Yang Ping. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 126-145). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Abstract not available

This thesis records a series of experiments conducted to gain further insight into factors which influence the expression, ligand binding and functional activity of the beta-2 adrenergic receptor. These studies were prompted by previous reports that the postulated beta-2 adrenergic receptor abnormality in allergic asthma could be induced, induced by autoantibodies. I established and optimised beta-2 adrenergic receptor ligand binding and functional assays in guinea pig lung membranes and then conducted an original study of beta adrenergic receptor expression in the guinea pig foetal lung. I found that beta adrenergic receptor expression in the foetal lung was dormant for 80% of the gestation period. After day 53 there was a surge in receptor expression which increased beyond term.

A disfunção das pregas vocais (DPV) é caracterizada por movimento paradoxal de fechamento das pregas vocais, ocorrendo de forma episódica e involuntária durante a inspiração, levando à obstrução das vias aéreas. Os pacientes que apresentam DPV costumam não responder ao tratamento indicado para asma, levando ao uso inapropriado de corticóides sistêmicos com efeitos colaterais, freqüentes passagens em setores de emergência, hospitalizações por vezes desnecessárias e, com menos freqüência, intubação e traqueostomia. O objetivo principal deste estudo foi o de investigar a relação desta problemática com a economia psíquica destes pacientes, no que diz respeito à psicogênese e as possibilidades de tratamento por meio do método clínico de investigação e tratamento psicanalíticos. Para isto, foram incluídos 5 pacientes do sexo feminino, com idades entre 30 e 55 anos, que foram acompanhadas em tratamento psicanalítico no ambulatório do Serviço de Imunologia Clínica e Alergia do Instituto Central do HCFMUSP. Constatamos que a DPV aparece de maneira singular na vida de cada paciente investigada, porém com características peculiares que indicam uma localização psíquica capaz de operar como uma satisfação inconsciente frente a um conflito anterior. A princípio, abordar a paciente como se esta não possuísse asma pode levar a uma reação negativa, interpretada por elas como um fingimento ou uma estratégia consciente de obter ganhos primários. A interlocução entre o psicanalista e os demais profissionais da equipe mostra-se de significativa importância / Vocal fold dysfunction (VFD) is characterized by paradoxical movement of closing of the vocal folds, occurring of irregularly and involuntary form during the inspiration, leading to the blockage of the aerial ways. The patients who present VFD do not answer to the treatment indicated for asthma, leading to the unnecessary use of systemic steroids with collateral effect, frequent visits in emergency sectors, hospitalizations and, sometimes, intubations and tracheotomies. The main objective of this study was to investigate the relation of this problematic and the psychic economy of these patients, in whom it says respect to psychogenic explanation and the possibilities of psychoanalytical treatment. For this, 5 patients of the feminine sex had been enclosed, with ages between 30 and 55 years, that had been followed in psychoanalytical treatment in the clinic of the Service of Clinical Imunologia and Allergy of the Central Institute of the HCFMUSP. We evidence that the VFD appears in singular way in the life of each investigated patient, however with peculiar characteristics that indicate a psychic localization capable to operate as an unconscious satisfaction to a previous conflict. To approach the patient as if this did not possess asthma can lead to a negative reaction, interpreted for them as a deceit or a conscientious strategy to get primary profits. The interlocution between the psychoanalyst and the members of the team reveals of significant importance

The regulation of systemic immune responses is dependent on individual cell responses that will concur to induce a coherent response against a stimulus. In turn, cell response is dependent on the processing of intracellular signals generated at the cell membrane and transmitted through successive protein modifications to the nucleus in order to activate gene transcription. This is referred to as intracellular signalling. Tight control of these mechanisms is required to generate an appropriate cell response to environmental stimulations and globally to establish an appropriate immune response. Among protein modifications used to transmit a signal to the nucleus, protein tyrosine phosphorylation represents a pivotal method used by immune cells to rapidly induce signalling. While protein tyrosine kinases (PTKs) phosphorylate proteins, protein tyrosine phosphatases (PTPs) regulate the signalling by removing the phosphate group. The goal of this study was to better characterize intracellular signalling events involved in allergic asthma, a chronic inflammatory disease involving a Th2 immune response. In a first time, we investigated the role of PTPs in the development of asthma. We show that inhibition of global PTP activity in mice, during either the allergen sensitization or the allergen challenge phase, reduces asthma development and is linked to an increased Th1 response in the spleen and lung. Secondly, we revealed that TC-PTP inhibition reduces asthma development, while PTP-1B inhibition exacerbates inflammatory cells recruitment to the lung. Inhibition of either SHP-1 or PTP-PEST activity did not significantly modulate asthma development in our model. In a third set of experiments, we got interested in the signalling pathways triggered by the pro-inflammatory molecules myeloid-related proteins (MRPs) 8 and 14. MRPs are small cytosolic proteins recently described to have extracellular functions. MRP8 expression is resistant to corticosteroid treatment, and potentially promotes inflammation in corticosteroid-treated patients. We identified that MRPs induce signal through the action of TLR-4 and trigger the activation of MEK/ERK and JNK pathways that lead to NF-kappaB translocation. Collectively, our data provide a new characterization of signalling pathways engaged in allergic asthma. This should be helpful in the elaboration of new therapeutic approaches targeting precise pathways to inhibit mechanisms of inflammation.

