COX-1 is found in many different tissues, but coX-2 is usually found only in tissues that have become inflamed. Older NSAIDs, such as aspirin, ibuprofen, naproxen, and many others, inhibit both COX-1 and COX-2 enzymes. Decreasing the amount of prostaglandins made by coX-2 in inflamed tissues is anti-inflammatory and is useful for treating the symptoms of arthritis. older NSAIDs inhibit COX-2 but also inhibit COX-1 and thus decrease the amount of thromboxane made by platelets. Decreasing thromboxane and making platelets less sticky can be helpful for preventing heart attacks, strokes, and illnesses caused by blood clots, but it can also increase the risk of bleeding. Aspirin is a unique NSAID because it has very long-lasting effects on the platelet COX-1 enzyme, and this is why aspirin is used to prevent heart attacks and strokes. COX-1, in addition to being found on platelets, is also found in the stomach where the prostaglandins it makes protect against ulcers. The result is that older NSAIDs that block COX-1 and COX-2 are more likely to cause peptic ulcers as a side effect. To overcome this increased risk of peptic ulcer, scientists developed drugs that blocked COX-2 and did not have much effect on COX-1. These drugs are sometimes called COX-2 selective NSAIDs (see rofecoxib, cele-coxib, and valdecoxib).
COX-2 selective drugs are no more effective in decreasing pain and inflammation than nonselec-tive NSAIDs but cause GI side effects less often. Other common side effects of NSAIDs such as hypertension and decreased kidney function do occur with COX-2 selective drugs, perhaps because some COX-2 is present in normal kidneys. COX-2 selective drugs have no effect on COX-1 and therefore do not decrease platelet stickiness and cannot be used to prevent heart attacks. in fact, in one clinical trial a few more heart attacks occurred in people taking high doses of the COX-2 selective drug rofecoxib than in those taking an older, non-selective NSAID, naproxen. It is not clear if this was a chance finding, or if naproxen decreased the frequency of heart attack because of its effects on COX-1 in platelets, or if rofecoxib increased the chance of heart attack. Standard doses of COX-2 selective drugs have not been associated with an increased risk of heart attack.
cystic fibrosis The most common lethal genetic disorder in western caucasian populations, cystic fibrosis is the result of an abnormality in the gene for the CFTR or cystic fibrosis transmembrane regulator and affects about 1 in every 3,000 births in Caucasian Americans and 1 in every 15,000 births in African Americans. Cystic fibrosis affects many different glands, including those lining the walls of the intestines, lungs, and sinuses. symptoms of the disease often start in childhood. A common symptom is poor absorption of food because the intestinal glands that are important for digesting food are not functional. Repeated attacks of pneumonia are common because the glands in the layer lining the passages of the lungs are not able to stop the normal lung secretions from plugging up the airways and causing infections. Antibiotics and other medical advances have improved the prognosis and, perhaps because more patients with cystic fibrosis are surviving into their thirties, arthritis-related problems are now recognized more often.
Cystic fibrosis arthritis A few patients with cystic fibrosis have developed a type of arthritis that seems to be specifically associated with the illness. This arthritis comes in acute attacks lasting days or weeks, can affect one or several joints, and is often accompanied by a skin rash, usually erythema nodosum. Tests for rheumatoid factor and antinuclear antibodies (see Appendix II) and X rays are usually negative. The cause is not known, but because patients with cystic fibrosis suffer from recurrent infections, several investigators have searched for an infectious cause. Infection could cause arthritis either directly or indirectly. According to one theory, infection could trigger an autoimmune response and cause arthritis because the molecular structure of parts of some infectious organisms is similar to that of parts of the human genome. Researchers have not consistently found particular infections to be associated with arthritis in cystic fibrosis. Another possibility is that genetic variability in people with cystic fibrosis may explain why only some get arthritis. Thus, the actual genetic variant of cystic fibrosis a person has, as well as his or her individual immune response genes, may be important. so far there is little information to support this suggestion. A plausible explanation is that because patients with cystic fibrosis have poor pancreatic function and therefore do not absorb food well, they are more likely to develop enteropathic arthritis, a condition that causes a similar type of arthritis. information about responses to different treatments is limited. NSAIDs can improve symptoms, and some studies show that they may also help the respiratory problems. if possible, immunosuppressive drugs are avoided because patients with cystic fibrosis are already predisposed to developing infections.
Hypertrophic pulmonary osteoarthropathy Any chronic lung problem, including cystic fibrosis that causes clubbing (swelling of the tips of the fingers), can cause hypertrophic pulmonary osteoarthropathy. The treatment of this condition is based on decreasing the underlying infections, usually with rotating courses of antibiotics.
