Although inflammation is a well-organized local response of a living tissue to injury, it has both good and detrimental effects on the local tissue and the whole body system. This lecture shall describe the effects of acute inflammation on the body system. In other words, the systemic responses of the body to acute inflammation shall be our focus.
Among the systemic effects of acute inflammation are
- Acute phase response and increased production of acute phase proteins
- Leukocytosis: increased production of white blood cells
Increased production of acute phase proteins ‘The acute phase response’
Acute phase response is an important aspect of systemic response to acute inflammation. Acute phase response constitutes the increased production of proteins called acute phase proteins. Of note, the liver produces acute phase proteins in steady state concentrations under normal health conditions. However, the liver synthesizes and release very high concentrations of acute phase proteins in response to acute inflammation.
Functionally, most acute phase proteins act as opsonins and recognition molecules that bind to microbes and make the microbe ‘palatable’ to phagocytes. Therefore acute phase response is an important part of the systemic response to acute inflammation.
Inflammatory cytokines released during acute inflammation act on liver inducing the liver to up-regulate its synthesis of acute phase proteins.
Interestingly, during acute phase response, the liver increases its synthesis of positive acute phase proteins while decreasing its synthesis of negative acute phase proteins.
Examples of positive acute phase proteins are C-reactive protein, serum Amyloid A, serum Amyloid P component, complement proteins, metal-binding proteins, lipopolysaccharide-binding protein and mannose-binding protein. An example of negative acute phase proteins is albumin.
Leukocytosis describes an abnormally high number of total circulating white blood cells. Generally, abnormally high white blood count indicates an infection. Moreover, recall that microbial infections are one of the commonest causes of inflammation.
Differentially, the nature of the Leukocytosis is suggestive of the class of pathogens involved. Neutrophilic leukocytosis (abnormally high neutrophil count) indicates bacterial infection and acute inflammation whereas lymphocytic leukocytosis (abnormally high lymphocyte count) indicates viral infection and chronic inflammation.
During inflammation, tissue mast cells and macrophages release significant amounts of tumor necrosis factor-α (TNF-α). TNF-α stimulates endothelial cells and macrophages to produce colony-stimulating factors such as GM-CSF, G-CSF, and M-CSF. The colony stimulating factors stimulate hematopoiesis in the bone marrow, by stimulating proliferation of hematopoietic stem cells. The increased proliferation of hematopoietic stem cells results in an increase in the number of leukocytes that leave bone marrow into blood circulation.
Note that lymphoid organs and tissues normally contain significantly large numbers of lymphocytes. Therefore, the presence of large numbers of lymphocytes in such organs does not confirm inflammation. However, visible swelling of lymphoid organs and tissues is a sign of infection.
Fever, one of the commonest systemic responses to inflammation, most often occurs in response to pathogen-induced inflammation. In other words, fever most frequently accompanies inflammation that results from infection.
The pathogenesis of fever begins with the production of inflammatory cytokines by macrophages and other cells of the immune system. During certain infections, macrophages phagocytose the pathogen, degrades the pathogen, and produce interleukin-1 (IL-1) in response to endotoxins produced by the phagocytosed pathogen.
IL-1 travels in bloodstream and reaches the hypothalamus of the brain. In the hypothalamus, IL-1 induces vascular endothelial cells of the anterior hypothalamus to synthesize prostaglandins. Prostaglandins are a family of mediators; however, prostaglandin E2 is principally responsible for resetting the hypothalamic thermoregulatory set point temperature to a much higher value.
Once the thermoregulatory set point temperature rises above normal, nerve signal will arise from the center to thermoregulatory effector organs causing these organs to act to maintain core body temperature at the reset high point. Consequently, peripheral blood vessels constrict to prevent heat loss and conserve heat in the body; involuntary contractions of skeletal muscles occur making the individual to shiver and generate more body heat. The combination of the peripheral vasoconstriction and shivering raises core body temperature, a condition called fever.
Pyrogens induce fever
Pyrogens are substances that induce fever. We have two classes of pyrogens;
- Exogenous pyrogens: pyrogens that invade the body from the outside
- Endogenous pyrogens: pyrogens that arise from within the body
Exogenous pyrogens come from outside the body. Examples of exogenous pyrogens are pathogenic microbes, endotoxins produced by microbes, as well as other products derived from pathogenic microbes. A very typical exogenous pyrogen is lipopolysaccharide, which is a component of cell walls of al gram-negative bacteria. Once exogenous pyrogens invade the body, they induce host body system to produce endogenous pyrogens. Moreover, few components of bacterial cell wall can bind to, and reset the hypothalamic ‘set point’ directly without enlisting the help of endogenous pyrogens.
Host cells produce endogenous pyrogens. Examples of endogenous pyrogens are IL-1, TNF-α, IFN-γ, PGE2. Neutrophils, monocytes, macrophages, and a variety of host cells produce endogenous pyrogens in response to exogenous pyrogens and other pathogenic materials. Endogenous pyrogens enter blood and circulate to the thermoregulatory control center in the hypothalamus. This center controls body temperature by stimulating various heat loss and heat gain mechanisms. In the hypothalamus, the pyrogens stimulate vascular endothelial cells of the hypothalamic center to produce PGE2; PGE2 binds to thermoregulatory center and mediates the rise in thermoregulatory ‘set point’.
Does Fever have any protective role?
Generally, immune biologists believe that fever serves two basic protective functions:
- Fever enhances the ability of white blood cells to kill pathogens and boosts overall immune functions generally.
- Fever impairs the multiplication and replication of many pathogens. Actually, many pathogens are unable to survive high temperature.