scholarly journals Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia

2019 ◽  
Vol 216 (10) ◽  
pp. 2348-2361 ◽  
Author(s):  
Quang T. Le ◽  
Jonathan J. Lyons ◽  
Andrea N. Naranjo ◽  
Ana Olivera ◽  
Robert A. Lazarus ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mast Cells ◽  
Clinical Features ◽  
Hormone Receptor ◽  
Cell Types ◽  
The Novel ◽  
Monogenic Disorder ◽  
Α Subunit ◽  
Gene Copies ◽  
Protease Activated Receptor 2

Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2α- and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/β-Tryptase, but not homotetramer, activates protease-activated receptor-2 (PAR2), which is expressed on cell types such as smooth muscle, neurons, and endothelium. Also, only α/β-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the α subunit of the EGF-like module–containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of α-tryptase protomers on neighboring β-tryptase protomers likely result in the novel substrate repertoire of α/β-tryptase tetramers that in turn cause some of the clinical features of hereditary α-tryptasemia and of other disorders involving mast cells.

scholarly journals Production of proteolytic enzymes in mast cells, fibroblasts, vascular smooth muscle and endothelial cells cultivated under normoxic or hypoxic conditions

2010 ◽  
pp. 711-719 ◽  
Author(s):  
H Maxová ◽  
L Bačáková ◽  
V Lisá ◽  
J Novotná ◽  
H Tomášová ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Mast Cells ◽  
Vascular Smooth Muscle ◽  
Serine Proteases ◽  
Proteolytic Enzymes ◽  
Cell Types ◽  
In Vitro Production ◽  
Hypoxic Conditions

Matrix metalloproteinases (MMPs) is a family of proteolytic enzymes involved in remodeling of extracellular matrix. Although proteolytic enzymes are produced by many cell types, mast cells seem to be more important than other types in remodeling of pulmonary arteries during hypoxia. Therefore, we tested in vitro production of MMPs and serine proteases in four cell types (mast cells, fibroblasts, vascular smooth muscle cells and endothelial cells) cultivated for 48 h under normoxic or hypoxic (3 % O2) conditions. MMP-13 was visualized by immunohistochemistry, MMP-2 and MMP-9 were detected by zymography in cell lysates. Enzymatic activities (MMPs, tryptase and chymase) were estimated in the cultivation media. Hypoxia had a minimal effect on total MMP activity in the cultivation media of all types of cells, but immunofluorescence revealed higher intensity of MMP-13 in the cells exposed to hypoxia except of fibroblasts. Tryptase activity was three times higher and chymase activity twice higher in mast cells cultivated in hypoxia than in those cultured in normoxia. Among all cell types studied here, mast cells are the most abundant source of proteolytic enzymes under normoxic and hypoxic conditions. Moreover, in these cells hypoxia increases the production of both specific serine proteases tryptase and chymase, which can act as MMPs activators.

Mechanosensitivity of STREX-lacking BKCa channels in the colonic smooth muscle of the mouse

2010 ◽  
Vol 299 (6) ◽  
pp. G1231-G1240 ◽  
Author(s):  
Wei Wang ◽  
Haixia Huang ◽  
Dongyan Hou ◽  
Ping Liu ◽  
Hua Wei ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Adult Mouse ◽  
Smooth Muscles ◽  
Cell Types ◽  
Potential Mechanism ◽  
Gi Tract ◽  
Bkca Channels ◽  
Α Subunit ◽  
Membrane Stretch ◽  
Mechanoelectric Transduction

Stretch sensitivity of Ca2+-activated large-conductance K+ channels (BKCa) has been observed in a variety of cell types and considered to be a potential mechanism in mechanoelectric transduction (MET). Mechanical stress is a major stimulator for the smooth muscle in the gastrointestinal (GI) tract. However, much about the role and mechanism of MET in GI smooth muscles remains unknown. The BKCa shows a functional diversity due to intensive Slo I alternative splicing and different α/β-subunit assembly in various cells. The stress-regulated exon (STREX) insert is suggested to be an indispensable domain for the mechanosensitivity of BKCa. The purpose of this study was to determine whether the BKCa in colonic myocytes of the adult mouse is sensitive to mechanical stimulation and whether the STREX insert is a crucial segment for the BKCa mechanosensitivity. The α- and β1-subunit mRNAs and the α-subunit protein of the BKCa channels were detected in the colonic muscularis. We found that the BKCa STREX-lacking variant was abundantly expressed in the smooth muscle, whereas the STREX variant was not detectable. We demonstrated that the STREX-lacking BKCa channels were also sensitive to membrane stretch. We suggest that in addition to the STREX domain, there are other additional structures in the channel responsible for mechanically coupling with the cell membrane.

scholarly journals Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ofir Klein ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Cell Types ◽  
Secretory Cells ◽  
Regulated Exocytosis ◽  
Open Questions ◽  
Conflicting Evidence ◽  
Compound Exocytosis

Anaphylaxis is a notorious type 2 immune response which may result in a systemic response and lead to death. A precondition for the unfolding of the anaphylactic shock is the secretion of inflammatory mediators from mast cells in response to an allergen, mostly through activation of the cells via the IgE-dependent pathway. While mast cells are specialized secretory cells that can secrete through a variety of exocytic modes, the most predominant mode exerted by the mast cell during anaphylaxis is compound exocytosis—a specialized form of regulated exocytosis where secretory granules fuse to one another. Here, we review the modes of regulated exocytosis in the mast cell and focus on compound exocytosis. We review historical landmarks in the research of compound exocytosis in mast cells and the methods available for investigating compound exocytosis. We also review the molecular mechanisms reported to underlie compound exocytosis in mast cells and expand further with reviewing key findings from other cell types. Finally, we discuss the possible reasons for the mast cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence in different mast cell models, and the open questions in the field which remain to be answered.

