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American Journal of Respiratory Cell and Molecular Biology

Elizabeth A Middleton, Matthew T Rondina, Hansjorg Schwertz, Guy A Zimmerman
Platelets are essential cellular effectors of hemostasis and contribute to disease as circulating effectors of pathologic thrombosis. These are their most widely known biologic activities. Nevertheless, recent observations demonstrate that platelets have a much more intricate repertoire beyond these traditional functions, and are specialized for contributions to vascular barrier integrity, organ repair, antimicrobial host defense, inflammation, and activities across the immune continuum. Paradoxically, some of these newly-discovered activities of platelets appear to contribute to tissue injury based on clinical investigations and animal models of disease...
March 19, 2018: American Journal of Respiratory Cell and Molecular Biology
Youngji Cho, Galeb Abu-Ali, Hiroki Tashiro, David I Kasahara, Traci A Brown, Jeffrey D Brand, Joel A Mathews, Curtis Huttenhower, Stephanie A Shore
Previous reports demonstrate that the microbiome impacts allergic airway responses, including airway hyperresponsiveness, a characteristic feature of asthma. Here we examined the role of the microbiome in pulmonary responses to a non-allergic asthma trigger, ozone. We depleted the microbiota of conventional mice with either a single antibiotic (ampicillin, metronidazole, neomycin, or vancomycin) or a cocktail of all four antibiotics given via the drinking water. Mice were then exposed to room air or ozone. In air-exposed mice, airway responsiveness was not different in antibiotic- versus control water-treated mice...
March 12, 2018: American Journal of Respiratory Cell and Molecular Biology
Hans Petersen, Rodrigo Vazquez Guillamet, Paula Meek, Akshay Sood, Yohannes Tesfaigzi
Chronic obstructive pulmonary disease (COPD) is a syndrome that comprises several lung pathologies, but subphenotyping the various disease subtypes has been difficult. One reason may be that current efforts which are focused on studying COPD once it has occurred do not allow to trace back the different origins of disease. This prespective proposes that emphysema originates when susceptible airway, endothelial, and/or hematopoietic cells are exposed to environmental toxins, such as cigarette smoke, biomass fuel, or traffic emissions...
March 9, 2018: American Journal of Respiratory Cell and Molecular Biology
Li Eon Kuek, Paul Griffin, Paul Martinello, Alison N Graham, Paul Kalitsis, Philip J Robinson, Graham A Mackay
Primary ciliary dyskinesia (PCD) is an inherited, currently incurable condition. In the respiratory system, PCD causes impaired functioning of the mucociliary escalator leading to nasal congestion, cough and recurrent otitis media which commonly progresses to cause more serious and permanent damage including hearing deficits, chronic sinusitis and bronchiectasis. New treatment options for the condition are thus necessary. In characterising an immortalised human bronchial epithelial cell line (BCi-NS1.1), grown at an air/liquid interface to permit differentiation, we have identified that these cells have dyskinetic motile cilia...
February 26, 2018: American Journal of Respiratory Cell and Molecular Biology
Robert M Tighe, Anastasiya Birukova, Michael J Yeager, Sky W Reece, Kymberly M Gowdy
Accurate and reproducible assessments of experimental lung injury and inflammation are critical to basic and translational research. In particular, investigators use varied methods of bronchoalveolar lavage and euthanasia but their impact to assessments of injury and inflammation are unknown. To define potential effects, we compared methods of lavage and euthanasia in uninjured mice and following a mild lung injury model (ozone). C57BL/6J male mice age 8-10 weeks underwent BAL following euthanasia with ketamine/xylazine, carbon dioxide (C02 ), or isoflurane...
February 26, 2018: American Journal of Respiratory Cell and Molecular Biology
Jens Klockgether, Nina Cramer, Sebastian Fischer, Lutz Wiehlmann, Burkhard Tümmler
RATIONALE: The chronic airway infections with Pseudomonas aeruginosa determine morbidity in most individuals with cystic fibrosis (CF). P. aeruginosa may persist for decades in CF lungs which provides the rare opportunity to study the long-term within-host evolution of a bacterial airway pathogen. OBJECTIVES: To resolve the genetic adaptation of P. aeruginosa in CF lungs from the onset of colonization until the patient's death or permanent replacement by another P...
