Protein Kinase C α and β compensate for each other to promote stem cell factor-mediated KIT phosphorylation, mast cell viability and proliferation
Mast cells (MCs) develop from hematopoietic progenitors and differentiate into mature MCs that reside within connective or mucosal tissues. Though the number of MCs in tissues usually remains constant, inflammation and asthma disturb this homeostasis, leading to proliferation of MCs. Understanding the signaling events behind this proliferative response could lead to the development of novel strategies for better management of allergic diseases. MC survival, proliferation, differentiation, and migration are all maintained by a MC growth factor, stem cell factor (SCF) via its receptor, KIT. Here, we explored how protein kinase C (PKC) redundancy influences MC proliferation in bone marrow-derived MC (BMMC). We found that SCF activates PKCα and PKCβ isoforms, which in turn modulates KIT phosphorylation and internalization. Further, PKCα and PKCβ activate p38 mitogen activated protein kinase (MAPK), and this axis subsequently regulates SCF-induced MC cell proliferation. To ascertain the individual roles of PKCα and PKCβ, we knocked down either PKCα or PKCβ or both via short hairpin RNA (shRNA) and analyzed KIT phosphorylation, p38 MAPK phosphorylation, and MC viability and proliferation. To our surprise, downregulation of neither PKCα nor PKCβ affected MC viability and proliferation. In contrast, blocking both PKCα and PKCβ significantly attenuated SCF-induced cell viability and proliferation, suggesting that PKCα and PKCβ compensate for each other downstream of SCF signaling to enhance MC viability and proliferation. Our results not only suggest that PKC classical isoforms are novel therapeutic targets for SCF/MC-mediated inflammatory and allergic diseases, but they also emphasize the importance of inhibiting both PKCα and β isoforms simultaneously to prevent MC proliferation.
Lakshminarayan Reddy Teegala
Yasmine Elshoweikh
Ravindra Gudneppanavar
Sathwika Thodeti
Sabita Pokhrel
Erik Southard
Charles K Thodeti
Sailaja Paruchuri
FASEB J
. 2022 May;36(5):e22273. doi: 10.1096/fj.202101838RRR.
2022
English
Transient receptor potential vanilloid channel regulates fibroblast differentiation and airway remodeling by modulating redox signals through NADPH oxidase 4.
ASTHMA; CAPSAICIN receptors; GROWTH factors; NICOTINAMIDE adenine dinucleotide phosphate; OXIDATION-reduction reaction; TRP channels
Asthma is characterized by pathological airway remodeling resulting from persistent myofibroblast activation. Although transforming growth factor beta 1 (TGFβ1), mechanical signals, and reactive oxygen species (ROS) are implicated in fibroblast differentiation, their integration is still elusive. We identified that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel mediates lung fibroblast (LF) differentiation and D. farinae-induced airway remodeling via a novel
Al-Azzam N; Teegala LR; Pokhrel S; Ghebreigziabher S; Chachkovskyy T; Thodeti S; Gavilanes I; Covington K; Thodeti CK; Paruchuri S
Scientific Reports
2020
2020-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1038/s41598-020-66617-2" target="_blank" rel="noreferrer noopener">10.1038/s41598-020-66617-2</a>
The Effect Of Mold Sensitization And Humidity Upon Allergic Asthma
allergic rhinitis; allergy; asthma; bronchial responsiveness; childhood asthma; children; dampness; dry cold-air; exercise-induced asthma; home; humidity; induced bronchoconstriction; mold; pulmonary-function; respiratory health survey; Respiratory System; severity
