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1.
FASEB J ; 38(5): e23531, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-38466220

RESUMEN

Inhaled aeroallergens can directly activate airway epithelial cells (AECs). Exposure to cockroach allergens is a strong risk factor for asthma. Cockroach allergens mediate some of their effects through their serine protease activity; protease activity is also a major contributor to allergenicity. The Th2 cytokine interleukin-13 (IL-13) induces upregulation of the eosinophil chemotactic factor CCL26. CCL26 induces eosinophil migration in allergic inflammation. In this work, we studied the effect of cockroach proteases on IL-13-induced effects. Immersed cultures of the human bronchial epithelial cell line BEAS-2B and air-liquid interface (ALI) cultures of primary normal human bronchial epithelial (NHBE) cells were stimulated with IL-13, Blattella Germanica cockroach extract (CE), or both. IL-13-induced genes were analyzed with qRT-PCR. IL-13 induced upregulation of CCL26, periostin, and IL-13Rα2 in bronchial epithelial cells which were decreased by CE. CE was heat-inactivated (HICE) or pre-incubated with protease inhibitors. HICE and CE preincubated with serine protease inhibitors did not prevent IL-13-induced CCL26 upregulation. CE-degraded IL-13 and specific cleavage sites were identified. CE also decreased IL-4-induced CCL26 upregulation and degraded IL-4. Other serine proteases such as bovine trypsin and house dust mite (HDM) serine proteases did not have the same effects on IL-13-induced CCL26. We conclude that CE serine proteases antagonize IL-13-induced effects in AECs, and this CE effect is mediated primarily through proteolytic cleavage of IL-13. IL-13 cleavage by cockroach serine proteases may modulate CCL26-mediated effects in allergic airway inflammation by interfering directly with the pro-inflammatory effects of IL-13 in vivo.


Asunto(s)
Blattellidae , Humanos , Animales , Bovinos , Interleucina-13 , Interleucina-4 , Serina Proteasas , Serina Endopeptidasas , Inflamación , Quimiocina CCL26
2.
Allergy ; 78(3): 767-779, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36207765

RESUMEN

BACKGROUND: Type 2-high asthma is characterized by elevated levels of circulating Th2 cells and eosinophils, cells that express chemoattractant-homologous receptor expressed on Th2 cells (CRTh2). Severe asthma is more common in women than men; however, the underlying mechanism(s) remain elusive. Here we examined whether the relationship between severe asthma and type 2 inflammation differs by sex and if estrogen influences Th2 cell response to glucocorticoid (GC). METHODS: Type 2 inflammation and the proportion of blood Th2 cells (CD4+ CRTh2+ ) were assessed in whole blood from subjects with asthma (n = 66). The effects of GC and estrogen receptor alpha (ERα) agonist on in vitro differentiated Th2 cells were examined. Expression of CRTh2, type 2 cytokines and degree of apoptosis (Annexin V+ , 7-AAD) were determined by flow cytometry, qRT-PCR, western blot and ELISA. RESULTS: In severe asthma, the proportion of circulating Th2 cells and hospitalizations were higher in women than men. Women with severe asthma also had more Th2 cells and serum IL-13 than women with mild/moderate asthma. Th2 cells, eosinophils and CRTh2 mRNA correlated with clinical characteristics associated with asthma control in women but not men. In vitro, GC and ERα agonist treated Th2 cells exhibited less apoptosis, more CRTh2 as well as IL-5 and IL-13 following CRTh2 activation than Th2 cells treated with GC alone. CONCLUSION: Women with severe asthma had higher levels of circulating Th2 cells than men, which may be due to estrogen modifying the effects of GC, enhancing Th2 cell survival and type 2 cytokine production.


