect people via binding to envelope spike proteins. Herein we report development and characterization
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Neutrophil Extracellular Traps Increase Airway Mucus Viscoelasticity and Slow Mucus Particle Transit Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Rosalie S. Linssen; Guihong Chai; Jonathan Ma; Apparao B. Kummarapurugu; Job B. M. van Woensel; Reinout A. Bem; Logan Kaler; Gregg A. Duncan; Lei Zhou; Bruce K. Rubin; Qingguo Xu
Mucus obstruction is a key feature of many inflammatory airway diseases. Neutrophil extracellular traps (NETs) are released upon neutrophil stimulation and consist of extracellular chromatin networks studded with cytotoxic proteins. When released in the airways, these NETs can become part of the airway mucus. We hypothesized that the extracellular DNA and/or oxidative stress (e.g., by the release of
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Opsin 3–Gαs Promotes Airway Smooth Muscle Relaxation Modulated by G Protein Receptor Kinase 2 Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Amy D. Wu; William Dan; Yi Zhang; Shruti Vemaraju; Brian A. Upton; Richard A. Lang; Ethan D. Buhr; Dan E. Berkowitz; George Gallos; Charles W. Emala; Peter D. Yim
Recently, we characterized blue light–mediated relaxation (photorelaxation) of airway smooth muscle (ASM) and implicated the involvement of opsin 3 (OPN3), an atypical opsin. In the present study, we characterized the cellular signaling mechanisms of photorelaxation. We confirmed the functional role of OPN3 in blue light photorelaxation using trachea from OPN3 null mice (maximal relaxation 52 ± 13%
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TMEM16A Mediates Mucus Production in Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Inês Cabrita; Roberta Benedetto; Podchanart Wanitchakool; Joana Lerias; Raquel Centeio; Jiraporn Ousingsawat; Rainer Schreiber; Karl Kunzelmann
TMEM16A is a Ca2+-activated chloride channel that was shown to enhance production and secretion of mucus in inflamed airways. It is, however, not clear whether TMEM16A directly supports mucus production, or whether mucin and TMEM16A are upregulated independently during inflammatory airway diseases such as asthma and cystic fibrosis (CF). We examined this question using BCi-NS1 cells, a human airway
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Aspergillus fumigatus Recognition by Dendritic Cells Negatively Regulates Allergic Lung Inflammation Through a TLR2/MyD88 Pathway. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Pauline Percier,Sofie De Prins,Giresse Tima,Rudi Beyaert,Johan Grooten,Marta Romano,Olivier Denis
Aspergillus fumigatus is an opportunistic fungal pathogen responsible for a spectrum of clinical manifestations. Dendritic cells recognize pathogen-associated molecular patterns of Aspergillus via two main receptor families, Toll-like receptors (TLRs) and C-type lectin receptors (CLR). Here, the importance of TLR and CLR signaling in the regulation of T-helper cell type 2 (Th2) responses was analyzed
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Mechanisms Targeting the Unfolded Protein Response in Asthma. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Sanaz Dastghaib,P Sravan Kumar,Sajjad Aftabi,Gautam Damera,Azadeh Dalvand,Adel Sepanjnia,Mohammad Kiumarsi,Mohamad-Reza Aghanoori,Sukhwinder Singh Sohal,Sudharsan R Ande,Javad Alizadeh,Pooneh Mokarram,Saeid Ghavami,Pawan Sharma,Amir A Zeki
Lung cells are constantly exposed to various internal and external stressors that disrupt protein homeostasis. To cope with these stimuli, cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR). UPR stressors can impose greater protein secretory demands on the endoplasmic reticulum (ER), resulting in the development, differentiation, and survival of these cell
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The Gut-Lung Axis in Systemic Inflammation: Role of Mesenteric Lymph as Conduit. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2021-01-01 Yonggang Ma,Xiaoyuan Yang,Victor Chatterjee,Mack Wu,Sarah Y Yuan
Emerging evidence shows that after injury or infection, the mesenteric lymph acts as a conduit for gut-derived toxic factors to enter the blood circulation, causing systemic inflammation and acute lung injury. Neither the cellular and molecular identity of lymph factors nor their mechanisms of action have been well understood and thus have become a timely topic of investigation. This review will first