Introduction: Humidity is commonly associated with increased airway hyperresponsiveness in asthma. Objective: To examine mold sensitization in patients with allergic asthma or allergic rhinitis and self-reports of humidity as exacerbating factors of clinical symptoms. Methods: A retrospective, cross-sectional study at a University hospital outpatient allergy and asthma clinic was performed. A total of 106 patients with either allergic asthma or allergic rhinitis completed standard prick-puncture skin testing with 17 allergens and controls and completed standardized forms addressing trigger factors for clinical symptoms. Results: Allergic asthmatics sensitized to Cladosporium were more likely to have a more severe asthma severity class (odds ratio=4.26, confidence interval=1.3016.93). Sensitization to Alternaria, Cladosporium, Helminthosporium, Aspergillus and Dermatophagoides pteronyssinus in asthma was associated with higher likelihood for previous hospitalization, while sensitization to Cladosporium, Helminthosporium, Aspergillus, Dermatophagoides pteronyssinus and cockroach in asthma was associated with higher likelihood of having reduced pulmonary function based on forced expiratory volume in 1s. Furthermore, allergic asthmatics more commonly reported humidity as an exacerbating factor of symptoms than did patients only with allergic rhinitis (68.42% vs 42.86%, respectively; P<0.05). Conclusion: Mold sensitization is highly associated with more severe asthma, while humidity is more of an exacerbating factor in patients with allergic asthma as compared with allergic rhinitis alone. Further delineation between mold sensitization and humidity is needed to determine whether these are independent factors in asthma. Please cite this paper as: Hayes D Jr, Jhaveri MA, Mannino DM, Strawbridge H and Temprano J. The effect of mold sensitization and humidity upon allergic asthma. Clin Respir J 2013; 7: 135144.
Hayes D; Jhaveri M A; Mannino D M; Strawbridge H; Temprano J
Clinical Respiratory Journal
2013
2013-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1111/j.1752-699X.2012.00294.x" target="_blank" rel="noreferrer noopener">10.1111/j.1752-699X.2012.00294.x</a>
Methacholine Challenge Testing - Identifying Its Diagnostic Role, Testing, Coding, And Reimbursement
airway; asthma; bronchial hyperresponsiveness; clinical-practice guidelines; coding; cough; function test; General & Internal Medicine; histamine; management; practice management; private practice; pulmonary; reimbursement; Respiratory System; responsiveness; sensitivity; smokers; spirometry
Methacholine challenge testing (MCT), also sometimes described as bronchoprovocation testing, is widely performed for both research and diagnostic purposes. MCT is clinically useful when the patient presents with a history of symptoms suggesting asthma, but spirometry findings are normal. Typically, MCT is performed in a pulmonary function laboratory, a clinic, or a physician's office. MCT requires time, effort, and understanding. Two standard testing regimes are identified along with proper coding and reimbursement methodologies.
Birnbaum S; Barreiro T J
Chest
2007
2007-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1378/chest.06-1385" target="_blank" rel="noreferrer noopener">10.1378/chest.06-1385</a>
Insurance Status And The Variable Management Of Children Presenting To The Emergency Department With Bronchiolitis
asthma; bronchiolitis; care; coverage; Emergency Medicine; health-insurance; hospitalizations; infants; insurance; Pediatrics; respiratory syncytial virus; serious bacterial-infection; socioeconomic-status; united-states; us children
Damore D; Mansbach J M; Clark S; Ramundo M; Camargo C A
Pediatric Emergency Care
2010
2010-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1097/PEC.0b013e3181f39861" target="_blank" rel="noreferrer noopener">10.1097/PEC.0b013e3181f39861</a>
Methacholine Challenge Testing - Identifying Its Diagnostic Role, Testing, Coding, And Reimbursement
airway; asthma; bronchial hyperresponsiveness; clinical-practice guidelines; coding; cough; function test; General & Internal Medicine; histamine; management; practice management; private practice; pulmonary; reimbursement; Respiratory System; responsiveness; sensitivity; smokers; spirometry
Birnbaum S; Barreiro T J
Chest
2007
2007-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1378/chest.06-1385" target="_blank" rel="noreferrer noopener">10.1378/chest.06-1385</a>
Surfactant protein D alters allergic lung responses in mice and human subjects
inflammation; asthma; Immunology; polymorphism; lung; Allergy; endotoxin; Aspergillus; deficient mice; Allergy; aspergillus-fumigatus; d gene; emphysema; eosinophil; hygiene hypothesis; IL-13; sftpd gene; sp-a; surfactant protein D