Osteoporosis patients with cystic fibrosis often have a low absorption of vitamin D and calcium, two essential requirements for healthy bones. Also, because of chronic illness they are often not very active and therefore have a greater chance of developing osteoporosis. The treatment of osteoporosis in patients with cystic fibrosis is similar to that of other patients with osteoporosis, but particular attention is needed to ensure that enough vitamin D and calcium is absorbed.
Vasculitis A few patients with cystic fibrosis have developed vasculitis affecting the skin, internal organs, or both. No other cause was found, and therefore cystic fibrosis is thought perhaps to increase the risk of vasculitis.
Amyloidosis patients with chronic infection or inflammation have an increased chance of developing secondary amyloidosis, and a few cases have occurred in patients with cystic fibrosis.
cytokines Small molecules that act as messengers between cells, particularly cells that regulate the immune response. Cytokines are important for local communication between cells, in contrast to hormones, which circulate in the bloodstream and exert their effects on distant organs or tissues. Low levels of some cytokines can be detected in the circulating blood of healthy people, but they exert their main action over the very short distances between cells in the same locality. The first local messenger proteins discovered in 1969 were pro duced by lymphocytes and so were called lym-phokines. The name cytokine soon replaced the name lymphokine because other types of white blood cell also produced these messengers. Cyto-kines are produced mainly by white blood cells that have been activated. The cytokine is then released into the space between cells. if it comes into contact with its specific receptor on neighboring cells, it binds to the receptor and activates responses in the target cell. These may either increase or decrease inflammation and growth. More than 150 cytokines are currently known. However, the information made available by the human genome project will allow scientists to identify many new molecules that have a cytokine-like structure and then to work forward and discover their biological function. Many cytokines share functions so that often several cytokines can cause the same effects on target cells. Cytokines can be divided according to whether their main effect is to increase or decrease inflammation.
Cytokines that Increase Inflammation Tumor necrosis factor alpha (TNF-a) Tumor necrosis factor got its name from the observation that if scientists produced inflammation in animals that had experimental tumors, then the animals produced a substance, later called TNF, that could cause necrosis (death) of part of the tumors. TNF-a is produced mainly by monocytes and macrophages but can be produced by activated B and T cells and fibroblasts. it stimulates cells to produce other cytokines that increase inflammation such as interleukin-1 and interleukin-6. If TNF is injected into animals, it causes fever, loss of weight, and shock. TNF-a seems to be particularly important in rheumatoid arthritis because mice that have been genetically engineered to make too much TNF-a develop an illness similar to rheumatoid arthritis (RA). In humans, TNF-a is found in the synovial fluid of patients with RA, and blocking TNF-a with an antibody, or mopping it up with a decoy protein, is an effective treatment for RA (see ADALIMUMAB, ETANERCEPT, INFLIXIMAB). TNF binds to two receptors called p55 and p75. Some of these receptors are bound to cells, but others are not and are called soluble receptors. The soluble receptors can act as a sump to mop up TNF and stop it from reaching receptors bound to cells and activating them.
Interleukin-1 (IL-1) IL-1 is produced mainly by monocytes and macrophages but can be produced by endothelial cells that line blood vessels and by activated B and T cells. A lot of evidence suggests that IL-1 is important in RA. When IL-1 was injected into the knee joints of rabbits, it caused damage. In animal models of arthritis, blocking IL-1 with antibodies decreased the amount of joint damage. In humans, IL-1 is present in the synovial fluid of patients with RA.
IL-1 acts through two types of IL-1 receptors. Type I receptors are linked to cells so that the cells respond if this receptor is activated, but type II receptors are not linked to a signaling system and act as decoy receptors. Another mechanism used by the body to control IL-1 activity is to produce a protein that acts as an antagonist. This protein is called IL-1 receptor antagonist (IL-1ra) and binds to the same receptor site that IL-1 binds to but does not activate the cell. If IL-1ra has bound to the site where IL-1 would otherwise bind, the binding site is blocked and IL-1 cannot bind and activate the cell. This naturally occurring antagonist of IL-1 turned out to be therapeutically useful because it was manufactured and has been developed as a drug that is an effective treatment for RA (see anakinra.)
Interleukin-6 (IL-6) IL-6 is produced by mono-cytes, macrophages, activated T cells, and synovial fibroblasts that line joints and promotes inflammation.
Cytokines that Decrease Inflammation Interleukin-10 (IL-10) IL-10 is produced by monocytes, macrophages, and B and T cells. IL-10 acts on cells to stop them from producing IL-1 and TNF-a, cytokines that increase inflammation.
Interleukin-4 (IL-4) IL-4 is produced by T cells and acts on them so that they produce less IL-1 and TNF-a.
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