annual report - O'Brien Institute

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Macrophages and Inflammation Senior Scientist: Peter Vadiveloo Members of the Laboratory: Matias Abregu, Angela Arvanitis, Bruce Dowsing, Tanya Harkom, Effie Keramidaris, Wayne Morrison, Rosalind Romeo. ...and Major Collaborators: Fiona Clay c , Matthias Ernst c , Paul Hertzog b , John Hamilton d , Alastair Stewart a , and Gino Vairo e . aDepartment of Pharmacology, University of Melbourne bMonash Medical Centre, Clayton, Vic. cLudwig Institute for Cancer Research, Parkville Vic. dUniversity Department of Medicine, Royal Melbourne Hospital, Parkville. eWalter and Eliza Hall Institute, University of Melbourne, Parkville. Mechanisms of macrophage activation Macrophages are derived from white blood cells called monocytes. Macrophages are dynamic cells involved in many important processes in the body, making them an exciting cell type to study. Following surgery a variety of processes may occur at the repaired site, including wound healing, inflammation, fighting infection, new blood vessel formation (angiogenesis) and blood vessel thickening (atherosclerosis). Macrophages are known to play central roles in all of these processes. Our studies aim to discover the molecular mechanisms underlying macrophage functions since knowledge of fundamental biological processes will ultimately result in better treatment of patients following trauma and surgery. We have made the unique discovery that activated macrophages make a protein called cyclin D2. We believe this protein regulates macrophage functions. We are trying to better understand the role of cyclin D2 in activated macrophages. An exciting advance in these studies over the past year has been the beginning of experiments using cyclin D2 ‘knockout’ mice. These mice (which come from our colleagues at the Dana Farber Cancer Institute in Boston) have been genetically engineered with the cyclin D2 gene knocked out. Our preliminary data indicate cyclin D2 may regulate production of inflammatory cytokines by macrophages. Confirmation of this finding will provide a significant advance in our understanding of how macrophages work. In other work on this project, Honors student Matias Abregu is identifying cytokines that stimulate cyclin D2 synthesis in macrophages. In other studies that link in with work on nitric oxide (NO), we have shown that NO production by macrophages is mediated by type I IFNs, and that NO does not play a role in preventing proliferation during macrophage activation. Macrophages and new blood vessel formation (angiogenesis) Macrophages are known to secrete a number of proteins which regulate new blood vessel formation (angiogenesis). We have shown that angiogenesis is altered in mice lacking iNOS (inducible nitric oxide synthase). Given that macrophages make iNOS protein, we propose that synthesis of pro-angiogenic molecules such as vascular endothelial growth factor (VEGF) is altered in macrophages lacking iNOS. To explore this we are measuring the release of angiogenic molecules from macrophages derived from iNOS ‘knockout’ mice. Wound Healing in Tendons Senior Scientists: David McCombe, Tony Penington, Wayne Morrison. Members of the Laboratory: Rosalind Romeo, John Hurley. ...and Major Collaborators: Tracey Brown m , V Gunzler k , Erik W Thompson j and JF Williams k jVictorian Breast Cancer Research Consortium, St Vincent’s Hospital Melbourne. kDepartment of Engineering, University of Melbourne. mDepartment of Biochemistry and Cell Biology, Monash University Tendon adhesions are a significant complication of tendon injury or infection. After surgical repair of a tendon, scar tissue often forms around the tendon, binding it to the sheath (tunnel) in which it slides. In these experiment we have been attempting to mimic these tendon adhesions in the human using an animal model. We isolated a healthy tendon and injected an irritant substance (eg. carrageenan, iodine, oxytetracyclin, endotoxin or other abrasive agents) into the sheath to create adhesions. The animal was euthanised 1-3 weeks later and the limb isolated. A force transducer was used to pull the digit into full flexion so that the claw touches the sole of the foot, a measure of the strength of the adhesions. We also studied the effects of inhibitors of prolyl-4hydroxylase and collagen synthesis on flexor tendon adhesion formation and skin wound healing. Rats were divided equally into three groups to receive post-operative oral doses of two test drugs or no drug (control). Animals were sacrificed fourteen days after a zone II tendon crush injury with suture immobilization, and a dorsal skin patch excision. Tendon adhesion formation was estimated biomechanically using work of flexion (WOF) of the digit. Skin healing was measured using wound area and histology. Compared to the control group, WOF against adhesions was reduced by approximately 70% in both drug groups. All skin wounds healed equally well, but in both drug groups there was minimal deposition of scar collagen. These drugs may become useful clinically to reduce adhesions following flexor tendon surgery and in hand and foot surgery where modulating collagen scar formation is important. stabilised our position financially both among the business community and with government. We will greatly miss Alan’s calm and charm and sincerely thank him for his outstanding contributions. We wish him well for the future. This year through a generous donation of our Chairman we have been able to employ a Developmental Manager, Mr Sam Broughton. Sam has an excellent