To study the pulmonary responses to toxic insult, the biochemical and physiological effects of a known pulmonary toxicant (monocrotaline) were investigated. Monocrotaline is a pyrrolizidine alkaloid obtained from the seeds of Crotalaria spectabilis. When this alkaloid is administered to rats in their drinking water (20 mg/1) for 3 weeks, the lung is damaged, resulting in pulmonary hypertension, inhibition of serotonin transport by the pulmonary endothelium, and right heart hypertrophy. Preceeding the hypertrophy is a doubling of the mass of the lung and right ventricle. The change in mass of the lung preceeds that of the right ventricle. The increases in both organs is characterized by elevated RNA but not DNA. The lung mass increase is not accompanied by changes in collagenous proteins but is accompanied by an 86% increase in total lipids. The right ventricle however, responds to monocrotaline with a 400% increase in collagen protein and no change in lipid content, thereby indicating the lung and right ventricle respond differently to monocrotaline. Time course experiments established that the earliest observable event in monocrotaline induced lung damage is pulmonary edema which develops by day 5 and is resolved by day 10. Monocrotaline metabolites generated by an isolated liver and perfused through an isolated lung do not cause pulmonary edema even at concentrations of monocrotaline metabolites near 1 mM. These metabolites do however, alter the pulmonary endothelial transport of serotonin while other endothelial functions such as norepinephrine transport, angiotensin convertining enzyme and 5'-nucleotidase activities are unchanged. The effect of monocrotaline metabolites on pulmonary endothelial cell transport of serotonin is attenuated when the isolated livers are perfused under conditions which inhibit the formation of metabolites. Therefore, one of the pulmonary effects of monocrotaline that takes weeks to develop in vivo, inhibition of pulmonary endothelial transport of serotonin, can be observed under in vitro conditions. These results also directly demonstrate that the pulmonary damage caused by monocrotaline is a result of hepatic metabolism of monocrotaline to a pneumotoxic form.

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Background: A human ribosomal protein L9 (RPL9) encodes a protein that is a component of the 60S subunit. RPL9 is located on chromosome 4p14 and is approximately 5.5 kb in length and contains 8 exons. The message for human RPL9 is 712 nucleotides long. Some of the functions of RPL9 documented so far include the crucial involvement of the gene product in cell proliferation and protein biosynthesis. Lipoic acid synthetase (LIAS) is a 1.73 kb gene also located at chromosome 4p14. Alternative splicing occurs at these locus and two transcript variants encoding distinct isoforms have been identified but in this study the results represents both isoforms together. The protein encoded by LIAS gene belongs to the biotin and lipoic acid synthetases family and localizes in the mitochondrion. Function of lipoic acid synthetase is not yet well documented. Some studies have attempted to characterise its function by looking at the biological pathways at which LIAS gene product plays a crucial role, for example the biosynthesis of alpha-lipoic acid. Alpha lipoic acid is a natural antioxidant and it is also naturally-occurring enzyme co-factor found in a number of multi-enzyme complexes regulating oxidative metabolism. Motivation for study: RPL9 and LIAS were previously found to be mutated in CHO (Chinese Hamster Ovary) cell lines and these mutant lines had gained resistance to apoptosis. Aim: The main objective of this study was to evaluate the expression pattern of RPL9 and LIAS in lung cancer and to characterise their role in apoptosis and also to determine if the expression pattern of this genes varies between normal and diseased state of the tissue. Methods: In Situ hybridization, quantitative Real Time PCR, TUNEL and Bio-informatics have been employed in order to attain the objectives of this study. Results: In Situ hybridization showed that RPL9 localises in the cytoplasm and it is up-regulated in lung cancer relative to normal lung. LIAS localises in the cytoplasm and it is also up-regulated in lung cancer. The expression of RPL9 was relatively higher than that of LIAS determined by the intensity of localisation. Quantitative real time PCR confirmed the up-regulation of RPL9 and LIAS in lung cancer. RPL9 and LIAS were found to be up-regulated 8 and 4 fold respectively in lung A549 lung adenocarcinoma relative to MRC5 normal lung fibroblast cell lines. TUNEL showed the highest DNA fragmentation in adenocarcinoma, followed by squamous cell lung carcinoma then large cell lung carcinoma which is the same pattern observed in RPL9 and LIAS mRNA localisation by In Situ hybridization. To further characterise the role of RPL9 and LIAS in human, Bio-informatics tools were used and the results revealed that RPL9 is highly conserved through evolution, up-to 100 % identical to chimpanzee and 98 % to mouse. LIAS was found to be 91 % identical to rat and 90 % identical to mouse. It has been documented that the rate of conservation of a gene in evolution is believed to be correlated with its biological importance and its number of protein–protein interactions. Conclusion: All these discoveries coupled with resistance to apoptosis of CHO cell line in which RPL9 and LIAS were found to be mutated following promoter-trap mutagenesis, strongly suggests that RPL9 might be playing a role in cell cycle and apoptosis. RPL9 has been highly conserved through evolution. Manipulation of this gene can lead to greater biological discoveries in cancer research and the elevated expression of RPL9 can be used as a molecular marker for early detection of cancer.

University of Macau / Institute of Chinese Medical Sciences

To understand how the input impedance of the respiratory system relates to pressure and volume airflow of the airway branched structure, this thesis focuses on developing a mathematical model of the branched airway including trachea and branching airways. The 5-Lobe lung model is developed mathematically and experimentally. A computer model is constructed in the MathlabTM programming environment. It accounts for the effects of airways with varying cross-sectional area, flexible wall properties, and the bronchial tree within the lung using the mathematical methods developed in previous researches. The terminal impedances are determined by proposed idealized lobe models. A range of frequencies up to 256 Hz are tested on this model. Cases of study on obstructions by varying lung stiffness from healthy to unhealthy conditions are investigated.Mathematical model is validated by experiment investigations on the mechanical lung simulator, which is built in Diagnostic & Control Research Centre at Auckland University of Technology. The results conclude that mathematical methods used in this research are capable to produce predictable results of the input impedance.

1 v. (various pagings) ; / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Faculty of Medicine, 1972