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FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Naoya Miyashita,Masafumi Horie,Hiroshi I Suzuki,Minako Saito,Yu Mikami,Kenichi Okuda,Richard C Boucher,Maho Suzukawa,Akira Hebisawa,Akira Saito,Takahide Nagase
Fibroblasts provide a structural framework for multiple organs and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of FOXL1 (forkhead box L1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high FOXL1 transcripts associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, which is
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Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Ryo Ishii,Kenichi Okumura,Yohei Akazawa,Manpreet Malhi,Ryota Ebata,Mei Sun,Tao Fujioka,Hideyuki Kato,Osami Honjo,Golam Kabir,Wolfgang M Kuebler,Kim Connelly,Jason T Maynes,Mark K Friedberg
The potential benefit of heart rate reduction (HRR), independent of β-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding
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Cellular Microenvironment Stiffness Regulates Eicosanoid Production and Signaling Pathways. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Asres Berhan,Trudi Harris,Jade Jaffar,Fernando Jativa,Shenna Langenbach,Ingrid Lönnstedt,Monther Alhamdoosh,Milica Ng,Peter Lee,Glen Westall,Nick Wilson,Michael Wilson,Alastair G Stewart
Pathological changes in the biomechanical environment are implicated in the progression of idiopathic pulmonary fibrosis (IPF). Stiffened matrix augments fibroblast proliferation and differentiation and activates TGF-β1 (transforming growth factor-β1). Stiffened matrix impairs the synthesis of the antifibrogenic lipid mediator prostaglandin E2 (PGE2) and reduces the expression of the rate-limiting
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PAD4 Deficiency Improves Bleomycin-induced Neutrophil Extracellular Traps and Fibrosis in Mouse Lung. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Masaki Suzuki,Jun Ikari,Rie Anazawa,Nozomi Tanaka,Yusuke Katsumata,Ayako Shimada,Eiko Suzuki,Koichiro Tatsumi
Excessive release of neutrophil extracellular traps (NETs) has been implicated in several organ fibrosis, including pulmonary fibrosis. NETs constitute a phenomenon in which decorated nuclear chromatin with cytosolic proteins is released into the extracellular space. PAD4 (peptidylarginine deiminase 4) plays an important role in the formation of NETs. However, the role of NETs in the pathogenesis of
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Prenatal Exposure to E-Cigarette Aerosols Leads to Sex-dependent Pulmonary Extracellular Matrix Remodeling and Myogenesis in Offspring Mice. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Qixin Wang,Isaac K Sundar,Jason L Blum,Jill R Ratner,Joseph H Lucas,Tsai-Der Chuang,Ying Wang,Jie Liu,Virender K Rehan,Judith T Zelikoff,Irfan Rahman
Electronic-cigarette (e-cig) vaping is a serious concern, as many pregnant women who vape consider it safe. However, little is known about the harmful effects of prenatal e-cig exposure on adult offspring, especially on extracellular-matrix (ECM) deposition and myogenesis in the lungs of offspring. We evaluated the biochemical and molecular implications of maternal exposure during pregnancy to e-cig
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Lower PDL1/2 and AXL Expression on Lung Myeloid Cells Suggests Inflammatory Bias in Smoking and COPD. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Sreelakshmi Vasudevan,Joshua J Vásquez,Wenxuan Chen,Brandon Aguilar-Rodriguez,Erene C Niemi,Siyang Zeng,Whitney Tamaki,Mary C Nakamura,Mehrdad Arjomandi
Lung myeloid cells are important in pulmonary immune homeostasis and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Multiparameter immunophenotypic characterization of these cells is challenging because of their autofluorescence and diversity. We evaluated the immunophenotypic landscape of airway myeloid cells in COPD using time of flight mass cytometry. Cells from BAL, which
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Cigarillos Compromise the Mucosal Barrier and Protein Expression in Airway Epithelia. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Sabri H Abdelwahab,Boris Reidel,Jessica R Martin,Arunava Ghosh,James E Keating,Prashamsha Haridass,Jerome Carpenter,Gary L Glish,Robert Tarran,Claire M Doerschuk,Mehmet Kesimer