February 22, 2018: American Journal of Respiratory Cell and Molecular Biology
Freddy Romero, Xu Hong, Dilip Shah, Caleb B Kallen, Ivan Rosas, Zhi Guo, DeLeila Schriner, Julie Barta, Hoora Shaghaghi, Jan B Hoek, Clementina Mesaros, Augustine M Choi, Nathaniel W Snyder, Ross Summer
RATIONALE: Endoplasmic reticulum stress is evident in the alveolar epithelium of humans and mice with pulmonary fibrosis but neither the mechanisms causing ER stress nor its contribution to fibrosis are understood. A well-recognized adaptive response to ER stress is that affected cells induce lipid synthesis; however, we recently reported that lipid synthesis was downregulated in the alveolar epithelium in pulmonary fibrosis. OBJECTIVES: To determine whether lipid synthesis is needed to resolve ER stress and limit fibrotic remodeling in the lung...
February 21, 2018: American Journal of Respiratory Cell and Molecular Biology
Isaac K Sundar, Kahkashan Rashid, Janice Gerloff, Dongmei Li, Irfan Rahman
Cigarette smoke (CS) affects DNA damage and cellular senescence signaling pathways in the pathogenesis of chronic obstructive pulmonary disease (COPD). p16(INK4a) (p16: a cyclin-dependent kinase inhibitor) is a key marker of cellular senescence, which is induced by CS in lung cells. It is thought that removal of p16 attenuates premature aging by removing senesced cells. However, the role of p16 in CS-induced stress induce premature senescence (SIPS) and senescence-associated secretory phenotype (SASP during the development of COPD/emphysema is not known...
February 15, 2018: American Journal of Respiratory Cell and Molecular Biology
Kerstin W Sinkevicius, Kelly J Bellaria, Juliana Barrios, Patrizia Pessina, Manav Gupta, Christine Fillmore Brainson, Roderick T Bronson, Carla F Kim
Metastatic disease is the primary cause of death of lung cancer patients, but the mouse models of lung adenocarcinoma do not accurately recapitulate the tumor microenvironment or metastatic disease observed in patients. In this study, we conditionally deleted E-cadherin in an autochthonous lung adenocarcinoma mouse model driven by activated oncogenic Kras and p53 loss. Loss of E-cadherin significantly accelerated lung adenocarcinoma progression and decreased survival of the mice. Kras;p53;E-cadherin mice had a 41% lung tumor burden, invasive grade 4 tumors, and a desmoplastic stroma just 8 weeks after tumor initiation...
February 15, 2018: American Journal of Respiratory Cell and Molecular Biology
Ji-Min Lee, Masahiro Yoshida, Mi-So Kim, June-Hyuk Lee, Ae-Rin Baek, An Soo Jang, Do Jin Kim, Shunsuke Minagawa, Su Sie Chin, Choon-Sik Park, Jun Araya, Kazuyoshi Kuwano, Sung Woo Park
RATIONALE: Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase-1 and -3 (RIPK1/3) plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns (DAMPs), its association with IPF progression remains elusive...
February 14, 2018: American Journal of Respiratory Cell and Molecular Biology
Naofumi Kameyama, Shotaro Chubachi, Ahmed E Hegab, Hiroyuki Yasuda, Shizuko Kagawa, Akihiro Tsutsumi, Koichi Fukunaga, Masayuki Shimoda, Yae Kanai, Kenzo Soejima, Tomoko Betsuyaku
Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in COPD patients. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)-induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent carcinogen...
February 14, 2018: American Journal of Respiratory Cell and Molecular Biology
Rashika Joshi, Andrea Heinz, Qiang Fan, Shuling Guo, Brett Monia, Christian E H Schmelzer, Anthony S Weiss, Matthew Batie, Harikrishnan Parameswaran, Brian M Varisco
RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT deficiency...
February 8, 2018: American Journal of Respiratory Cell and Molecular Biology
Anne M Scruggs, Hailey B Koh, Priya Tripathi, Nicholas J Leeper, Eric S White, Steven K Huang
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by excessive scarring and fibroblast activation. We previously showed that fibroblasts from patients with IPF are hypermethylated at the CDKN2B gene locus resulting in decreased CDKN2B expression. Here, we examine how diminished CDKN2B expression in normal and IPF fibroblasts affect fibroblast function and how loss of CDKN2B contributes to IPF pathogenesis. We first confirmed that protein expression of CDKN2B was diminished in IPF lungs in situ...
February 8, 2018: American Journal of Respiratory Cell and Molecular Biology
Wendy K Steagall, Gustavo Pacheco-Rodriguez, Thomas N Darling, Olga Torre, Sergio Harari, Joel Moss
Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, affecting lungs, kidneys, and lymphatics. It is caused by the proliferation of abnormal smooth muscle-like LAM cells, with mutations and loss of heterozygosity in the tuberous sclerosis complex (TSC) 1 or, more frequently, 2 genes. Isolated pulmonary LAM cells have been difficult to maintain in culture and most studies of LAM lung cells involve mixtures of TSC2 wild-type and TSC2-null cells. A clonal population of LAM lung cells has not been established, making analysis of the cells challenging...