Asunto(s)
Asma , Receptores de Glucocorticoides , Humanos , Femenino , Receptores de Glucocorticoides/metabolismo , Receptor alfa de Estrógeno/metabolismo , Interleucina-13/metabolismo , Receptores Inmunológicos/genética , Receptores de Prostaglandina/genética , Inflamación/metabolismo , Asma/tratamiento farmacológico , Células Th2/metabolismo , Glucocorticoides/uso terapéutico , Prostaglandina D2/metabolismo
3.
Allergy ; 78(5): 1148-1168, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36794967

RESUMEN

Tremendous progress in the last few years has been made to explain how seemingly harmless environmental proteins from different origins can induce potent Th2-biased inflammatory responses. Convergent findings have shown the key roles of allergens displaying proteolytic activity in the initiation and progression of the allergic response. Through their propensity to activate IgE-independent inflammatory pathways, certain allergenic proteases are now considered as initiators for sensitization to themselves and to non-protease allergens. The protease allergens degrade junctional proteins of keratinocytes or airway epithelium to facilitate allergen delivery across the epithelial barrier and their subsequent uptake by antigen-presenting cells. Epithelial injuries mediated by these proteases together with their sensing by protease-activated receptors (PARs) elicit potent inflammatory responses resulting in the release of pro-Th2 cytokines (IL-6, IL-25, IL-1ß, TSLP) and danger-associated molecular patterns (DAMPs; IL-33, ATP, uric acid). Recently, protease allergens were shown to cleave the protease sensor domain of IL-33 to produce a super-active form of the alarmin. At the same time, proteolytic cleavage of fibrinogen can trigger TLR4 signaling, and cleavage of various cell surface receptors further shape the Th2 polarization. Remarkably, the sensing of protease allergens by nociceptive neurons can represent a primary step in the development of the allergic response. The goal of this review is to highlight the multiple innate immune mechanisms triggered by protease allergens that converge to initiate the allergic response.


Asunto(s)
Alérgenos , Hipersensibilidad , Humanos , Péptido Hidrolasas , Interleucina-33 , Inflamación , Células Th2
4.
Immunol Rev ; 282(1): 73-86, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29431203

RESUMEN

Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2 , sphingosine-1-phosphate, and ß-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines.


Asunto(s)
Degranulación de la Célula , Hipersensibilidad/inmunología , Mastocitos/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de IgE/metabolismo , Receptores Toll-Like/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Inmunización , Inmunoglobulina E/metabolismo , Mediadores de Inflamación/metabolismo , Transducción de Señal
5.
Allergy ; 76(1): 281-290, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32750154

RESUMEN

BACKGROUND: Allergic asthma is characterized by type 2 inflammation. We have shown the presence of increased type 2 inflammation in patients with severe asthma and those with frequent exacerbations. However, it is not known whether increased type 2 inflammation drives asthma exacerbations. This study aims to determine Th2 immune parameters in patients presenting to the emergency department (ED) with an acute asthma exacerbation and correlate these parameters with clinical and physiological measures of asthma. METHODS: Sixteen adults presenting to the ED with acute asthma exacerbations were recruited after giving informed consent. Ten patients returned 2 weeks later for follow-up. Physiological parameters, asthma control (ACQ6), asthma quality of life (AQLQ) questionnaires, and venous blood were collected during both visits. An immune cell profiling was performed by whole blood flow cytometry: CD4+ T cells, Th2 cells (CD4+ CRTh2+ T cells and % of CD4+ T cells expressing CRTh2), eosinophils and innate lymphoid cells (ILC2). RESULTS: During exacerbation, peripheral blood Th2 cell numbers correlated with ACQ6 and AQLQ scores, while ILC2 and eosinophil numbers did not. Subjects had higher % of CD4+ T cells expressing CRTh2 and worse FEV1 during exacerbation compared with the follow-up. The decrease in the % of CD4+ T cells expressing CRTh2 seen during the follow-up visit correlated with the improvement in lung function. CONCLUSIONS: These data suggest that Th2 cells in peripheral blood may be a sensitive measure of increasing symptoms in patients with asthma exacerbations and may serve as a biomarker of an asthma exacerbation.


