Abstract:
:Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide measurement, analysis of ciliary beating, transmission electron microscopy (TEM), and/or genetic testing. In most genetic PCD variants, laterality defects can occur. However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure. We have previously shown that several types of PCD can be diagnosed via immunofluorescence (IF) microscopy analyses. Here, using IF microscopy, we demonstrated that in individuals with PCD and CP defects, the CP-associated protein SPEF2 is absent in HYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells from 189 individuals with suspected PCD and situs solitus. Forty-one of the 189 individuals had undetectable SPEF2 and were subjected to a genetic analysis, which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of SPEF2 that is causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.
journal_name
Am J Respir Cell Mol Biolauthors
Cindrić S,Dougherty GW,Olbrich H,Hjeij R,Loges NT,Amirav I,Philipsen MC,Marthin JK,Nielsen KG,Sutharsan S,Raidt J,Werner C,Pennekamp P,Dworniczak B,Omran Hdoi
10.1165/rcmb.2019-0086OCsubject
Has Abstractpub_date
2020-03-01 00:00:00pages
382-396issue
3eissn
1044-1549issn
1535-4989journal_volume
62pub_type
杂志文章abstract::Acute lung injury induced by reactive oxygen gases such as ozone (O(3)) is focal and site-selective. To define patterns of acute epithelial injury along intrapulmonary airways, we developed a new analytic approach incorporating labeling of permeable cells, airway microdissection, and laser scanning confocal microscopy...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.22.2.3674
更新日期:2000-02-01 00:00:00
abstract::Primary pulmonary hypertension is characterized by increased pulmonary vascular resistance and smooth muscle proliferation. Stable analogs are increasingly being used to treat this disease, although no data exists comparing their effects on proliferation. We therefore investigated the antiproliferative activity of sev...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.26.2.4695
更新日期:2002-02-01 00:00:00
abstract::Geldanamycin is a benzoquinone ansamycin with multiple pharmacologic properties. Recent data demonstrated that geldanamycin conferred protection in an animal model of inflammation-associated acute lung injury. In the current study, we investigated the effects of geldanamycin on interleukin (IL)-8 gene expression and n...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.25.1.4384
更新日期:2001-07-01 00:00:00
abstract::Monkey Clara cell 10 kDa protein (CC10) was purified from monkey lung lavage. This protein showed an apparent molecular weight of about 10 kDa and 5 kDa under non-reducing and reducing conditions, respectively, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. From the amino acid sequence dat...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.15.3.8810640
更新日期:1996-09-01 00:00:00
abstract::Eosinophils are an important source of leukotriene (LT)C(4), which can be synthesized within lipid bodies-cytoplasmic organelles where eicosanoid formation may take place. Allergy-driven lipid body formation and function have never been investigated. Here, we studied the in vivo induction and role of lipid bodies with...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2005-0145OC
更新日期:2005-09-01 00:00:00
abstract::We have reported that von Hippel-Lindau protein (pVHL) expression is elevated in human and mouse fibrotic lungs and that overexpression of pVHL stimulates fibroblast proliferation. We sought to determine whether loss of pVHL in fibroblasts prevents injury and fibrosis in mice that are treated with bleomycin. We genera...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2015-0111OC
更新日期:2016-05-01 00:00:00
abstract::A small proline-rich protein, SPR1, is overexpressed in squamous metaplasia of bronchial epithelium. We studied the expression and regulation of SPR1 in a series of human bronchial epithelial cell lines representing a model of multistep bronchial carcinogenesis. These cell lines included a primary culture of tracheobr...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.22.1.3637
更新日期:2000-01-01 00:00:00
abstract::We examined the potential of several epithelial-derived factors to enhance neutrophil activation and survival. Neutrophils incubated in the presence of supernatants from nasal-derived primary epithelial cultures had significantly increased survival compared with neutrophils cultured in media alone. Of the cytokines re...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.21.2.3605
更新日期:1999-08-01 00:00:00
abstract::Previously it was reported that hyperoxia induced death of the human lung adenocarcinoma cell line (A549 cells) by necrosis, not by apoptosis. This study examined proliferation and death of untransformed human small airway epithelial (SAE) cells in normoxia or hyperoxia in comparison with A549 cells. We tested the hyp...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.19.3.2862m
更新日期:1998-09-01 00:00:00
abstract::Pulmonary carbonic anhydrase (CA) activity plays important roles in carbon dioxide exchange, fluid secretion, and pH regulation. This study reports the use of molecular and immunologic techniques to characterize expression of the high-activity cytosolic isoenzyme CA II in rat lung tissue. Northern blot analysis of RNA...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.10.5.7514010
更新日期:1994-05-01 00:00:00
abstract::Although neuroanatomical and neurophysiological features of neurons in the ferret trachea have been studied, the neural mediators associated with this plexus have not been completely characterized. The purpose of this study was to examine the occurrence of choline acetyltransferase (ChAT), nitric oxide synthase (NOS),...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.14.3.8845170
更新日期:1996-03-01 00:00:00
abstract::Endothelin-1 (ET-1) plays a critical role in endothelial dysfunction and contributes to the pathogenesis of pulmonary hypertension (PH). We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) stimulates microRNAs that inhibit ET-1 and pulmonary artery endothelial cell (PAEC) proliferation. The objec...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2014-0337OC
更新日期:2016-01-01 00:00:00
abstract::Heme oxygenase-1 (HO-1) is a stress-response protein, the expression of which is transcriptionally regulated by agents that cause oxidative stress. We have previously shown that lipopolysaccharide (LPS)-induced HO-1 gene transcription in RAW 264.7 macrophage cells is mediated by a distal enhancer called SX2, located 4...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.18.2.2910
更新日期:1998-02-01 00:00:00