A disfunção das pregas vocais (DPV) é caracterizada por movimento paradoxal de fechamento das pregas vocais, ocorrendo de forma episódica e involuntária durante a inspiração, levando à obstrução das vias aéreas. Os pacientes que apresentam DPV costumam não responder ao tratamento indicado para asma, levando ao uso inapropriado de corticóides sistêmicos com efeitos colaterais, freqüentes passagens em setores de emergência, hospitalizações por vezes desnecessárias e, com menos freqüência, intubação e traqueostomia. O objetivo principal deste estudo foi o de investigar a relação desta problemática com a economia psíquica destes pacientes, no que diz respeito à psicogênese e as possibilidades de tratamento por meio do método clínico de investigação e tratamento psicanalíticos. Para isto, foram incluídos 5 pacientes do sexo feminino, com idades entre 30 e 55 anos, que foram acompanhadas em tratamento psicanalítico no ambulatório do Serviço de Imunologia Clínica e Alergia do Instituto Central do HCFMUSP. Constatamos que a DPV aparece de maneira singular na vida de cada paciente investigada, porém com características peculiares que indicam uma localização psíquica capaz de operar como uma satisfação inconsciente frente a um conflito anterior. A princípio, abordar a paciente como se esta não possuísse asma pode levar a uma reação negativa, interpretada por elas como um fingimento ou uma estratégia consciente de obter ganhos primários. A interlocução entre o psicanalista e os demais profissionais da equipe mostra-se de significativa importância / Vocal fold dysfunction (VFD) is characterized by paradoxical movement of closing of the vocal folds, occurring of irregularly and involuntary form during the inspiration, leading to the blockage of the aerial ways. The patients who present VFD do not answer to the treatment indicated for asthma, leading to the unnecessary use of systemic steroids with collateral effect, frequent visits in emergency sectors, hospitalizations and, sometimes, intubations and tracheotomies. The main objective of this study was to investigate the relation of this problematic and the psychic economy of these patients, in whom it says respect to psychogenic explanation and the possibilities of psychoanalytical treatment. For this, 5 patients of the feminine sex had been enclosed, with ages between 30 and 55 years, that had been followed in psychoanalytical treatment in the clinic of the Service of Clinical Imunologia and Allergy of the Central Institute of the HCFMUSP. We evidence that the VFD appears in singular way in the life of each investigated patient, however with peculiar characteristics that indicate a psychic localization capable to operate as an unconscious satisfaction to a previous conflict. To approach the patient as if this did not possess asthma can lead to a negative reaction, interpreted for them as a deceit or a conscientious strategy to get primary profits. The interlocution between the psychoanalyst and the members of the team reveals of significant importance