Asunto(s)
Asma , Células Th2 , Adulto , Asma/diagnóstico , Biomarcadores , Humanos , Inmunidad Innata , Linfocitos , Calidad de Vida
6.
Ann Allergy Asthma Immunol ; 127(2): 249-256.e2, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33895420

RESUMEN

BACKGROUND: Myeloid cells, especially dendritic cells and macrophages, play important roles in asthma pathophysiology. Monocytes (Mo) and macrophages express protease-activated receptor-2 (PAR-2), a proinflammatory serine protease receptor implicated in the pathophysiology of allergic airway inflammation. We have revealed that patients with severe asthma and those with a history of frequent asthma exacerbations exhibit increased PAR-2 expression on peripheral blood monocytes. OBJECTIVE: To determine PAR-2 expression on peripheral blood intermediate monocytes (IMMo) in subjects with increased airway inflammation, either as a result of an asthma exacerbation or after an inhalation allergen challenge. METHODS: A total of 16 adults who presented to the emergency department with asthma exacerbations were recruited after giving an informed consent. After 2 weeks, 10 patients returned for follow-up. A total of 11 patients with mild asthma treated only with as-needed bronchodilators were recruited and underwent inhalation allergen challenge after providing an informed consent. Immune cell profiling was performed by whole blood flow cytometry in both groups of patients. RESULTS: PAR-2 expression in peripheral blood IMMo increased in patients with an asthma exacerbation compared with those with stable disease, but this expression decreased after treatment of the asthma exacerbation. Subjects with mild asthma had an increase in percentages of IMMo expressing PAR-2 after an allergen challenge. Patients who presented to the emergency department had lower dendritic cell and dendritic cell subset numbers in peripheral blood during exacerbation compared with after treatment. CONCLUSION: Increased PAR-2 expression on Mo during periods of increased airway inflammation may initiate a positive feedback loop leading to systemic inflammatory changes.


Asunto(s)
Asma/sangre , Pruebas de Provocación Bronquial , Células Dendríticas/inmunología , Leucocitos Mononucleares/metabolismo , Receptor PAR-2/sangre , Adolescente , Adulto , Asma/patología , Recuento de Células , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor PAR-2/biosíntesis , Adulto Joven
7.
J Immunol ; 203(2): 441-452, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31182479

RESUMEN

Protease-activated receptor 2 (PAR-2) is expressed in various tissues, including lung, and when activated, promotes inflammation, differentiation, and migration of dendritic cells. We found that combining influenza virosomes containing hemagglutinin and neuraminidase with a PAR-2 agonist peptide (PAR-2AP) in an intranasal prime boost approach increased survival of mice challenged weeks later with lethal influenza virus over that by virosome or PAR-2AP prime boost alone. No weight loss occurred from influenza challenge after virosome-plus-PAR-2AP prime boost compared with either virosomes or PAR-2AP alone. Thus, virosomes plus PAR-2AP prevented morbidity as well as mortality. Through adoptive transfer, CD8+ lung T cells but not CD4+ T cells from virosomes plus PAR-2AP-primed mice protected from lethal influenza virus challenge and enhanced survival with less weight loss and faster recovery. Virosome-plus-PAR-2AP prime boost resulted in greater percentages of T effector memory phenotype cells (Tem) in lung, and higher frequencies of CD8 Tem and T central memory cells displayed effector functions in response to virus challenge in vivo. Virosome-plus-PAR-2AP prime boost also resulted in greater percentages of Ag-specific CD8+ T cells, both Tem and T central memory cells, in lungs of animals subsequently challenged with live influenza virus. Our findings indicate that PAR-2AP, a short peptide, may be a new and useful mucosal adjuvant.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Receptor PAR-2/agonistas , Virosomas/inmunología , Traslado Adoptivo/métodos , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Línea Celular , Perros , Femenino , Memoria Inmunológica/efectos de los fármacos , Pulmón/inmunología , Pulmón/virología , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos C57BL , Orthomyxoviridae/inmunología , Virosomas/efectos de los fármacos
8.
J Allergy Clin Immunol ; 144(4): 883-896, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31476322

RESUMEN

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.


Asunto(s)
Mastocitosis/diagnóstico , Mastocitosis/terapia , Humanos
10.
J Pharmacol Exp Ther ; 365(2): 354-367, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29555876

RESUMEN

Receptor-interacting protein kinase 2 (RIP2 or RICK, herein referred to as RIPK2) is linked to the pathogen pathway that activates nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses, we used the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% and also inhibited NFκB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggests effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis, and pancreatitis.


Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Dominio Catalítico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colitis Ulcerosa/tratamiento farmacológico , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/química , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/metabolismo
11.
Immunology ; 145(3): 391-403, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25684443

RESUMEN

Airway epithelial cells (AECs) express a variety of receptors, which sense danger signals from various aeroallergens/pathogens being inhaled constantly. Proteinase-activated receptor 2 (PAR-2) is one such receptor and is activated by cockroach allergens, which have intrinsic serine proteinase activity. Recently, dual oxidases (DUOX), especially DUOX-2, have been shown to be involved in airway inflammation in response to Toll-like receptor activation. However, the association between PAR-2 and DUOX-2 has not been explored in airways of allergic mice. Therefore, this study investigated the contribution of DUOX-2/reactive oxygen species (ROS) signalling in airway reactivity and inflammation after PAR-2 activation. Mice were sensitized intraperitoneally with intact cockroach allergen extract (CE) in the presence of aluminium hydroxide followed by intranasal challenge with CE. Mice were then assessed for airway reactivity, inflammation, oxidative stress (DUOX-2, ROS, inducible nitric oxide synthase, nitrite, nitrotyrosine and protein carbonyls) and apoptosis (Bax, Bcl-2, caspase-3). Challenge with CE led to up-regulation of DUOX-2 and ROS in AECs with concomitant increases in airway reactivity/inflammation and parameters of oxidative stress, and apoptosis. All of these changes were significantly inhibited by intranasal administration of ENMD-1068, a small molecule antagonist of PAR-2 in allergic mice. Administration of diphenyliodonium to allergic mice also led to improvement of allergic airway responses via inhibition of the DUOX-2/ROS pathway; however, these effects were less pronounced than PAR-2 antagonism. The current study suggests that PAR-2 activation leads to up-regulation of the DUOX-2/ROS pathway in AECs, which is involved in regulation of airway reactivity and inflammation via oxidative stress and apoptosis.


Asunto(s)
Asma/inmunología , Inflamación/inmunología , NADPH Oxidasas/inmunología , Receptor PAR-2/inmunología , Hipersensibilidad Respiratoria/inmunología , Alérgenos/inmunología , Animales , Antiinfecciosos/inmunología , Antiinfecciosos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Asma/metabolismo , Asma/prevención & control , Compuestos de Bifenilo/inmunología , Compuestos de Bifenilo/farmacología , Western Blotting , Cucarachas , Modelos Animales de Enfermedad , Oxidasas Duales , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Inflamación/metabolismo , Inflamación/prevención & control , Masculino , Ratones Endogámicos BALB C , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Compuestos Onio/inmunología , Compuestos Onio/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Piperazinas/inmunología , Piperazinas/farmacología , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Receptor PAR-2/antagonistas & inhibidores , Receptor PAR-2/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/prevención & control , Sistema Respiratorio/inmunología , Sistema Respiratorio/metabolismo , Sistema Respiratorio/patología , Transducción de Señal/inmunología , Regulación hacia Arriba/inmunología
12.
Proc Natl Acad Sci U S A ; 109(41): 16660-5, 2012 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-23012429

RESUMEN

Proteinase-Activated receptor-2 (PAR(2)), a G-protein-coupled Receptor, activated by serine proteinases, is reported to have both protective and proinflammatory effects in the airway. Given these opposing actions, both inhibitors and activators of PAR(2) have been proposed for treating asthma. PAR(2) can signal through two independent pathways: a ß-arrestin-dependent one that promotes leukocyte migration, and a G-protein/Ca(2+) one that is required for prostaglandin E(2) (PGE(2)) production and bronchiolar smooth muscle relaxation. We hypothesized that the proinflammatory responses to PAR(2) activation are mediated by ß-arrestins, whereas the protective effects are not. Using a mouse ovalbumin model for PAR(2)-modulated airway inflammation, we observed decreased leukocyte recruitment, cytokine production, and mucin production in ß-arrestin-2(-/-) mice. In contrast, PAR(2)-mediated PGE(2) production, smooth muscle relaxation, and decreased baseline airway resistance (measures of putative PAR(2) "protective" effects) were independent of ß-arrestin-2. Flow cytometry and cytospins reveal that lung eosinophil and CD4 T-cell infiltration, and production of IL-4, IL-6, IL-13, and TNFα, were enhanced in wild-type but not ß-arrestin-2(-/-) mice. Using the forced oscillation technique to measure airway resistance reveals that PAR(2) activation protects against airway hyperresponsiveness by an unknown mechanism, possibly involving smooth muscle relaxation. Our data suggest that the PAR(2)-enhanced inflammatory process is ß-arrestin-2 dependent, whereas the protective anticonstrictor effect of bronchial epithelial PAR(2) may be ß-arrestin independent.