track record both in Victoria and South Australia where he has worked with several bodies, most recently the Red Cross. We are hopeful that this will lead to new avenues of fundraising and increase our professionalism in the marketplace. This year we have instituted a younger group under the auspices of the Microsurgery Foundation. We are especially indebted to them for their generosity for coming on board and believe this will be an exciting development for us in the future. We are indebted to many large donors and funding bodies, many of whom have repeatedly supported us in a major way. These include the Victorian State Government, National Health & Medical Research Council, Transport Accident Commission, The Jack Brockhoff Foundation, National Australia Bank, Evelyn M. Coy Estate, The Wellcome Trust, BHP Community Trust, Tattersall’s, L.E.W. Carty Charitable Fund, HIH Insurance Ltd. We are grateful to Ms Sue McKay and Ms Liliana Pepe and their staff in the Experimental and Medical Surgical Unit. For many years they have provided an outstanding level of cooperation and support to the staff of the Bernard O’Brien Institute of Microsurgery. We also thank Dr Jim Shaw, Chairman of St. Vincent’s Hospital Animal Ethics Committee and his board members who oversee all our projects and ensure the highest standards of animal care are maintained. We are also grateful to the ward staff and operating theatre staff of both St. Vincent’s Public and Private Hospitals. Wayne A Morrison MD, BS, FRACS Director MICROSURGERY FOUNDATION 24 17
Barbara Walker Centre for Pain Management Bernard O’Brien Institute of Microsurgery Director Dr Andrew Muir I am pleased to report that significant progress has been made in the management and treatment of pain at the Barbara Walker Centre for Pain Management, in this our second full year of operation. The mission of the Centre is to provide specialist multi-disciplinary assessment and treatment services for the management of complex pain across all disciplines of medicine. Through its association with the Bernard O’Brien Institute of Microsurgery, the Barbara Walker Centre for Pain Management conducts medical research to improve clinical outcomes for acute pain sufferers. Research · Two posters presentations were submitted to the IASP’s 9 th World Congress on Pain in August 1999 and subsequently accepted for publication. The presentations related to “Assessing Dynamic Standing Balance in Clinic Patients: the Step Test” and “The Depression Anxiety Stress Scale in Patients with Persistent Pain”. · Collaborative research with the Australian Centre for Neuropharmacology in an international multi-centre trial of a novel pharmaceutical for the treatment of post herpetic neuralgia. · Development of protocols in respect to undertaking research into: a) Prospective survey of posture types of patients presenting assessment at Barbara Walker Centre for Pain Management. b) Register of women taking anticonvulsant medications for the treatment of persistent, neuropathic pain. Clinical Activity Clinical activity is a core function of the Barbara Walker Centre for Pain Management. The number of patients that we treat is dependent upon referrals that we receive. We are indeed fortunate to have the support of those in general medical practice, who have welcomed our specialist initiatives in the treatment of pain and who refer their patients to us. During the past year we have seen in excess of 1,000 patients which is a significant increase over the numbers we treated in our first year. All clients receive an individual assessment of their condition and tailored programs are devised for treatment encompassing a range of specialist services. The START program is an important component of our clinical activity and we have seen the number of participants increase during the year under review. Medical Education Education is an important function of the Barbara Walker Centre for Pain Management. In other circumstances it is specifically the blood supply to tissues that is interrupted and, when it is not restored, death (necrosis) of the part will ensue. Even if the circulation is restored the toxic products that have accumulated in the devascularised part will trigger an inflammatory response in an attempt to prevent these toxins causing harm to the body. This process is known as the ischaemia-reperfusion injury and it can cause death of the part despite a “successful” revascularisation. This typically occurs following replantation or tissue transfer and is more severe the longer the part has been detached from the body. Factors Involved in Ischaemia-Reperfusion Injury We have been investigating the mechanisms of ischaemia-reperfusion (IR) injury and techniques to minimise the damage caused by this process. This research has direct application to all microvascular reconstructive procedures that are currently performed as well as increasing the success rates of replantation. It is vitally important in organ transplantation and in reducing the damage caused by strokes and heart attacks. In the future the research will enable tissues to be preserved for prolonged periods leading to tissue banks. (a) Mast cell factors To determine the role of mast cells (a type of white blood cell) in IR injury to skeletal muscle, mast celldeficient mice and their corresponding genetically normal (i.e. wild type) mice were subjected to tourniquet ischaemia and reperfusion. Muscle viability after this injury was 9% in wild type controls and 94% in mast cell-deficient animals (P
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