abstract::In this study, we investigated the effect of the novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) on the growth of human lung carcinoma cell lines. AHPN inhibits the proliferation of all cell lines tested, irrespective of the lung tumor type, in a concentration- and time-de...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.18.3.2974
更新日期:1998-03-01 00:00:00
abstract::The lung epithelium constitutes a selective barrier that separates the airways from the aqueous interstitial compartment. Regulated barrier function controls water and ion transport across the epithelium and is essential for maintaining lung function. Tight junctions (TJs) seal the epithelial barrier and determine the...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2015-0071OC
更新日期:2016-05-01 00:00:00
abstract::The mesothelium contains both procoagulant and fibrinolytic activities. An imbalance between these activities could account for the abnormal fibrin turnover and pleural fibrin deposition that is characteristic of pleural inflammation. Procoagulant activity of human pleural mesothelial cells (HPMC) is in part due to ti...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb/7.4.414
更新日期:1992-10-01 00:00:00
abstract::Although several studies have demonstrated that the pulmonary collectins surfactant protein (SP)-A and SP-D contribute to innate immunity by enhancing pathogen phagocytosis, the role of SP-A and SP-D in regulating production of free radicals and cytokines is controversial. We hypothesized that the state and mechanism ...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.23.6.4083
更新日期:2000-12-01 00:00:00
abstract::The inflammatory process plays a crucial role in the onset and progression of several lung pathologies, including cystic fibrosis (CF), and the involvement of NF-κB is widely recognized. The specific inhibition of NF-κB by decoy oligonucleotides delivered within the lung may be beneficial, although rationally designed...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2012-0473OC
更新日期:2013-08-01 00:00:00
abstract::We investigated mechanically induced cell-to-cell Ca2+ signaling in a preparation of rabbit tracheal epithelium close to its in vivo condition. We used confocal microscopy to analyze changes in intracellular free calcium concentration ([Ca2+]i) in intact ciliated tracheal mucosal explants loaded with the Ca2+-indicato...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb.18.5.3105
更新日期:1998-05-01 00:00:00
abstract::Glucose moves into airway secretions after a glucose load. Therefore people with diabetes or hyperglycemia spend a significant proportion of each day with glucose in their airways secretions. This study investigated the effects of glucose on isolated human airways and on cultured airway smooth muscle (ASM) cells. Huma...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2011-0449OC
更新日期:2012-10-01 00:00:00
abstract::Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as a potential therapy for increasing tissue oxygenation, yet they have not reached their full potential because of unwanted hemodynamic side effects (vasoconstriction, low cardiac output, and oxygen delivery) due in part to nitric oxide (NO) scavenging...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2008-0364OC
更新日期:2010-02-01 00:00:00
abstract::Transforming growth factor-beta (TGF-beta) is a cytokine implicated in wound healing and in the pathogenesis of pulmonary fibrosis. TGF-beta stimulates myofibroblast differentiation characterized by expression of contractile smooth muscle (SM)-specific proteins such as SM-alpha-actin. In the present study, we examined...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2008-0288OC
更新日期:2009-09-01 00:00:00
abstract::The pathological hallmarks of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, include inflammation, arrested alveolarization, and dysregulated angiogenesis. Severe BPD is often complicated by pulmonary hypertension (PH) that significantly increases morbidity and mortality. Glycogen synth...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2012-0383OC
更新日期:2013-05-01 00:00:00
abstract::Surfactant protein (SP)-D, a 43-kD multifunctional collagen-like lectin, is synthesized and secreted by the airway epithelium. SP-D knockout (SP-D [-/-]) mice exhibit an increase in the number and size of airway macrophages, peribronchiolar inflammation, increases in metalloproteinase activity, and development of emph...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2003-0091OC
更新日期:2004-03-01 00:00:00
abstract::Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluri...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2013-0529OC
更新日期:2014-09-01 00:00:00
abstract::Obesity affects the incidence and severity of asthma in at least two major phenotypes: an early-onset allergic (EOA) form that is complicated by obesity and a late-onset nonallergic (LONA) form that occurs only in the setting of obesity. Both groups exhibit airway hyperresponsiveness to methacholine challenge but exhi...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章,评审
doi:10.1165/rcmb.2016-0019PS
更新日期:2016-05-01 00:00:00
abstract::A strong correlation exists between smoking and lung cancer; however, susceptibility to lung cancer among smokers is not uniform. Similarly, mice show differential susceptibility to the tobacco carcinogen nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which produces lung tumors in A/J but not in C3...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2005-0330OC
更新日期:2007-01-01 00:00:00
abstract::Nontypable Haemophilus influenzae (NTHI) is being increasingly recognized as a cause of both adult pneumonia and acute infectious exacerbations in chronic bronchitis. We used a mouse model to study the immune enhancement of pulmonary clearance of NTHI after a primary immunization. BALB/c mice were immunized with whole...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb/1.3.201
更新日期:1989-09-01 00:00:00
abstract::IL-13 is a T-helper class 2 cytokine that induces goblet cell hyperplasia and mucus production in airway epithelial cells. Because macrolide antibiotics are known to have immunomodulatory and mucoregulatory properties, the aim of this study was to examine the effect of clarithromycin on IL-13-induced goblet cell hyper...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2010-0327OC
更新日期:2011-11-01 00:00:00
abstract::We have previously characterized dog mastocytoma cells propagated in nude mice. We have established two of these lines (C1 and C2) in continuous culture. Freshly disaggregated mastocytoma cells were cultured in Dulbecco's modified Eagle's medium (DME)-H16 mixed with 50% Ham's F12 and supplemented with histidine and 5%...
journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/ajrcmb/3.5.413
更新日期:1990-11-01 00:00:00