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Heart disease prevention should start with the young, studies suggest
SCIENCE AND MEDICINE
There’s no pain without brain
I
n 1982 John Vane (William Harvey Research Institute, London, UK) was awarded a Nobel Prize for his work on non-steroidal anti-inflammatory drugs. This week, two studies published in Nature show that Vane’s hypothesis—that production of prostaglandin E2 (PGE2) by cyclooxygenase induction at the site of peripheral inflammation is responsible for producing inflammatory pain—is incomplete. “There is also a major central component”, explains Clifford Woolf (Massachusetts General Hospital, Charlestown, MA, USA), the lead author of one of the studies. Woolf’s team applied a chemical to the hind paws of rats to induce mild inflammation. “We found that a localised experimental peripheral inflammation results in a rapid (within a few hours) substantial induction of cyclo-oxygenase 2 [COX-2] in neurons in the spinal cord and brain, and that this in turn results in a large increase in PGE2 in the cerebrospinal fluid”, explains Woolf (Nature 2001; 410: 471-75). In another study published this month, the same research group show that PGE2 increases the excitability of neurons in the spinal cord, such that innocuous inputs, such as gentle touch, elicit pain—a phenomenon called central sensitisation (J Neurosci 2001; 21: 1750–56).
Importantly, Woolf’s team was able to show that this upregulation of COX-2 was not due to afferent input from nerve fibres innervating the inflamed hind paw, since blockade of sciatic nerve conduction produced little pain relief. Rather, the data suggest that a humoral signalling molecule is responsible. Indeed, they found a 10 000-fold increase in the cerebrospinal fluid concentration of the pro-inflammatory cytokine, IL-1, following peripheral inflammation. “It seems that it is mainly the increase in cerebrospinal levels of IL-1 that tells the brain about local inflammation”, explains Tamas Bartfai (Scripps Research Institute, La Jolla, CA, USA) in an accompanying commentary. Furthermore, intrathecal administration of drugs that inhibit the production of IL-1, or that block the IL-1 receptor on neurons, markedly reduced the hyperalgesia. The inhibition was less effective when the same drugs were given systemically, however. “This work should encourage drug companies to try and develop centrally acting COX-2 or IL-1 antagonists that are active at low concentrations”, says Lucy Donaldson (University of Bristol, UK). Since many blood-borne signalling molecules released from the site of inflammation, such as IL-1,
cannot cross the blood-brain barrier, the question remains as to what triggers the production of IL-1 in the cerebrospinal fluid. In the second Nature paper, Anders Blomqvist (University of Linköping, Sweden) and co-workers show that systemic injection of IL-1 can result in the production of PGE2 through the induction of COX-2 and the newly discovered microsomal prostaglandin E synthase in bloodbrain-barrier cells. Since PGE2 activates the synthesis of IL-1 by microglia, this could explain Woolf’s observation of a large increase in IL-1 concentration in the cerebrospinal fluid. “Our data have obvious clinical relevance”, Blomqvist told The Lancet. “Microsomal, glutathione dependent, prostaglandin E synthase is a potential new drug target for the treatment of CNS-controlled acute phase reactions such as pain and fever, and because it is the final enzyme in prostaglandin E synthesis, its inhibition may carry fewer systemic side-effects than the presently used COX inhibitors.” Donaldson is not convinced, however: “I’m not sure that targeting prostaglandin E synthase would be any better as a therapy, as PGE2 is important elsewhere for normal and pathophysiological function.” James Butcher
Heart disease prevention should start with the young, studies suggest fforts to prevent heart disease should start when people are still young, according to two new US studies. In the first study, researchers followed 11 016 men who were 29-years-old on average when they entered the study more than 20 years ago. At the time they enrolled, all the participants were screened for risk factors associated with cardiovascular disease, including elevated serum cholesterol, hypertension, and smoking. The researchers report that during the 20 years of follow-up 455 of the men died, 155 from cardiovascular disease. 123 died of coronary artery disease, making it the leading cause of death overall. The investigators found that the risk factors that can predict a middle-aged man’s risk of dying from heart disease—such as age, systolic blood pressure, and cigarette smoking—could also predict a
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THE LANCET • Vol 357 • March 24, 2001
younger man’s risk. And, in general, the relative risks associated with these factors had the same magnitude in the younger men—except for elevated cholesterol concentrations, which were associated with even higher risk (Ann Intern Med 2001; 134: 433–39) “There is a wake-up call here that we should be attending to the prevention of these risk factors much earlier in life”, says Philip Greenland of Northwestern University Medical School (Chicago, IL), the paper’s senior author. In the second report a team of US researchers examined the coronary arteries and aortas of 629 men and 227 women, aged 15 to 34 years, who had died from an accident, homicide, or suicide, and who had normal lipoprotein profiles (Circulation 2001; 103: 1546–50). They found that even though these young men and women had normal
lipoprotein concentrations, those with other cardiovascular risk factors, such as hypertension, smoking, obesity, and diabetes, had a significantly higher risk for having atherosclerotic changes, such as fatty streaks and raised lesions, in their blood vessels. The location, whether it was in a coronary artery or the aorta, for example, and type of lesion varied depending on the risk factors involved and the individual’s sex and race. Lead author Henry McGill (University of Texas Health Science Center, San Antonio, TX, USA) said that the lesson of the study is that all the risk factors for heart disease need to be addressed. “Instead of focusing on cholesterol, obesity, or smoking what we’ve got to promote is a healthy lifestyle.” Michael McCarthy
939
For personal use only. Reproduce with permission from The Lancet Publishing Group.