Asunto(s)
Arrestinas/metabolismo , Inflamación/metabolismo , Pulmón/metabolismo , Receptor PAR-2/metabolismo , Animales , Arrestinas/genética , Asma/genética , Asma/metabolismo , Asma/patología , Hiperreactividad Bronquial/genética , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/patología , Líquido del Lavado Bronquioalveolar/química , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Citocinas/metabolismo , Dinoprostona/metabolismo , Citometría de Flujo , Inflamación/genética , Inflamación/patología , Interleucina-13/metabolismo , Leucocitos/metabolismo , Leucocitos/patología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Receptor PAR-2/genética , Arrestina beta 2 , beta-Arrestinas
13.
Respir Res ; 15: 71, 2014 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-24970330

RESUMEN

BACKGROUND: Pulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis. METHODS: To determine the role of Rac2 in pulmonary fibrosis we used a bleomycin-induced mouse model. Anesthetized C57BL/6 wild type and rac2-/- mice were instilled intratracheally with bleomycin sulphate (1.25 U/Kg) or saline as control. Bronchoalveolar lavage (BAL) samples were collected at days 3 and 7 of treatment and analyzed for matrix metalloproteinases (MMPs). On day 21 after bleomycin treatment, we measured airway resistance and elastance in tracheotomized animals. Lung sections were stained for histological analysis, while homogenates were analyzed for hydroxyproline and total collagen content. RESULTS: BLM-treated rac2-/- mice had reduced MMP-9 levels in the BAL on day 3 and reduced neutrophilia and TNF and CCL3/MIP-1α levels in the BAL on day 7 compared to BLM-treated WT mice. We also showed that rac2-/- mice had significantly lower mortality (30%) than WT mice (70%) at day 21 of bleomycin treatment. Lung function was diminished in bleomycin-treated WT mice, while it was unaffected in bleomycin-treated rac2-/- mice. Histological analysis of inflammation and fibrosis as well as collagen and hydroxyproline content in the lungs did not show significant differences between BLM-treated rac2-/- and WT and mice that survived to day 21. CONCLUSION: Rac2 plays an important role in bleomycin-induced lung injury. It is an important signaling molecule leading to BLM-induced mortality and it also mediates the physiological changes seen in the airways after BLM-induced injury.


Asunto(s)
Bleomicina/toxicidad , Neumonía/inducido químicamente , Neumonía/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Proteínas de Unión al GTP rac/deficiencia , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/mortalidad , Fibrosis Pulmonar/mortalidad , Proteína RCA2 de Unión a GTP
15.
J Leukoc Biol ; 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38725289

RESUMEN

While several functions of the endogenous prion protein (PrP) have been studied, the homeostatic function of PrP is still debated. Notably, PrP is highly expressed on mast cells, granular immune cells that regulate inflammation. When activated, mast cells shed PrP though the mechanism and consequences of this are not yet understood. First, we tested several mast cell lines and found that, while PrP was almost always present, the total amount differed greatly. Activation of mast cells induced a cleavage of the N-terminal region of PrP, and this was reduced by protease inhibitors. Exogenous mast cell proteases caused a similar loss of the PrP N-terminus. Additionally, mast cells shed PrP in an ADAM10-dependent fashion even in the absence of activation. Our results suggest that PrP is cleaved from resting mast cells by ADAM10 and from activated mast cells by mast cell proteases. PrP also appears to affect mast cell function, as Prnp-/- BMMC showed lower levels of degranulation and cytokine release, as well as lower levels of both FcεRI and CD117. Finally, we sought to provide clinical relevance by measuring the levels of PrP in bodily fluids of asthmatic patients, a disease that involves the activation of mast cells. We found an N-terminal fragment of PrP could be detected in human sputum and serum and the amount of this PrP fragment was decreased in the serum of patients with asthma.

