Thesis (PhD)--University of South Australia, 1997

Thesis (M.H.S.)--Boise State University, 2009. / Title from t.p. of PDF file (viewed Apr. 6, 2010). Includes bibliographical references (leaves 35-38).

Thesis (M.H.S.)--Boise State University, 2009. / Includes bibliographical references (leaves 35-38).

Abstract Fibrotic pulmonary and pleural disorders represent a group of intrathoracic disorders with different etiologies and prognoses. A prominent part of both pulmonary and pleural fibrotic disorders remains etiologically unknown. An essential feature for all these disorders is an increase and disarray of many extracellular matrix proteins which take part in the remodeling of the fibrotic tissue. Further, the injury in pulmonary as well as in pleural fibrosis occurs often at the border between the epithelial or mesothelial and the mesenchymal cells breaking the epithelial basement membrane. Tenascin is an oligomeric matrix glycoprotein of the extracellular matrix. The best known isoforms are tenascin -C, -X, -R, -Y and -W. Tenascin-C is synthesized during embryonic development, expressed in a variety of tumors, being absent or scantily expressed in most adult tissues. The function of tenascin-C is still unclear. In lung, tenascin-C has been shown to be expressed in fetal lung during branching morphogenesis, benign and malignant lung tumors, idiopathic pulmonary fibrosis, sarcoidosis and asthma. The aim of the present study was to study tenascin-C (later called tenascin) expression in various types of pulmonary fibrosis such as usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), bronchiolitis obliterans organizing pneumonia (BOOP), sarcoidosis and extrinsic allergic alveolitis as well as in fibrotic and inflammatory disorders of the pleura of different etiologies. Further, the aims were to compare the accumulation of tenascin with the prognosis in UIP, to confirm the immunohistochemical findings in UIP by Western blotting and immunoelectron miscroscopic (immuno-EM) studies, to investigate which cells synthesize tenascin in UIP and in pleural fibrosis by mRNA in situ hybridization, and to determine whether epithelial lining fluid (ELF) and serum tenascin concentration are increased in patients with UIP, sarcoidosis and extrinsic allergic alveolitis. Tenascin was shown to be increased by immunohistochemical studies in all types of pulmonary and pleural fibrotic disorders included in the study. In UIP, increased tenascin expression was associated with a shortened survival time of the patients. In immuno-EM, labeling for tenascin was seen within type II pneumocytes. UIP cases showed reactivity for a polypeptide of Mr = 200 000 by Western blotting. Myofibroblasts and type II pneumocytes were mainly shown to synthesize tenascin in UIP. Also in pleural fibrosis myofibroblasts, and in addition possibly mesothelial cells, were observed to be responsible for its synthesis. ELF and serum tenascin concentrations were increased in UIP, sarcoidosis and extrinsic allergic alveolitis. In conclusion, tenascin expression is increased in pulmonary and pleural fibrotic disorders, especially in newly formed fibrosis. In UIP, tenascin is actively synthesized at the sites of recent epithelial injury, suggesting that it plays an important role in the fibrogenesis in the lung.

M.Med. (Internal Medicine), Faculty of Health Sciences, University of the Witwatersrand, 2011. / Background Cystic fibrosis (CF) is one of the most common fatal autosomal recessive inherited conditions in the Caucasian population. Survival of patients with cystic fibrosis has increased due to optimal medical therapy and as a consequence, later complications such as cystic fibrosis related diabetes (CFRD) may develop. Materials and methods A retrospective patient file review was conducted on all the patient files in the Adult Cystic Fibrosis Unit, Ward 496, Charlotte Maxeke Johannesburg Academic Hospital. The aim of the review was to determine the prevalence of Cystic fibrosis related diabetes (CFRD) and to determine the characteristics of patients with CFRD in terms of age, gender, genotype, lung function, body mass index (BMI), HBA1c, use of corticosteroids and pancreatic function. Patients were classified as normal glucose tolerance, impaired glucose tolerance or CFRD based on the results of oral glucose tolerance testing. For statistical analysis, patients with impaired glucose tolerance and CFRD were analyzed together under the group abnormal glucose homeostasis. 50 patient files were reviewed. Results 12 patients (24%) had normal glucose tolerance, 10 (20%) had impaired glucose tolerance, 23 (46%) had CFRD without fasting hyperglycaemia and 3 patients (6%) had CFRD with fasting hyperglycaemia. 2 patients (4%) did not have OGTT done and therefore could not be categorised. The prevalence of CFRD was 54 % (including all patients with CFRD without fasting hyperglycaemia and patients with CFRD with fasting hyperglycaemia). 75 % of patients had abnormal glucose homeostasis. Statistical analysis failed to demonstrate any significant difference in the characteristics of patients with and without CFRD. This may be related to the small sample size. HBA1c values were higher in patients with abnormal glucose homeostasis compared to patients with normal glucose tolerance. Conclusions The prevalence of CFRD in the adult cystic fibrosis population at Charlotte Maxeke Johannesburg Academic Hospital correlates with the prevalence of CFRD in other cystic fibrosis centres. There were no statistically significant differences in the characteristics of patients with and without CFRD.