Smoking remains a leading cause of preventable morbidity and mortality worldwide. Despite a downward trend in cigarette use, less-regulated tobacco products, such as cigarillos, which are often flavored to appeal to specific demographics, such as younger people, are becoming increasingly popular. Cigar/cigarillo smoking has been considered a safer alternative to cigarettes; however, the health risks
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Immune Modulation to Improve Survival of Viral Pneumonia in Mice. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Shradha Wali,Jose R Flores,Ana Maria Jaramillo,David L Goldblatt,Jezreel Pantaleón García,Michael J Tuvim,Burton F Dickey,Scott E Evans
Viral pneumonias remain global health threats, as exemplified in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, requiring novel treatment strategies both early and late in the disease process. We have reported that mice treated before or soon after infection with a combination of inhaled Toll-like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) are broadly protected against
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Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Shotaro Matsumoto,Xiaohui Fang,Maret G Traber,Kirk D Jones,Charles Langelier,Paula Hayakawa Serpa,Carolyn S Calfee,Michael A Matthay,Jeffrey E Gotts
Electronic-cigarette, or vaping, product use–associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized
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Single Nucleus RNASeq Profiling of Mouse Lung: Reduced Dissociation Bias and Improved Rare Cell Type Detection Compared with Single Cell RNASeq. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Jeffrey R Koenitzer,Haojia Wu,Jeffrey J Atkinson,Steven L Brody,Benjamin D Humphreys
Single-cell RNA sequencing (scRNASeq) has advanced our understanding of lung biology, but its utility is limited by the need for fresh samples, loss of cell types by death or inadequate dissociation, and transcriptional stress responses induced during tissue digestion. Single-nucleus RNA sequencing (snRNASeq) has addressed these deficiencies in other tissues, but no protocol exists for lung tissue
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Application of Proteomics in Sarcoidosis. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-12-01 Candace R Guerrero,Lisa A Maier,Timothy J Griffin,LeeAnn Higgins,Charles P Najt,David M Perlman,Maneesh Bhargava
Sarcoidosis is a multisystem disease with heterogeneity in manifestations and outcomes. System-level studies leveraging “omics” technologies are expected to define mechanisms contributing to sarcoidosis heterogeneous manifestations and course. With improvements in mass spectrometry (MS) and bioinformatics, it is possible to study protein abundance for a large number of proteins simultaneously. Contemporary
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The Proinflammatory Activity of Structurally Altered Elastic Fibers. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Shadi Mehraban,George Gu,Shuren Ma,Xingjian Liu,Gerard Turino,Jerome Cantor
The mechanisms responsible for the increased loss of pulmonary function following acute lung inflammation in chronic obstructive pulmonary disease remain poorly understood. To investigate this process, our laboratory developed a hamster model that uses a single intratracheal instillation of LPS to superimpose an inflammatory response on lungs treated with intratracheal elastase 1 week earlier. Parameters
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Increasing Sphingolipid Synthesis Alleviates Airway Hyperreactivity. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Andrea F Heras,Arul Veerappan,Randi B Silver,Charles W Emala,Tilla S Worgall,Jose Perez-Zoghbi,Stefan Worgall
Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (serine palmitoyl-CoA transferase)
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Cellular Source of Cysteinyl Leukotrienes following Chlorine Exposure. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Toby McGovern,Satoshi Ano,Soroor Farahnak,Sarah McCuaig,James G Martin