16.
Allergy Asthma Clin Immunol ; 20(1): 8, 2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-38308375

RESUMEN

BACKGROUND: Proteinase-activated receptor 2 (PAR-2) is a G-protein coupled receptor associated with many inflammatory diseases, including asthma. We have shown an association between PAR-2 expression in peripheral blood monocytes and asthma severity as well as blood PAR-2 mRNA level and lung function. Since F2RL1 (the gene encoding PAR-2) polymorphisms affect PAR-2 expression, we hypothesize they may affect asthma severity. METHODS: We recruited 76 subjects with asthma of varying severity and collected clinical (FEV1 [% predicted], FEV1/FVC, IgE) and immunological (PAR-2 mRNA, blood eosinophils) disease parameters. We also genotyped these individuals for 3 F2RL1 SNPs (-45C/T, -149C/G, c.621C/T). RESULTS: We found that the F2RL1 SNP "C" allele of -45C/T (rs1529505) was associated with PAR-2 mRNA and blood eosinophils. F2RL1 SNP c.621C/T (rs631465) was associated with PAR-2 mRNA. The F2RL1 SNP -149C/G (rs2242991) had no association with any of the parameters studied. This study identified one F2RL1 SNP rs1529505 is associated with parameters of asthma, but not asthma severity. CONCLUSION: Larger studies are needed to further elucidate the role of PAR-2 in the pathophysiology of asthma and the influence of genetic variation.

17.
Allergy Asthma Clin Immunol ; 20(1): 30, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38600554

RESUMEN

PURPOSE: Immunoglobulin replacement therapy is a standard treatment for patients with antibody production deficiencies, which is of interest in patients with chronic obstructive pulmonary disease (COPD). This systematic review, registered with PROSPERO (CRD42021281118), assessed the current literature regarding immunoglobulin replacement therapy on COPD clinical outcomes in patients with low immunoglobulin G (IgG) serum concentrations. METHODS: Literature searches conducted from inception to August 23, 2021, in databases including MEDLINE, EMBASE, and CINAHL. Population (sex, age, comorbidities), baseline clinical characteristics (pulmonary function testing results, IgG levels), and outcome (hospitalizations, emergency department visits) were extracted after title/abstract and full text screening. The Cochrane risk of bias assessment form was used for risk of bias assessment of randomized controlled trials and the National Heart, Lung, and Blood Institute (NHLBI) assessment was used for pre and post studies. RESULTS: A total of 1381 studies were identified in the preliminary search, and 874 records were screened after duplicates were removed. Screening 77 full texts yielded four studies that were included in the review. CONCLUSION: It is unclear whether immune globulin replacement therapy reduces acute exacerbation frequency and severity in COPD. Current evidence suggests that it is worth considering, but better developed protocols for administration of immune globulin supplementation is required for future randomized controlled trials.

18.
Br J Nutr ; 109(6): 990-1000, 2013 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-22849952

RESUMEN

Fish oil supplementation during pregnancy has been associated with lower levels of cord blood IL-13, suggesting that the administration of n-3 fatty acids may attenuate the development of allergic disease. The present study aimed to investigate the mechanism by which n-3 fatty acid administration influences the production of IL-13. Pregnant BALB/c mice were fed nutritionally complete high-fat diets (15 %, w/w) with an n-3 fatty acid-enriched (DHA 1 %, w/w) or control diet (0 % DHA) immediately following delivery. Pups were exposed during suckling and weaned to the maternal diet for the remainder of the study. The production of IL-13, IL-4, IL-10 and interferon-γ from the splenocytes of ovalbumin (ova)-sensitised animals was assessed following in vitro ova stimulation or unstimulated conditions. Human T helper type 2 (Th2) cells were mitogen-stimulated in the presence or absence of DHA (10 µM) and assessed for IL-13 and IL-4 expression using intracellular flow cytometry. The influence on transcriptional activation was studied using a human IL-13 promoter reporter construct and electromobility shift assay. Ova-activated splenocytes from DHA-fed mice produced less IL-13 (57.2 (se 21.7) pg/ml) and IL-4 (7.33 (SE 3.4) pg/ml) compared with cells from the animals fed the control diet (161.5 (SE 45.0), P< 0.05; 33.2 (SE 11.8), P< 0.05). In vitro, DHA inhibited the expression of IL-13 protein from human Th2 cells as well as transcriptional activation and binding of the transcription factors cyclic AMP response element binding and activating transcription factor 2 to the human IL-13 promoter. These data indicate the potential of n-3 fatty acids to attenuate IL-13 expression, and suggest that they may subsequently reduce allergic sensitisation and the development of allergic disease.


