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Immune Dysfunction in Cystic Fibrosis
Başlık:
Immune Dysfunction in Cystic Fibrosis
Yazar:
Leung, Steven Tsz King, author.
ISBN:
9780355986884
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (66 pages)
Genel Not:
Source: Masters Abstracts International, Volume: 57-06M(E).
Advisors: Sean V. Murphy Committee members: Victor E. Ortega; Michael Seeds.
Özet:
Cystic Fibrosis (CF) is one of the most widespread life-shortening genetic diseases. CF is often diagnosed at birth; there is no cure, and many CF patients die from chronic lung disease at a young age. Patients with CF experience declining pulmonary function related to chronic airway infection, inflammation and scarring. While the mechanism connecting abnormal CFTR function to chronic bacterial infection and inflammation of the airway has not been fully elucidated, recent evidence suggests that CF patients may have defects in their mucosal immunity, resulting in a predisposition to infection and production of a disproportionate inflammatory response to microbial stimuli. Studies show increased cytokine expression in sputum and bronchoalveolar lavage fluid samples in CF patients. To determine if this is secondary to the chronic inflammatory environment of the lungs or innate to CF immune cells itself, leukocytes were isolated from peripheral blood and stimulated with LPS and compared to healthy donors. Our hypothesis is that there will be an increase in cytokine expression in blood leukocytes as well, with a further increase in expression after LPS stimulation. This will demonstrate that the chronic inflammatory response is inherent to the CF mutation itself, as blood is sterile and devoid of infection.
Our study demonstrated that there was increased NF-&kgr;B mRNA gene expression in CF compared to healthy controls. However, NF-&kgr;B protein level was decreased when assessed by ELISA, even after stimulation with LPS, which is contradictory to what we hypothesized. Furthermore, there was decreased neutrophil elastase, IL-1beta, CCL-2, IL-6, and IL-10 protein levels after LPS stimulation. There were also differences between stable and CFPE samples as well, with the CFPE group demonstrated a decreased gene expression in NF-&kgr;B after LPS stimulation. These findings suggest that there is an innate immune dysfunction in CF which is independent of chronic infection and inflammation in the lungs, resulting in impaired cytokine secretion, and a further dysfunction which may lead to the pathogenesis of CFPE.
Currently, the only treatment option for end-stage pulmonary disease in CF is lung transplantation. There are no therapies that can reverse pulmonary fibrosis once established, leading to a permanent and irreversible decline in function. As such, anti-fibrotic therapies are an attractive option to restore lung function and decrease morbidity and mortality. In this study, we have successfully established a murine pulmonary fibrosis model, using bleomycin as our causative agent. We were able to demonstrate a decrease in inspiratory capacity, forced vital capacity, forced expiratory volume, and total lung capacity, which is consistent with the pathophysiology of pulmonary fibrosis. Furthermore, our study demonstrated increased Ashcroft scores in our bleomycin group compared to saline group, corresponding to an increased amount of fibrosis in the bleomycin samples. Establishment of a murine pulmonary fibrosis will enable us to test new agents in hopes of developing a new treatment modality for CF.
Notlar:
School code: 0248
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(692083.1) | 692083-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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