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Rationale: Tissue remodeling and complement activation are asthma hallmarks. Type V collagen [col(V)], a cryptic antigen, becomes exposed during lung remodeling. IL-17 is key to anti-col(V) immunity, and regulates complement activation. We have reported that col(V)-induced tolerance down regulates IL-17 and prevents immune-mediated lung diseases. Objectives: Determine a role for anti-col(V) immunity in asthma. Methods: Serum anti-col(V) antibodies were measured in asthma patients, and immunohistochemistry utilized to detect interstitial col(V) in fatal asthma. Balb/c mice were tolerized with col(V) prior to sensitization with ovalbumin (OVA), and subsequent OVA intranasal challenge. Airway hyper-responsiveness (AHR) to methacholine was measured; and RT-PCR utilized to determine local Il17 transcripts. Bronchoalveolar lavage levels of C3a¸ C5a and OVA-specific IgE were measured; and immunohistochemistry utilized to detect expression of complement regulatory proteins, expression, CD46/Crry and CD55, in lung tissue. Results: Compared to normal subjects, anti-col(V) antibodies were increased in asthmatics; and interstitial col(V) was over expressed in fatal asthma. OVA-induced AHR up regulated anti-col(V) antibodies systemically, and increased OVA-specific IgE and C3a in BAL, and parenchymal Il17 transcripts. Col(V)-induced tolerance abrogated AHR, down regulated OVA-induced T cell proliferation, as well as total and OVA-specific IgE, C3a, IL-17 expression and tracheal smooth muscle contraction. Crry/CD46 and CD55, key to preventing complement activation, were down regulated on goblet cells in murine allergic airway disease. Conclusions: Anti-col(V) immunity correlates with asthma pathogenesis, and col(V)-induced tolerance may be a novel therapeutic for asthma. Decreased expression of Crry/CD46 and CD55 on goblet cells may in part account for complement activation in asthma.

Indiana University-Purdue University Indianapolis (IUPUI) / More than 300 million people world-wide suffer from breathlessness, wheezing, chest tightness, and coughing characteristic of chronic bronchial asthma, the global incidence of which is on the rise. Allergen-sensitization and challenge elicits pulmonary expression of chemoattractants that promote a chronic eosinophil-rich infiltrate. Eosinophils are increasingly recognized as important myeloid effectors in chronic inflammation characteristic of asthma, although few eosinophil molecular signaling pathways have successfully been targeted in asthma therapy. p21 activated kinases (PAKs), members of the Ste-20 family of serine/threonine kinases, act as molecular switches in cytoskeletal-dependent processes involved in cellular motility. We hypothesized that PAK1 modulated eosinophil infiltration in an allergic airway disease (AAD) murine model. In this model, Pak1 deficient mice developed reduced inflammatory AAD responses in vivo with notable decreases in eosinophil infiltration in the lungs and broncho-alveolar lavage fluids (BALF). To test the importance of PAK1 in hematopoietic cells in AAD we used complementary bone marrow transplant experiments that demonstrated decreased eosinophil inflammation in hosts transplanted with Pak1 deficient bone marrow. In in vitro studies, we show that eotaxin-signaling through PAK1 facilitated eotaxin-mediated eosinophil migration. Ablating PAK1 expression by genetic deletion in hematopoietic progenitors or siRNA treatment in derived human eosinophils impaired eotaxin-mediated eosinophil migration, while ectopic PAK1 expression promoted this migration. Together these data suggest a key role for PAK1 in the development of atopic eosinophil inflammation and eotaxin-mediated eosinophil migration.

Indiana University-Purdue University Indianapolis (IUPUI) / Regulatory T (Treg) cells represent an important layer of immune-regulation indispensible for curtailing exuberant inflammatory responses and maintaining self-tolerance. Treg cells have translational potential for autoimmunity, inflammation, transplantation and cancer. Therefore, delineating the molecular underpinnings underlying the development, suppressor function and stability of Tregs is particularly warranted. The transcriptional repressor Bcl6 is a critical arbiter of helper T cell fate, promoting the follicular helper (Tfh) lineage while repressing Th1, Th2 and Th17 differentiation. Bcl6-deficient mice develop a spontaneous and severe Th2-type inflammatory disease including myocarditis and pulmonary vasculitis, suggesting a potential role for Bcl6 in Treg cell function. Bcl6-deficient Treg cells are competent in controlling Th1 responses, but fail to control Th2 inflammation in an airway allergen model. Importantly, mice with Bcl6 deleted specifically in the Treg lineage develop severe myocarditis, thus highlighting a critical role for Bcl6 in Treg-mediated control of Th2 inflammation. Bcl6-deficient Tregs display an intrinsic increase in Th2 genes and microRNA-21 (miR-21) expression. MiR-21 is a novel Bcl6 gene target in T cells and ectopic expression of miR-21 directs Th2 differentiation in non-polarized T cells. MiR-21 is up-regulated in mouse models of airway inflammation and also in human patients with eosinophilic esophagitis and asthma. Thus, miR-21 is a clinically relevant biomarker for Th2-type pathologies. Our results define a key function for Bcl6 in repressing Gata3 function and miR-21 expression in Tregs, and provide greater understanding of the control of Th2 inflammatory responses by Treg cells.