Asunto(s)
Ácidos Grasos Omega-3/farmacología , Interleucina-13/antagonistas & inhibidores , Interleucina-13/genética , Animales , Dieta Alta en Grasa , Ácidos Docosahexaenoicos , Femenino , Humanos , Hipersensibilidad/prevención & control , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Interleucina-13/biosíntesis , Interleucina-4/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Embarazo , Regiones Promotoras Genéticas , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Transcripción Genética/efectos de los fármacos
19.
Curr Allergy Asthma Rep ; 13(3): 262-70, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23585216

RESUMEN

House dust mite (HDM) allergens are the most prevalent allergens associated with asthma and rhinitis around the world. The mechanisms of allergic sensitization and allergic airway inflammation after exposure to HDM have been studied extensively, but many questions remain unanswered. Airway epithelial cells are the first line of defense against external antigens and are considered an important player in the development of allergic airway inflammation. Both genetic susceptibility to allergic sensitization and HDM composition play decisive roles in the outcome of HDM-epithelium interactions, especially regarding airway epithelial dysfunction and allergic inflammation. Interactions between HDM and the airway epithelium have consequences for both development of allergy and asthma and development of allergic airway inflammation. This review will describe in detail these interactions and will identify issues that require more study.


Asunto(s)
Alérgenos/fisiología , Antígenos Dermatofagoides/fisiología , Asma/inmunología , Hipersensibilidad/inmunología , Mucosa Respiratoria/inmunología , Animales , Dermatophagoides pteronyssinus/inmunología , Humanos , Mediadores de Inflamación
20.
J Immunol ; 186(5): 3164-72, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21270400

RESUMEN

We have shown that proteinase-activated receptor-2 (PAR(2)) activation in the airways leads to allergic sensitization to concomitantly inhaled Ags, thus implicating PAR(2) in the pathogenesis of asthma. Many aeroallergens with proteinase activity activate PAR(2). To study the role of PAR(2) in allergic sensitization to aeroallergens, we developed a murine model of mucosal sensitization to cockroach proteins. We hypothesized that PAR(2) activation in the airways by natural allergens with serine proteinase activity plays an important role in allergic sensitization. Cockroach extract (CE) was administered to BALB/c mice intranasally on five consecutive days (sensitization phase) and a week later for four more days (challenge phase). Airway hyperresponsiveness (AHR) and allergic airway inflammation were assessed after the last challenge. To study the role of PAR(2), mice were exposed intranasally to a receptor-blocking anti-PAR(2) Ab before each administration of CE during the sensitization phase. Mucosal exposure to CE induced eosinophilic airway inflammation, AHR, and cockroach-specific IgG1. Heat-inactivated or soybean trypsin inhibitor-treated CE failed to induce these effects, indicating that proteinase activity plays an important role. The use of an anti-PAR(2) blocking Ab during the sensitization phase completely inhibited airway inflammation and also decreased AHR and the production of cockroach-specific IgG1. PAR(2) activation by CE acts as an adjuvant for allergic sensitization even in the absence of functional TLR4. We conclude that CE induces PAR(2)-dependent allergic airway sensitization in a mouse model of allergic airway inflammation. PAR(2) activation may be a general mechanism used by aeroallergens to induce allergic sensitization.


Asunto(s)
Alérgenos/inmunología , Blattellidae/inmunología , Receptor PAR-2/metabolismo , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/fisiología , Administración Intranasal , Alérgenos/administración & dosificación , Animales , Blattellidae/enzimología , Hiperreactividad Bronquial/enzimología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Línea Celular Transformada , Modelos Animales de Enfermedad , Activación Enzimática/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Mucosa Nasal/enzimología , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Ratas , Receptor PAR-2/deficiencia , Receptor PAR-2/inmunología , Hipersensibilidad Respiratoria/enzimología
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