Exposure of mice to high concentrations of chlorine leads to the synthesis of cysteinyl leukotrienes (cysLTs). CysLTs contribute to chlorine-induced airway hyperresponsiveness. The aim of the current study was to determine the cellular source of the cysLTs. To achieve this aim, we exposed mice to 100 ppm of chlorine for 5 minutes. Intranasal instillation of clodronate in liposomes and of diphtheria
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DNGR1-Cre-mediated Deletion of Tnfaip3/A20 in Conventional Dendritic Cells Induces Pulmonary Hypertension in Mice. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Thomas Koudstaal,Jennifer A C van Hulst,Tridib Das,Stefan F H Neys,Daphne Merkus,Ingrid M Bergen,Michiel A de Raaf,Harm Jan Bogaard,Louis Boon,Geert van Loo,Joachim G J V Aerts,Karin A Boomars,Mirjam Kool,Rudi W Hendriks
Chronic perivascular inflammation is a prominent feature in the lungs of idiopathic pulmonary arterial hypertension. Although the proportions of conventional dendritic cells (cDCs) and plasmacytoid DCs are increased in idiopathic pulmonary arterial hypertension lungs, it remains unknown whether activated cDCs play a pathogenic role. The Tnfaip3 gene encodes the ubiquitin-binding protein A20, which
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Role of Hypoxia-Inducible Factors in Regulating Right Ventricular Function and Remodeling during Chronic Hypoxia-Induced Pulmonary Hypertension. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Kimberly A Smith,Gregory B Waypa,V Joseph Dudley,G R Scott Budinger,Hiam Abdala-Valencia,Elizabeth Bartom,Paul T Schumacker
Pulmonary hypertension (PH) and right ventricular (RV) hypertrophy frequently develop in patients with hypoxic lung disease. Chronic alveolar hypoxia (CH) promotes sustained pulmonary vasoconstriction and pulmonary artery (PA) remodeling by acting on lung cells, resulting in the development of PH. RV hypertrophy develops in response to PH, but coronary arterial hypoxemia in CH may influence that response
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Mitochondrial Fission Mediated Cigarette Smoke-induced Pulmonary Endothelial Injury. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Zhengke Wang,Alexis White,Xing Wang,Junsuk Ko,Gaurav Choudhary,Thilo Lange,Sharon Rounds,Qing Lu
Cigarette smoke (CS) exposure increases the risk for acute respiratory distress syndrome in humans and promotes alveolar–capillary barrier permeability and acute lung injury in animal models. However, the underlying mechanisms are not well understood. Mitochondrial fusion and fission are essential for mitochondrial homeostasis in health and disease. In this study, we hypothesized that CS caused endothelial
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Extracellular Vesicles from Fibroblasts Induce Epithelial Cell Senescence in Pulmonary Fibrosis. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Tsukasa Kadota,Yusuke Yoshioka,Yu Fujita,Jun Araya,Shunsuke Minagawa,Hiromichi Hara,Atsushi Miyamoto,Souichiro Suzuki,Sakashi Fujimori,Tadasu Kohno,Takeshi Fujii,Kazuma Kishi,Kazuyoshi Kuwano,Takahiro Ochiya
Aberrant epithelial–mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung
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Type I Collagen Signaling Regulates Opposing Fibrotic Pathways through Alpha2Beta1 Integrin. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Manisha Agarwal,Mitchell Goheen,Shijing Jia,Song Ling,Eric S White,Kevin K Kim
Fibrosis is characterized by fibroblast activation, leading to matrix remodeling culminating in a stiff, type I collagen–rich fibrotic matrix. Alveolar epithelial cell (AEC) apoptosis is also a major feature of fibrogenesis, and AEC apoptosis is sufficient to initiate a robust lung fibrotic response. TGF-β (transforming growth factor-β) is a major driver of fibrosis and can induce both AEC apoptosis
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TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Erin M O'Leary,Yufeng Tian,Recep Nigdelioglu,Leah J Witt,Rengul Cetin-Atalay,Angelo Y Meliton,Parker S Woods,Lucas M Kimmig,Kaitlyn A Sun,Gizem A Gökalp,Gökhan M Mutlu,Robert B Hamanaka
Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-β (transforming growth factor-β)–dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant
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A Micro-Engineered Airway Lung-Chip Models Key Features of Viral-Induced Exacerbation of Asthma. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Janna C Nawroth,Carolina Lucchesi,Deion Cheng,Abhishek Shukla,Justin Ngyuen,Tanvi Shroff,Antonio Varone,Katia Karalis,Hyun-Hee Lee,Stephen Alves,Geraldine A Hamilton,Michael Salmon,Remi Villenave
