Revolutionary new results concerning substances that play major roles in the inflammatory response have been published in the American scientific journal PNAS in two articles from Karolinska Institutet. Inflammation is important in, for example, cardiovascular disease. The results open the way for the development of new drugs both for prevention and for treatment.
Conditions and diseases that involve inflammation include severe infection, arthritis, asthma and arteriosclerosis. Certain substances, such as cytokines, are formed during the inflammation response and contribute to its various aspects. Professor Jesper Haeggström and his group, working in close collaboration with Professor Jan Palmblad's group, show in the first of two articles published in Proceedings of the National Academy of Sciences (2 May 2006) that several of these substances can influence the cells of the blood vessel wall such that they start to express receptors for a leukotriene, LTB4.
This enables the cells to react to LTB4 and to transmit signals that reinforce the inflammation. LTB4 is a powerfully chemotactic and immuno-modulating substance that is important for the motion of white blood cells over the walls of the blood vessel when the tissue becomes damaged and inflamed. It has previously been believed that the cells of the blood vessel wall are silent, unable to react to LTB4.
The demonstration of new factors that control the interplay between the blood vessel cells and the white blood cells that are crucial in the inflammatory process will enable the development of new drugs to be targeted against these factors. New drugs may in the long term become available for use during chronic inflammation such as arthritis, asthma and cardiovascular disease.
The second of the two articles presents the first report of a study that has been carried out in collaboration with arteriosclerosis researchers and surgeons at the Karolinska University Hospital, Solna. The study has investigated all enzymes and receptors that are involved in the formation and signalling of leukotrienes in arteriosclerotic tissue (hardened and calcified arteries). The experimental material has been obtained from the biobank Karolinska Endoarterectomies, in which material from patients who have received surgery for hardened arteries has been collected.
Three enzymes that have increased levels in arteriosclerotic tissue have been identified in the study; the levels of two of these enzymes are particularly highly increased in patients who are experiencing or who have recently experienced symptoms of acute vascular disease with the formation of clots. These three enzymes are vital for the formation of the immuno-modulating substance LTB4, and one of them, leukotriene A4 (LTA4) hydrolase, is particularly important. The focus that has now been placed on these critical enzymes and signal substances may accelerate the development of drugs for both the treatment and the prevention of hardening of the arteries and heart attacks.
The research at Karolinska Institutet into eicosanoids, of which both leukotrienes and prostaglandins are examples, has long been in the international vanguard. Professor Bengt Samuelsson was one of three scientists awarded the Nobel Prize in Physiology or Medicine in 1982 for the discovery of these substances, and has participated in the study on leukotrienes and arteriosclerosis. Professor Jesper Haeggström is carrying on the work into eicosanoids and is the leader for a major EU project, EICOSANOX (www.eicosanox.org) that is looking at these central substances and the role they play in several major widespread diseases: cardiovascular disease, arteriosclerosis, dementia and cancer.
"Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B4". Qui H, Johansson A-S, Sjöström M. Wan M, Schröder O, Palmblad J, Haeggström JZ. PNAS 103: 6913-18, 2 May 2006.
"Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human arterosclerotic lesions correlates with symptoms of plaque instability". Qui H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong C-H, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggström JZ. PNAS 103:8161-6,12 May 2006.
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Professor Jesper Z. Haeggström