scholarly journals 458. Molecular SARS-CoV-2 Testing During the COVID-19 Outbreak: Experiences of a Hospital in Southeast Michigan, USA

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S296-S297
Author(s):  
Trini A Mathew ◽  
Jonathan Hopkins ◽  
Diane Kamerer ◽  
Shagufta N Ali ◽  
Daniel Ortiz ◽  
...  
Keyword(s):  
Clinical Features ◽  
Diagnostic Testing ◽  
Beaumont Hospital ◽  
High Capacity ◽  
Turnaround Time ◽  
Molecular Diagnostic ◽  
The Novel ◽  
Repeat Testing ◽  
Asymptomatic Patients ◽  
Novel Coronavirus

Abstract Background The novel Coronavirus SARS CoV-2 (COVID-19) outbreak was complicated by the lack of diagnostic testing kits. In early March 2020, leadership at Beaumont Hospital, Royal Oak Michigan (Beaumont) identified the need to develop high capacity testing modalities with appropriate sensitivity and specificity and rapid turnaround time. We describe the molecular diagnostic testing experience since initial rollout on March 16, 2020 at Beaumont, and results of repeat testing during the peak of the COVID-19 pandemic in MI. Methods Beaumont is an 1100 bed hospital in Southeast MI. In March, testing was initially performed with the EUA Luminex NxTAG CoV Extended Panel until March 28, 2020 when testing was converted to the EUA Cepheid Xpert Xpress SARS-CoV-2 for quicker turnaround times. Each assay was validated with a combination of patient samples and contrived specimens. Results During the initial week of testing there was > 20 % specimen positivity. As the prevalence grew the positivity rate reached 68% by the end of March (Figure 1). Many state and hospital initiatives were implemented during the outbreak, including social distancing and screening of asymptomatic patients to increase case-finding and prevent transmission. We also adopted a process for clinical review of symptomatic patients who initially tested negative for SARS-CoV-2 by a group of infectious disease physicians (Figure 2). This process was expanded to include other trained clinicians who were redeployed from other departments in the hospital. Repeat testing was performed to allow consideration of discontinuation of isolation precautions. During the surge of community cases from March 16 to April 30, 2020, we identified patients with negative PCR tests who subsequently had repeat testing based on clinical evaluation, with 7.1% (39/551) returning positive for SARS- CoV2. Of the patients who expired due to COVID-19 during this period, 4.3% (9/206) initially tested negative before ultimately testing positive. Figure 1 BH RO testing Epicurve Figure 2: Screening tool for repeat COVID19 testing and precautions Conclusion Many state and hospital initiatives helped us flatten the curve for COVID-19. Our hospital testing experience indicate that repeat testing may be warranted for those patients with clinical features suggestive of COVID-19. We will further analyze these cases and clinical features that prompted repeat testing. Disclosures All Authors: No reported disclosures

scholarly journals Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2

2014 ◽  
Vol 1842 (9) ◽  
pp. 1613-1621 ◽  
Author(s):  
Nina Wronkowitz ◽  
Sven W. Görgens ◽  
Tania Romacho ◽  
Laura A. Villalobos ◽  
Carlos F. Sánchez-Ferrer ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Protease Activated Receptor 2

Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the α subunit of the epithelial sodium channel

2009 ◽  
Vol 70 (2) ◽  
pp. 252-258 ◽  
Author(s):  
Felix G. Riepe ◽  
Miguel X. P. Van Bemmelen ◽  
Francois Cachat ◽  
Hansjörg Plendl ◽  
Ivan Gautschi ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
The Novel ◽  
Α Subunit ◽  
Heterozygous Carriers

Childhood Asthma: Update

1992 ◽  
Vol 13 (11) ◽  
pp. 403-412
Author(s):  
Gail G. Shapiro
Keyword(s):  
Smooth Muscle ◽  
Mast Cells ◽  
Airway Inflammation ◽  
Immunoglobulin E ◽  
Bronchial Hyperresponsiveness ◽  
Basement Membrane Thickening ◽  
Infiltrating Cells ◽  
Lung Biopsies ◽  
Airways Reactivity ◽  
Mast Cell Mediator Release

Definition and Pathophysiology Asthma is a reversible airways disease characterized by both smooth muscle hyperreactivity and airway inflammation. During the 1970s and early 1980s the focus was on smooth muscle constriction, and it was believed that better bronchodilators would greatly diminish our difficulties in controlling this condition. This, unfortunately, was not the case. The emphasis of therapy today has turned to airway inflammation. Lung biopsies from patients who have asthma show destruction of respiratory epithelium, basement membrane thickening, and inflammatory cellular infiltrate. Among the infiltrating cells are eosinophils, macrophages, and neutrophils that are called to the site of inflammation by the chemotactic products released by activated mast cells. Upon their arrival, these cells release their own products of inflammation, which amplify this immunologic response. A variety of neuropeptides also play a role, some serving to stabilize and others to destabilize the airway. One result of this airway inflammation is airways reactivity, also known as bronchial hyperresponsiveness. A common example of this scenario is the child who has allergic asthma and encounters a problematic allergen. This child has immunoglobulin E (IgE) to this allergen bound to mast cells in his or her airway. Upon exposure to the allergen, the binding of IgE and antigen triggers mast cell mediator release within minutes.

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