Viral-induced exacerbation of asthma remains a major cause of hospitalization and mortality. New human-relevant models of the airways are urgently needed to understand how respiratory infections may trigger asthma attacks and to advance treatment development. Here, we describe a new human-relevant model of rhinovirus-induced asthma exacerbation that recapitulates viral infection of asthmatic airway
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Poly(ADP-ribose) Polymerase Inhibition in Acute Lung Injury: A Re-emerging Concept. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Csaba Szabo,Vanessa Martins,Lucas Liaudet
PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current
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Advances in Alpha-1 Antitrypsin Gene Therapy. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-30 Reka Lorincz,David T Curiel
AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung. Inherited serum deficiency disorders, such as hemophilia and AATD, have been considered ideal candidates for gene therapy. Although viral vector–meditated transduction of the liver has demonstrated utility in hemophilia, similar success
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KD025 Shifts Pulmonary Endothelial Cell Bioenergetics and Decreases Baseline Lung Permeability. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Ji Young Lee,Reece P Stevens,Mary Kash,Chun Zhou,Anna Koloteva,Phoibe Renema,Sunita S Paudel,Troy Stevens
KD025 is a ROCK2 inhibitor currently being tested in clinical trials for the treatment of fibrotic lung diseases. The therapeutic effects of KD025 are partly due to its inhibition of profibrotic pathways and fat metabolism. However, whether KD025 affects pulmonary microvascular endothelial cell (PMVEC) function is unknown, despite evidence that alveolar–capillary membrane disruption constitutes major
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Plasmalemmal Vesicle Associated Protein (PV1) in Caveolae Controls Lung Endothelial Permeability. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Joshua H Jones,Emily Friedrich,Zhigang Hong,Richard D Minshall,Asrar B Malik
Caveolae are prominent plasmalemmal invaginations in endothelial cells, especially in the lung vasculature, which comprises a vast surface area. PV1 (plasmalemmal vesicle–associated protein-1), a 60-kD glycoprotein expressed in endothelial cells, is essential for generating spoke-like diaphragmatic structures that span the neck region of endothelial caveolae. However, their role in caveolae-mediated
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Optimal Oxygen Targets in Term Lambs with Meconium Aspiration Syndrome and Pulmonary Hypertension. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Munmun Rawat,Praveen Chandrasekharan,Sylvia F Gugino,Carmon Koenigsknecht,Lori Nielsen,Stephen Wedgwood,Bobby Mathew,Jayasree Nair,Robin Steinhorn,Satyan Lakshminrusimha
Optimal oxygen saturation as measured by pulse oximetry (SpO2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the SpO2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO2) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance
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Intranasal Leptin Prevents Opioid Induced Sleep Disordered Breathing in Obese Mice. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Carla Freire,Huy Pho,Lenise J Kim,Xin Wang,Jhansi Dyavanapalli,Stone R Streeter,Thomaz Fleury-Curado,Luiz U Sennes,David Mendelowitz,Vsevolod Y Polotsky
Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a μ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep
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Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Ram P Naikawadi,Gary Green,Kirk D Jones,Natalia Achtar-Zadeh,Julia E Mieleszko,Isabel Arnould,Jasleen Kukreja,John Greenland,Paul J Wolters
Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)—the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether
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ATF4 Mediates Mitochondrial Unfolded Protein Response (UPRmt) in Alveolar Epithelial Cells. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Dingyuan Jiang,Huachun Cui,Na Xie,Sami Banerjee,Ruiming Liu,Huaping Dai,Victor J Thannickal,Gang Liu
