2990 Microsurgery.qxd - O'Brien Institute

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Scientific Research Bernard O’Brien Institute of Microsurgery Expression of cyclin D1 in human cultured airway smooth muscle cells Asthma is a complex disease characterized by airway inflammation and bronchial hyperresponsiveness. An increase in the amount of smooth muscle in the airway is due to both hypertrophy (an increase in cell size) and hyperplasia (an increase in cell number). Increased production of cyclin D1 protein appears to be a key regulatory step for cells to divide. Exposing cultured human airway smooth muscle (HASM) cells in vitro to growth stimuli such as thrombin simulates the in vivo growth. Bronchodilators such as salbutamol are used by asthma sufferers during acute asthma attacks. Salbutamol is a ß 2 agonist that inhibits cell division and reduces the level of cyclin D1 protein. Our aims were to examine the effects of thrombin and salbutamol on cyclin D1 (mRNA) levels in cultured HASM cells. Northern Hybridisation showed that the expression of cyclin D1 message was maximal at 16 hours. The presence of salbutamol alone did not alter the level of cyclin D1 mRNA expression compared to control. Thrombin alone increased cyclin D1 mRNA expression by two fold. The combination of salbutamol and thrombin did not alter the amounts of message made in response to thrombin. We have also investigated the effects of glucocorticoids which are used as ‘preventers’ of asthma. Glucocorticoids reduce both the level of cyclin D1 protein and the level of its gene message indicating that these drugs have a different cellular action compared with the ß 2 agonists. We are now investigating whether these two different types of anti-asthma drugs produce longer effects when used in combination. Important protective proteins in the lungs of patients with emphysema This study examined the role of secretory leucocyte proteinase inhibitor (SLPI) as a protective antiproteinase in the lungs and how it may prevent the development of emphysema. Attention focused on the balance between destructive enzymes such as neutrophil elastase (NE) and protective antiproteinases such as alpha-1-antitrypsin (A1AT) and SLPI. It is known that only an estimated 10-15% of patients with A1AT deficiency develop the destructive lung disease known as emphysema. It was hypothesized that SLPI, produced locally in the lung, might be an important, additional protein which assists A1AT in protecting the lung against degradation by NE in those chronic airways limitation (CAL) patients who fail to develop emphysema. In those patients who develop emphysema, we hypothesize that they are deficient in both A1AT and SLPI. In a group of 34 CAL patients, one-third of whom were current smokers, we determined the net proteinase activity in lung lavage fluid using an enzyme assays for neutrophil elastase. In addition we used a sensitive biochemical assay to determine the respective concentrations of A1AT and SLPI in lung lavage fluid and the serum fraction of the circulating blood. In lung lavage fluid, the mean levels of SLPI were approximately one-third those of A1AT on a molar basis, whereas SLPI was present in barely detectable levels in serum. SLPI levels in the lung lavage fluid of CAL patients who were current smokers were significantly lower than those of non-CAL, non-smoking controls. A net balance in favour of proteinases was found in only 2 out of 34 patients, both undergoing an inflammatory episode at the time the specimens were collected. Given that SLPI is equally efficient as A1AT in neutralising neutrophil elastase activity, these results suggest that SLPI is present in the lung in levels sufficiently high to play a significant protective role in CAL patients. Since SLPI is synthesized by lung epithelial cells, it may provide the first line of defence against proteinase attack from neutrophil elastase, the major enzyme which degrades the molecules of the lung. Thus, the biochemical tests using lung lavage fluid and serum described in this study can be used to gain a better assessment of the proteinase-antiproteinase balance and therefore of the risk of developing emphysema. 25
Full and Part-Time Staff Bernard O’Brien Institute of Microsurgery Director Wayne Morrison MD, BS, FRACS Chief Research Scientist NH & MRC Senior Research Fellow Alastair Stewart (to 2/98) BSc(Hons), PhD Ross Vlahos (to 2/98) BSc(Hons), PhD Chief Executive Officer Geoffrey Renton BHA(UNSW), FACHSE, MNIA, AFAIM Senior Research Officers Kenneth Knight BSc(Hons), PhD, FACB, FAACB, MRCPath Research Fellows Tim Bennett FRACS (Australia) Senior Research Fellows Allan MacLeod MB BS, FRACS Geraldine Mitchell BSc(Hons), MSc PhD Michael Dowd MB BS (Australia) Anthony Berger MB BS, FRACS Bruce Dowsing BSc(Hons), PhD Ruitong Fan MD (China) Anthony Costello MB BS, FRACS Aurora Messina BSc(Hons), PhD Glykeria Pantazi MD (Greece) Damien Ireland MB BS, FRACS Peter Vadiveloo BSc(Hons), PhD Yoshio Tanaka MD (Japan) Anthony Penington MB BS, FRACS Research Officers Jane Barker BSc(Hons), PhD Milind Wagh MS, MCh (India) Consultant Pathologist John Hurley MD, PhD, MB BS, FRACP, FRCPA, FRCPath, FRACR(Hon) Daniel Crowe (to 2/98) BSc(Hons), PhD Zi-Jun Zhang MD (China) 26
Page 1 and 2: Bernard O’Brien Institute of Micr
Page 3 and 4: Patrons PATRON-IN-CHIEF His Excelle
Page 5 and 6: Chairman’s Report Microsurgery Fo
Page 7 and 8: Overview of Research Bernard O’Br
Page 9 and 10: Director’s Report Bernard O’Bri
Page 11 and 12: Director’s Report Bernard O’Bri
Page 13 and 14: Scientific Research Bernard O’Bri
Page 25: Scientific Research Bernard O’Bri
Page 29 and 30: Publications Bernard O’Brien Inst
Page 31 and 32: Collaborations Bernard O’Brien In
Page 33 and 34: Presentations Bernard O’Brien Ins
Page 35 and 36: Visiting Lecturers Bernard O’Brie
Page 37 and 38: Named Fellowships Bernard O’Brien
Page 39 and 40: Financial Statements PROFIT AND LOS
Page 41: Donations Bernard O’Brien Institu

2990 Microsurgery.qxd - O'Brien Institute

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