The effects of the antifibrotic drug Halofuginone hydrobromide (Halo) on muscle function, regeneration and cardiorespiratory function were studied using mdx mice. It was hypothesized that Halo treatment would resolve pre-established fibrosis and prevent collagen deposits, improving muscle and cardio-respiratory function. Mice 8-9 mos were treated with saline or Halo for 5 (n = 4/group), 10 (n = 5/group) and 12 weeks (n = 4-5/group). Muscle strength and endurance, respiration and muscle susceptibility to damage were assessed. Tissues were collected from all mice. Additional mice were treated for 10 wks (3-4 wks n = 9-10/group; 8-9 mos n = 8-9/group) for echocardiography. Halo reduced fibrosis. As a consequence, there was muscle repair and damage was reduced. There were functional improvements and disease progression was slowed. There was resolution of pre-existing fibrosis and reduction of new collagen synthesis. This treatment could improve quality of life and lengthen the lifespan of DMD patients. / May 2007

Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.

Thesis--PlanB (M.S.)--University of Wisconsin--Stout, 2003. / Includes bibliographical references.

The prevention of heart failure in our aging population has become a healthcare priority. As part of the normal aging process patients have been shown to develop age-related myocardial fibrosis, which is characterized by excess deposition and a lack of clearance of extracellular matrix (ECM) proteins, contributing to the development of heart failure. The increase in ECM proteins is caused by an imbalance between the following: (1) collagen biosynthesis by fibroblasts, (2) post-synthetic collagen processing (cross-linking) which stabilizes collagen, and (3) collagen degradation. The focus of this thesis lays mainly on collagen biosynthesis and processing, and how interrupting these can affect the overall balance of collagen in the myocardium. The two main objectives of this thesis lay in 1 – characterizing the role of a key pro-fibrotic signal in the TGFβ pathway, connective tissue growth factor (CTGF), in hypertension induced myocardial fibrosis development, and 2 – investigating the role of lysyl oxidase (LOX), an enzyme involved in the crosslinking of collagen that has been implicated in age-related myocardial fibrosis development. This thesis provides novel evidence that CTGF regulation is an important step in the early stages of myocardial fibrosis development through regulating new collagen synthesis and that CTGF is produced as a downstream mediator of TGFβ after AngII exposure not directly through AngII-AT1R signaling. Additionally, novel evidence is presented that LOX inhibition reduces age-related myocardial fibrosis and that the decrease in collagen protein content observed after LOX inhibition is associated with a significant decrease in new pro-collagen 1 mRNA synthesis. This suggests that LOX inhibition also inhibits new collagen synthesis by an unknown mechanism. Overall, these studies have contributed new mechanistic knowledge about myocardial fibrosis development and explored potential therapeutic strategies aimed at interrupting collagen homeostasis, which are key to understanding myocardial fibrosis development.

The effects of the antifibrotic drug Halofuginone hydrobromide (Halo) on muscle function, regeneration and cardiorespiratory function were studied using mdx mice. It was hypothesized that Halo treatment would resolve pre-established fibrosis and prevent collagen deposits, improving muscle and cardio-respiratory function. Mice 8-9 mos were treated with saline or Halo for 5 (n = 4/group), 10 (n = 5/group) and 12 weeks (n = 4-5/group). Muscle strength and endurance, respiration and muscle susceptibility to damage were assessed. Tissues were collected from all mice. Additional mice were treated for 10 wks (3-4 wks n = 9-10/group; 8-9 mos n = 8-9/group) for echocardiography. Halo reduced fibrosis. As a consequence, there was muscle repair and damage was reduced. There were functional improvements and disease progression was slowed. There was resolution of pre-existing fibrosis and reduction of new collagen synthesis. This treatment could improve quality of life and lengthen the lifespan of DMD patients.