Background: Surfactant protein (SP) D has been proposed to be protective in allergic airway responses. Objective: We aimed to determine the effect of SP-D deficiency on murine and human airway allergy. Methods: Immunologic responses of SP-D gene-deficient mice (Sftpd(-/-)) at baseline and after 4 intranasal Aspergillus fumigatus exposures were assessed. In addition, the significance of a single nucleotide polymorphism (Met(11)Thr) in the human SP-D gene (known to decrease SP-D function) was investigated. Results: Macrophage and neutrophil bronchoalveolar lavage fluid levels and large airway mucus production were increased in naive Sftpd(-/-) mice in association with increased lung CCL17 levels and CD4(+) T cell numbers. T(H)2-associated antibody levels (IgG1 and IgE) were significantly lower in 4- to 5-week-old Sftpd(-/-) mice (P <.05). Accordingly, naive Sftpd(-/-) splenocytes released significantly less IL-4 and IL-13 on anti-CD3/CD28 stimulation (P <.01). After intranasal allergen exposures, a modest decrease in bronchoalveolar lavage fluid eosinophilia and IL-13 levels was observed in Sftpd(-/-) mice compared with values seen in wild-type mice in association with decreased airway resistance (P <.01). A single nucleotide polymorphism in the SFTPD gene, affecting SP-D levels and pathogen binding, was associated with decreased atopy in black subjects and potentially lower asthma susceptibility in white subjects. Conclusion: Sftpd(-/-) mice have an impaired systemic T(H)2 response at baseline and reduced inflammation and airway responses after allergen exposure. Translational studies revealed that a polymorphism in the SFTPD gene was associated with lower atopy and possibly asthma susceptibility. Taken together, these results support the hypothesis that SP-D-dependent innate immunity influences atopy and asthma.
Brandt E B; Mingler M K; Stevenson M D; Wang N; Hershey G K K; Whitsett J A; Rothenberg M E
Journal of Allergy and Clinical Immunology
2008
2008-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.jaci.2008.02.011" target="_blank" rel="noreferrer noopener">10.1016/j.jaci.2008.02.011</a>
Office Management of COPD in Primary Care: A 2009 Clinical Update
chronic obstructive pulmonary disease; spirometry; asthma; General & Internal Medicine; risk-factors; randomized; follow-up; controlled-trial; double-blind; obstructive pulmonary-disease; questionnaire; differentiating copd; dyspnea; receptor partial agonist; smoking-cessation; sustained-release bupropion; symptom-based; tobacco smoking
Primary care physicians (PCPs) usually are the first to diagnose and care for patients with chronic obstructive pulmonary disease (COPD). This article discusses key teaching points of recently published guidelines for PCPs and the common challenges of treating COPD patients in a primary care setting, and clarifies common misconceptions. First, PCPs should choose one of the published screening tools to assess for COPD. Spirometry is a useful tool to confirm the diagnosis of COPD to distinguish COPD from asthma, to stage the disease for determining treatment, and it can help with smoking cessation efforts. Chest radiographs do not help to diagnose COPD but are useful to rule out other causes of dyspnea and cough. Differentiating COPD from asthma is important because it affects treatment decisions and prognosis. Second, the goals of COPD treatment are to relieve symptoms, improve exercise tolerance, prevent exacerbations, and improve quality (although not necessarily extend quantity) of life. Chronic obstructive pulmonary disease can be treated at any stage, and the treatments are adjusted in a stepwise approach based on disease severity. Third, as part of the long-term management of COPD, smoking cessation should be discussed at every visit, and inhaler technique should be reviewed at regular intervals. Chronic obstructive pulmonary disease patients should also receive the recommended influenza and pneumococcal vaccinations. Primary care physicians are in a unique position to identify COPD patients early, to implement primary and secondary preventive measures, and to provide care that addresses the full spectrum of COPD and its comorbidities.