February 6, 2018: American Journal of Respiratory Cell and Molecular Biology
Richard G James, Stephen R Reeves, Kaitlyn A Barrow, Maria P White, Veronika A Glukhova, Candace Haghighi, Dana Seyoum, Jason S Debley
RATIONALE: Bronchial epithelial cells (BECs) from healthy children inhibit human lung fibroblast (HLF) expression of collagen and fibroblast-myofibroblast transition (FMT) while asthmatic BECs do so less effectively, suggesting diminished epithelial-derived regulatory factors contribute to airway remodeling. Preliminary data demonstrated secretion of the activin A-inhibitor FSTL3 by healthy BECs was greater than that by asthmatic BECs. OBJECTIVES: Determine the relative secretion of FSTL3 and activin A by asthmatic and healthy BECs and if FSTL3 inhibits FMT...
February 2, 2018: American Journal of Respiratory Cell and Molecular Biology
Andrea L Frump, Mona Selej, Jordan A Wood, Marjorie Albrecht, Bakhtiyor Yakubov, Irina Petrache, Tim Lahm
17β-estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible remain unknown. We hypothesized the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1α (HIF-1α)-dependent increases in ERβ expression. Sprague Dawley rats or ERα or ERβ knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. The effects of hypoxia were also studied in primary rat or human pulmonary artery endothelial cells (PAECs)...
February 2, 2018: American Journal of Respiratory Cell and Molecular Biology
Mozibur Rahman, Rui Sun, Subhendu Mukherjee, Bernd Nilius, Luke J Janssen
We previously described several ionic conductances in human pulmonary fibroblasts (HPFs), including one activated by two structurally distinct TRPV4-channel agonists: 4α-phorbol-12,13-didecanoate (4αPDD) and GSK1016790A. However, the TRPV4-activated current exhibited peculiar properties: it developed slowly over many minutes, exhibited reversal potentials that could vary by tens of millivolts even within a given cell, and was not easily reversed by subsequent addition of two distinct TRPV4-selective blockers (RN-1734 or HC-067047)...
February 2, 2018: American Journal of Respiratory Cell and Molecular Biology
Mariel Maldonado, Alfonso Salgado-Aguayo, Iliana Herrera, Sandra Cabrera, Blanca Ortíz-Quintero, Claudia A Staab-Weijnitz, Oliver Eickelberg, Remedios Ramírez, Anne M Manicone, Moisés Selman, Annie Pardo
Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive aging-associated disease of unknown etiology. Growing body of evidence indicates that aberrant activated alveolar epithelial cells induce the expansion and activation of the fibroblast population leading to the destruction of the lung architecture. Some Matrix Metalloproteinases (MMPs) are upregulated in IPF, indicating that they may be important in the pathogenesis and/or progression of IPF. Here, we studied the expression of MMP28 in this disease and evaluated its functional effects in two alveolar epithelial cell lines and in human primary bronchial epithelial cells...
January 26, 2018: American Journal of Respiratory Cell and Molecular Biology
Nicholas M Maurice, Brahmchetna Bedi, Ruxana T Sadikot
Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multi-drug resistant infections, especially in immunocompromised and hospitalized patients. P. aeruginosa is an important cause of nosocomial and ventilator-associated pneumonia characterized by high prevalence and fatality rates. P. aeruginosa also causes chronic lung infections in individuals with cystic fibrosis (CF). Multi-drug and totally drug resistant strains of P. aeruginosa are increasing threats that contribute to high mortality in these patients...
January 26, 2018: American Journal of Respiratory Cell and Molecular Biology
Richard T Amison, Simon Cleary, Yanira Riffo-Vasquez, Maidda Bajwa, Clive P Page, Simon C Pitchford
BACKGROUND: Platelet activation occurs in patients with allergic inflammation, and platelets can be activated directly by allergen via an IgE-dependent process. Platelets activate antigen-presenting cells (APCs) such as CD11c+ dendritic cells (DCs) in vitro. Whilst CD11c+ DCs are requisite for allergen sensitization, the role of platelets in this process is unknown. OBJECTIVES: We investigated whether platelets were necessary for allergen sensitization. METHODS: Balb/c mice sensitised to ovalbumin (OVA), were exposed to subsequent aerosolized allergen (OVA challenge)...
January 24, 2018: American Journal of Respiratory Cell and Molecular Biology
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