Research Doctorate - Doctor of Philosophy (PhD) / Airway inflammation is a key feature of asthma. Currently, airway inflammation can be detected through both invasive and non- invasive methods. Non invasive methods are safe, feasible and a potentially useful way to assess airway inflammatory markers in both healthy children and children with asthma. In this thesis, a variety of non-invasive markers (induced sputum, exhaled nitric oxide, and exhaled breath condensate) was used to investigate childhood asthma. The aim of the first study was to compare and contrast the different airway markers between healthy children and children with asthma. The second study described the different airway inflammatory phenotypes in children with asthma, and examined clinical predictors of these phenotypes; whereas the third study investigated the effects of environmental tobacco smoke (ETS) exposure on airway inflammation in childhood asthma. The final study assessed the knowledge and attitudes of parents of children with asthma towards passive smoking. The studies used both cross- sectional and longitudinal designs. Children with stable asthma aged between 7 - 17 years underwent clinical assessment, spirometry, exhaled nitric oxide (FeNO), exhaled breath condensate and sputum induction. Urinary cotinine was assayed to assess tobacco smoke exposure. These studies have found that children with asthma show differences in both clinical pattern and pathological pattern compared to healthy children. These differences were apparent with elevated FeNO and sputum eosinophils. In children with asthma, there was heterogeneity of airway inflammation. There were 2 stable inflammatory patterns: eosinophilic asthma and paucigranulocytic asthma. Unlike adult asthma, these phenotypes have different clinical features, which may facilitate detection of the phenotypes in clinical practice. ETS exposure in children with asthma was common and associated with a non- eosinophilic pattern of airway inflammation. In children who had a change in ETS exposure, sputum eosinophils were decreased whereas sputum neutrophils were increased during ETS exposure compared to a non- ETS exposure period. Fractional exhaled nitric oxide levels were decreased after exposure to ETS compared to those at the time of non- ETS exposure. The severity of asthma was increased in children living with parents who smoked. As a result, parents of children with asthma, especially smoking parents should be more aware about the harmful effects of smoking on their children’s health and themselves. Health risk awareness about tobacco smoke helps parental smokers alter their smoking behavior as well as protecting children from ETS exposure. In conclusion, the important findings of this thesis are the description of the inflammatory phenotypes in childhood asthma, the identification of clinical predictors of these phenotypes and the determination of the effects of ETS exposure on airway inflammatory patterns in childhood asthma. These results should facilitate understanding and management of childhood asthma and prompt treatment studies based on markers of airway inflammation.

Thesis (M.S.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains xi, 107 p. : ill. (some col.) Includes abstract. Includes bibliographical references (p. 98-107).

Thesis (Ph. D.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 195-206).

Thesis (M.S.)--University of Nevada, Reno, 2008. / "December, 2008." Includes bibliographical references (leaves 60-64). Online version available on the World Wide Web.

Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors of the immunoglobin family expressed by epithelium and macrophages. RAGE expression increases following ligand binding and when diverse cells are exposed to a variety of insults including cigarette smoke extract (CSE). The current research sought to characterize the pro-inflammatory contributions of RAGE expressed by alveolar macrophages (AMs) following CSE exposure. Acute exposure of mice to CSE via nasal instillation revealed diminished bronchoalveolar lavage (BAL) cellularity and fewer AMs in RAGE null mice compared to controls. Primary AMs were obtained from BAL, exposed to CSE in vitro, and RNA, DNA, and protein were analyzed. CSE significantly increased RAGE expression by wild type AMs. Employing ELISAs, wild type AMs exposed to CSE had increased levels of active Ras, a small GTPase that perpetuates pro-inflammatory signaling. Conversely, RAGE null AMs had less Ras activation compared to wild type AMs after exposure to CSE. In RAGE null AMs, assessment of p38 MAPK and NF-κB, important intracellular signaling intermediates induced during an inflammatory response, revealed CSE-induced inflammation occurs at least in part via RAGE signaling. For example, activated p38 was diminished in RAGE null AMs compared to controls and assessment of phosphorylated NF-κB in CSE exposed RAGE null AMs suggest lessened nuclear translocation of NF-κB compared to wild type AMs exposed to CSE. Importantly, quantitative RT-PCR revealed that mRNA expression of pro-inflammatory cytokines including TNF-α and IL-1β were detectably decreased and analysis of secreted proteins by ELISA displayed diminished IL-1β in RAGE null AMs exposed to CSE compared to CSE-exposed wild type AMs. These results reveal that primary AMs orchestrate CSE-induced inflammation, at least in part, via RAGE-mediated mechanisms.

The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in pro-inflammatory signaling and its role in irreversible pulmonary remodeling. The current research evaluated for the first time the in vivo effects of short-term tobacco smoke exposure in RAGE null and control mice compared to identical animals exposed to room air only. Quantitative real time PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after four weeks of exposure and an anticipated absence of RAGE expression in RAGE null mice regardless of smoke exposure. Inflammatory cell behaviors were confirmed by measuring active Ras, NF-κB, and cytokine synthesis and secretion. Furthermore, bronchoalveolar lavage fluid (BALF) was procured from RAGE null and control animals after exposure for the assessment of total protein in order to indirectly measure vascular permeability, inflammatory cells and chemoattractant molecules involved in the inflammatory response. As a general theme, inflammation induced by tobacco smoke exposure was influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to tobacco smoke. Furthermore, research may demonstrate RAGE signaling as an important therapeutic target capable of ameliorating cell level inflammation in those coping with exposure.

No description available.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Thesis (M. Phil.)--University of Hong Kong, 1996. / Includes bibliographical references (leaf 143-160).

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 6 uppsatser.