acute phase response. Perhaps this is the key to understanding the placebo effect.
THE ACUTE PHASE RESPONSE
Dealing with injury and infection is vital to survival. It is hardly surprising, then, that all animals possess mechanisms designed specifically to deal with wound healing and microbial defence. In mammals such as ourselves, these mechanisms are remarkably complex and, when they function correctly, produce an exquisitely choreographed suite of reactions which biologists are only now beginning to fully appreciate. The first stage in this process is known as the acute phase response, or, less technically, as inflammation.
For hundreds of years, Western medicine recognised the four signs of inflammation as tumor, rubor, calor and dolor – swelling, redness, heat and pain. In the last decades of the twentieth century, biologists discovered a few more. Besides these physical changes, there are also important psychological ones, including lethargy, apathy, loss of appetite and increased sensitivity to pain – a suite of symptoms that are collectively known as ‘sickness behaviour’.1 Taken together, the four classic signs of inflammation and the psychological symptoms of sickness behaviour constitute the complex set of processes referred to as the acute phase response.2
For a long time, doctors tended to regard the signs of inflammation and sickness behaviour as part of the disease process itself. The lethargy that commonly ensues after infection, for example, was thought to result from debilitation, as if the body had simply run out of energy. It is now known, however, that the various components of the acute phase response are not themselves pathological. On the contrary; they are actively produced by the body itself as part of the healing process. They may feel unpleasant, but they are actually good for you. In fact, feeling unpleasant is a vital part of their function.
PAIN
The value of feeling bad is nowhere better illustrated than in the case of pain. Pain, as everyone knows, is a great protector. The classic textbook illustration shows someone withdrawing their hand very rapidly from a hot stove they have just touched by accident. This acute pain is obviously beneficial, causing you to move away quickly from damaging objects. Even more important, however, is the second phase of pain that tends to follow the acute pain. Acute pain is sharp and stabbing, and ends when you are no longer in contact with the source of damage; the second type of pain is deep and spreading, and can last for minutes, hours, days, or even months. This kind of pain is not caused by pressure or heat from the outside world, but by chemicals released by the body itself. And, unlike acute pain, which produces rapid movement, the second type of pain causes you to keep the wounded area as still as possible, and encourages you to take extra care to shield the area from fresh injury while the process of repair is completed.
The capacity for pain, then, confers an advantage on those who have it. Exactly how advantageous this capacity is may be inferred from the sorry fate of those rare individuals who happen to be born without it. Almost everyone with this condition, which is known as congenital analgesia, is dead by the age of thirty. Without the capacity for acute pain, they do not withdraw from damaging objects unless their other senses inform them of the injury. One girl with the disorder, for example, knelt on a hot radiator while she gazed out of a window, blissfully unaware of the burning flesh. Her knees were scarred for the rest of her life, which was not very long, since she died at the age of twenty-two.3
It is not the lack of acute pain that kills people with congenital analgesia, however, but the lack of the second kind of pain. The lack of the deeper, longer-lasting second phase of pain is far more deadly than the lack of acute pain, since no effort is made to guard wounded areas. The result is that injuries never heal properly, and the accumulating mass of dead and damaged tissue becomes a target for bacteria, which eat their way into the bone marrow. Having bacteria inside your bones is a serious condition called osteomyelitis; this was what eventually killed the girl who knelt on the radiator.
Next time you are gripped by an intense pain, then, you might pause to consider how lucky you are. Evolution has endowed you with a vital defence mechanism, and without it your life expectancy would be considerably shorter. In a world where minor injuries such as scratches, burns, and bruises are common fare, it really is good to be able to feel bad.
SWELLING
The same logic applies to all the other aspects of the acute phase response. Swelling, for example, is also a defensive process, caused by the leakage of plasma and the migration of immune cells into the area of damaged tissue. All bodily damage, whether caused by injury or infection, consists of broken cells, and when the walls of a cell rupture, an array of molecules, which would not otherwise be released, spill out into the surrounding tissue. Some of these molecules trigger the sensory nerves to produce the ongoing, second type of pain just described. The sensory nerves also react by causing the blood vessels to widen, increasing local blood flow, and making the walls of the blood vessels more permeable. With greater blood flow, more white blood cells – the infantry of the immune system – can be carried to the site of the injury. The greater permeability of the blood-vessel walls enables the white blood cells to flow out of the arteries and veins into the surrounding tissue to defend against possible bacterial invaders. If no bacteria have found their way into the wound, particular white blood cells known as macrophages clear up the debris of the shattered cells by engulfing and digesting it. If bacteria have gained a foothold and started to multiply, the white cells form a barrier to create a pus-filled abscess in which the blood fluid – the serum – plays a key role in healing.
Besides clearing up debris and attacking bacteria themselves, the macrophages also release a number of chemical messengers. These signalling molecules, or cytokines, play a vital role in co-ordinating the acute phase response by facilitating both short-distance communication among the immune cells themselves, and long-distance communication between the immune cells at the injured site and the brain.
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