There’s no pain without brain
I
n 1982 John Vane (William Harvey Research Institute, London, UK) was awarded a Nobel Prize for his work on non-steroidal anti-inflammatory drugs. This week, two studies published in Nature show that Vane’s hypothesis—that production of prostaglandin E2 (PGE2) by cyclooxygenase induction at the site of peripheral inflammation is responsible for producing inflammatory pain—is incomplete. “There is also a major central component”, explains Clifford Woolf (Massachusetts General Hospital, Charlestown, MA, USA), the lead author of one of the studies. Woolf’s team applied a chemical to the hind paws of rats to induce mild inflammation. “We found that a localised experimental peripheral inflammation results in a rapid (within a few hours) substantial induction of cyclo-oxygenase 2 [COX-2] in neurons in the spinal cord and brain, and that this in turn results in a large increase in PGE2 in the cerebrospinal fluid”, explains Woolf (Nature 2001; 410: 471-75). In another study published this month, the same research group show that PGE2 increases the excitability of neurons in the spinal cord, such that innocuous inputs, such as gentle touch, elicit pain—a phenomenon called central sensitisation (J Neurosci 2001; 21: 1750–56).
Importantly, Woolf’s team was able to show that this upregulation of COX-2 was not due to afferent input from nerve fibres innervating the inflamed hind paw, since blockade of sciatic nerve conduction produced little pain relief. Rather, the data suggest that a humoral signalling molecule is responsible. Indeed, they found a 10 000-fold increase in the cerebrospinal fluid concentration of the pro-inflammatory cytokine, IL-1, following peripheral inflammation. “It seems that it is mainly the increase in cerebrospinal levels of IL-1 that tells the brain about local inflammation”, explains Tamas Bartfai (Scripps Research Institute, La Jolla, CA, USA) in an accompanying commentary. Furthermore, intrathecal administration of drugs that inhibit the production of IL-1, or that block the IL-1 receptor on neurons, markedly reduced the hyperalgesia. The inhibition was less effective when the same drugs were given systemically, however. “This work should encourage drug companies to try and develop centrally acting COX-2 or IL-1 antagonists that are active at low concentrations”, says Lucy Donaldson (University of Bristol, UK). Since many blood-borne signalling molecules released from the site of inflammation, such as IL-1,
cannot cross the blood-brain barrier, the question remains as to what triggers the production of IL-1 in the cerebrospinal fluid. In the second Nature paper, Anders Blomqvist (University of Linköping, Sweden) and co-workers show that systemic injection of IL-1 can result in the production of PGE2 through the induction of COX-2 and the newly discovered microsomal prostaglandin E synthase in bloodbrain-barrier cells. Since PGE2 activates the synthesis of IL-1 by microglia, this could explain Woolf’s observation of a large increase in IL-1 concentration in the cerebrospinal fluid. “Our data have obvious clinical relevance”, Blomqvist told The Lancet. “Microsomal, glutathione dependent, prostaglandin E synthase is a potential new drug target for the treatment of CNS-controlled acute phase reactions such as pain and fever, and because it is the final enzyme in prostaglandin E synthesis, its inhibition may carry fewer systemic side-effects than the presently used COX inhibitors.” Donaldson is not convinced, however: “I’m not sure that targeting prostaglandin E synthase would be any better as a therapy, as PGE2 is important elsewhere for normal and pathophysiological function.” James Butcher
Heart disease prevention should start with the young, studies suggest fforts to prevent heart disease should start when people are still young, according to two new US studies. In the first study, researchers followed 11 016 men who were 29-years-old on average when they entered the study more than 20 years ago. At the time they enrolled, all the participants were screened for risk factors associated with cardiovascular disease, including elevated serum cholesterol, hypertension, and smoking. The researchers report that during the 20 years of follow-up 455 of the men died, 155 from cardiovascular disease. 123 died of coronary artery disease, making it the leading cause of death overall. The investigators found that the risk factors that can predict a middle-aged man’s risk of dying from heart disease—such as age, systolic blood pressure, and cigarette smoking—could also predict a
E
THE LANCET • Vol 357 • March 24, 2001
younger man’s risk. And, in general, the relative risks associated with these factors had the same magnitude in the younger men—except for elevated cholesterol concentrations, which were associated with even higher risk (Ann Intern Med 2001; 134: 433–39) “There is a wake-up call here that we should be attending to the prevention of these risk factors much earlier in life”, says Philip Greenland of Northwestern University Medical School (Chicago, IL), the paper’s senior author. In the second report a team of US researchers examined the coronary arteries and aortas of 629 men and 227 women, aged 15 to 34 years, who had died from an accident, homicide, or suicide, and who had normal lipoprotein profiles (Circulation 2001; 103: 1546–50). They found that even though these young men and women had normal
lipoprotein concentrations, those with other cardiovascular risk factors, such as hypertension, smoking, obesity, and diabetes, had a significantly higher risk for having atherosclerotic changes, such as fatty streaks and raised lesions, in their blood vessels. The location, whether it was in a coronary artery or the aorta, for example, and type of lesion varied depending on the risk factors involved and the individual’s sex and race. Lead author Henry McGill (University of Texas Health Science Center, San Antonio, TX, USA) said that the lesson of the study is that all the risk factors for heart disease need to be addressed. “Instead of focusing on cholesterol, obesity, or smoking what we’ve got to promote is a healthy lifestyle.” Michael McCarthy
939
For personal use only. Reproduce with permission from The Lancet Publishing Group.