Although endoplasmic reticulum (ER) unfolded protein response (UPRER) is well known, mitochondrial unfolded protein response (UPRmt) has not been recognized in alveolar epithelial cells. Furthermore, ER stress and mitochondrial dysfunction are frequently encountered in alveolar epithelial cells from an array of lung disorders. However, these two scenarios have been often regarded as separate mechanisms
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Impact of Tregs on AT2 Cell Transcriptomes During Resolution of ALI and Contributions of IFN-γ. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Jason R Mock,Catherine F Dial,Miriya K Tune,Rodney C Gilmore,Wanda K O'Neal,Hong Dang,Claire M Doerschuk
By enhancing tissue repair and modulating immune responses, Foxp3+ regulatory T cells (Tregs) play essential roles in resolution from lung injury. The current study investigated the effects that Tregs exert directly or indirectly on the transcriptional profiles of type 2 alveolar epithelial (AT2) cells during resolution in an experimental model of acute lung injury. Purified AT2 cells were isolated
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PR1P Stabilizes VEGF and Upregulates its Signaling to Reduce Elastase Induced Murine Emphysema. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Avner Adini,Hao Wu,Duy T Dao,Victoria H Ko,Lumeng J Yu,Amy Pan,Mark Puder,Selome Z Mitiku,Ratnakar Potla,Hong Chen,James M Rice,Benjamin D Matthews
Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1–derived peptide), a novel short peptide
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New cis-acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Nerea Matamala,Gema Gomez-Mariano,Jose Antonio Perez,Beatriz Baladrón,María Torres-Durán,Francisco Javier Michel,Raquel Saez,Jose María Hernández-Pérez,Irene Belmonte,Francisco Rodriguez-Frias,Ignacio Blanco,Pavel Strnad,Sabina Janciauskiene,Beatriz Martinez-Delgado
Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and
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Functional Genomics of ATP-Binding Cassette Transporter A3 (ABCA3) Variants. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Jennifer A Wambach,Ping Yang,Daniel J Wegner,Hillary B Heins,Cliff Luke,Fuhai Li,Frances V White,F Sessions Cole
Rare or private, biallelic variants in the ABCA3 (ATP-binding cassette transporter A3) gene are the most common monogenic cause of lethal neonatal respiratory failure and childhood interstitial lung disease. Functional characterization of fewer than 10% of over 200 disease-associated ABCA3 variants (majority missense) suggests either disruption of ABCA3 protein trafficking (type I) or of ATPase-mediated
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You Say You Want a Resolution (of Fibrosis). Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Kamran Atabai,Christopher D Yang,Michael J Podolsky
In pathological fibrosis, aberrant tissue remodeling with excess extracellular matrix leads to organ dysfunction and eventual morbidity. Diseases of fibrosis create significant global health and economic burdens and are often deadly. Although fibrosis has traditionally been thought of as an irreversible process, a growing body of evidence demonstrates that organ fibrosis can reverse in certain circumstances
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Age-dependent Differences in T Cell Responses to Influenza A Virus. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-10-01 Andrew D Prigge,Ruihua Ma,Bria M Coates,Benjamin D Singer,Karen M Ridge
Respiratory infections from influenza A virus (IAV) cause substantial morbidity and mortality in children relative to adults. T cells play a critical role in the host response to IAV by supporting the innate and humoral responses, mediating cytotoxic activity, and promoting recovery. There are age-dependent differences in the number, subsets, and localization of T cells, which impact the host response
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Effects of Asthma and Human Rhinovirus A16 on the Expression of the SARS-CoV-2 Entry Factors in Human Airway Epithelium. Am. J. Respir. Cell Mol. Biol. (IF 5.373) Pub Date : 2020-09-18 Ryan C Murphy,Ying Lai,Kaitlyn A Barrow,Jessica A Hamerman,Adam Lacy-Hulbert,Adrian M Piliponsky,Steven F Ziegler,William A Altemeier,Jason S Debley,Sina A Gharib,Teal S Hallstrand