Belfer M H
Postgraduate Medicine
2009
2009-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.3810/pgm.2009.07.2034" target="_blank" rel="noreferrer noopener">10.3810/pgm.2009.07.2034</a>
The diagnosis of wheezing in children
asthma; disease; General & Internal Medicine; human bocavirus; infants
Wheezing in children is a common problem encountered by family physicians. Approximately 25 to 30 percent of infants will have at least one wheezing episode, and nearly one half of children have a history of wheezing by six years of age. The most common causes of wheezing in children include asthma, allergies, infections, gastroesophageal reflux disease, and obstructive sleep apnea. Less common causes include congenital abnormalities, foreign body aspiration, and cystic fibrosis. Historical data that help in the diagnosis include family history, age at onset, pattern of wheezing, seasonality, suddenness of onset, and association with feeding, cough, respiratory illnesses, and positional changes. A, focused examination and targeted diagnostic testing guided by clinical suspicion also provide useful information. Children with recurrent wheezing or a single episode of unexplained wheezing that does not respond to bronchodilators should undergo chest radiography. Children whose history or physical examination findings suggest asthma should undergo diagnostic pulmonary function testing.
Weiss L N
American Family Physician
2008
2008-04
Journal Article
n/a
Exercise-Induced Dyspnea in Children and Adolescents: Differential Diagnosis
Pediatrics; adults; asthma; induced bronchoconstriction; hyperventilation; vocal-cord dysfunction
Exercise-induced dyspnea in children and adolescents can occur for many reasons. Although asthma is the common cause, failure to prevent exercise-induced asthma by pretreatment with a bronchodilator, such as albuterol, indicates that other etiologies should be considered. Other causes of exercise-induced dyspnea include exercise-induced vocal cord dysfunction, exercise-induced laryngomalacia, exercise-induced hyperventilation, chest wall restrictive abnormalities, cardiac causes, and normal physiologic limitation. When exercise-induced dyspnea is not from asthma, cardiopulmonary exercise testing with reproduction of the patient's dyspnea is the means to identify the other causes. Cardiopulmonary exercise testing monitors oxygen use, carbon-dioxide production, end-tidal pCO(2) (partial pressure of carbon dioxide), and electrocardiogram. Additional components to testing are measurement of blood pH and pCO(2) when symptoms are reproduced, and selective flexible laryngoscopy when upper airway obstruction is observed to specifically identify vocal cord dysfunction or laryngomalacia. This approach is a highly effective means to identify exercise-induced dyspnea that is not caused by asthma.
Bhatia R; Abu-Hasan M; Weinberger M
Pediatric Annals
2019
2019-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3928/19382359-20190219-02" target="_blank" rel="noreferrer noopener">10.3928/19382359-20190219-02</a>
The Association of Acetaminophen and Asthma Prevalence and Severity.
Child; United States; Prevalence; UNITED States; ACETAMINOPHEN; ASTHMA; ASTHMA risk factors; CHILDREN; DISEASE prevalence; SEVERITY of illness index; Severity of Illness; Acetaminophen – Adverse Effects – In Infancy and Childhood; Asthma – Epidemiology – In Infancy and Childhood; Asthma – Risk Factors – In Infancy and Childhood
The epidemiologic association between acetaminophen use and asthma prevalence and severity in children and adults is well established. A variety of observations suggest that acetaminophen use has contributed to the recent increase in asthma prevalence in children: (1) the strength of the association; (2) the consistency of the association across age, geography, and culture; (3) the dose-response relationship; (4) the timing of increased acetaminophen use and the asthma epidemic; (5) the relationship between per-capita sales of acetaminophen and asthma prevalence across countries; (6) the results of a double-blind trial of ibuprofen and acetaminophen for treatment of fever in asthmatic children; and (7) the biologically plausible mechanism of glutathione depletion in airway mucosa. Until future studies document the safety of this drug, children with asthma or at risk for asthma should avoid the use of acetaminophen. [ABSTRACT FROM AUTHOR]
McBride John T
Pediatrics
2011
2011-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1542/peds.2011-1106" target="_blank" rel="noreferrer noopener">10.1542/peds.2011-1106</a>