Pathology
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Inflammatory Responses
Which of the following cytokines primarily stimulates production of C-reactive protein (CRP):
Answer:
Interleukin 6 (IL-6), a major proinflammatory cytokine, is produced in a variety of tissues, including activated leukocytes, adipocytes, and endothelial cells. C-Reactive protein is the principal downstream mediator of the acute phase response and is primarily derived via IL-6–dependent hepatic biosynthesis.Chemical Mediators of Inflammation
Pathology / Inflammatory Responses
Last Updated: 26th June 2019
Several different inflammatory mediator systems interact to produce inflammation:
- The complement system
- This cascading sequence of serum proteins is made of more than 20 components; the activated product on one protein activates another
- The complement system has roles in: activation of phagocytes, stimulating release of inflammatory mediators from mast cells/basophils, chemotaxis of neutrophils/macrophages, opsonisation of bacteria for phagocytosis, transport of immune complexes and direct lysis of target cells
- Kinins
- Small vasoactive peptides e.g. bradykinin
- Exert effect by increasing vascular permeability and producing pain
- Kinin system is stimulated by activated coagulation factor XII
- Prostaglandins and leukotrienes
- Membrane phospholipid of neutrophils and mast cells are metabolised during acute inflammation to form prostaglandins and leukotrienes (from arachidonic acid)
- Prostaglandins are chemotaxins for neutrophils and also increase vascular permeability
- Leukotrienes are vasoactive
- Platelet activation factors
- Platelet activation factors are released from mast cells and neutrophils during degranulation
- They induce platelet aggregation and degranulation, increase vascular permeability, induce leucocyte adhesion to the endothelium and stimulate synthesis of arachidonic acid derivatives
- Vasoactive amines
- Preformed inflammatory mediators that are rapidly released from inflammatory cells
- Examples are histamine and serotonin, released following degranulation of mast cells
- Cytokines
- Family of chemical messengers, secreted by leucocytes, that act over short distances by binding specific receptors on target cell surfaces
- They include: interleukins (act between leucocytes), interferons (inhibit replication of viruses within cells and activate macrophages and natural killer cells), growth factors, and tumour necrosis factors (kill tumour cells)
- Tumour necrosis factor alpha (TNFα) and interleukin-1 (IL-1) are key cytokines in acute inflammation
- Effects include: induction of fever and acute phase response, stimulation of leucocyte differentiation and maturation, leucocyte recruitment and activation, increased antibody production
- Nitric oxide
- Potent vasodilator that is released from endothelial cells and macrophages
- Regulates inflammation, actively reducing the effect of other proinflammatory mediators
- Acute-phase proteins (APPs)
- The acute phase response is a systemic reaction to infection or tissue injury induced by increased circulating levels of IL-1, IL-6 and TNFα produced by inflammatory cells and characterised by a rise in APPs, fever, leucocytosis, thrombocytosis, anorexia and weight loss
- APPs are mostly derived from the liver and examples include C-reactive protein (CRP), serum amyloid-A protein (SAA) and fibrinogen. CRP and SAA bind to bacterial cell walls and may act as opsonins
- At the same time, the production of a number of other plasma proteins is reduced; examples include albumin and transferrin
C-Reactive Protein
C-reactive protein (CRP) is as an acute phase protein produced by the liver. CRP binds to phosphorylcholine found on the surface of many bacteria and opsonises them for phagocytosis. C-reactive protein can be measured in the serum as a nonspecific marker of inflammation. A high or increasing CRP suggests an acute infection or inflammation but does not help in identifying its location or the condition causing it. In people with chronic inflammatory conditions, high concentrations of CRP suggest a flare-up or that treatment has not been effective. When results fall below 10 mg/L, there is no longer clinically active inflammation.
ESR has largely been superseded in clinical practice by measurement of CRP. Both CRP and ESR are elevated in the presence of inflammation, but the concentration of CRP rises and falls faster than ESR. CRP is not affected by as many other factors as is ESR, making it a better marker of some types of inflammation.
Erythrocyte Sedimentation Rate
The erythrocyte sedimentation rate (ESR) is an indirect nonspecific marker of inflammation. The ESR measures the rate at which red blood cells fall (sediment) when placed in a column for a period of one hour. Normally red cells fall slowly, leaving little clear plasma. Increased levels of acute phase proteins, such as fibrinogen, CRP or immunoglobulins, cause the red cells to fall more rapidly, increasing the ESR. The ESR is particularly helpful in diagnosing and monitoring treatment in two specific inflammatory diseases, temporal arteritis and polymyalgia rheumatica.
ESR is raised with inflammation and infection but also with anaemia, renal impairment, pregnancy and old age. People with multiple myeloma or Waldenstrom’s macroglobulinaemia (tumours that make large amounts of immunoglobulins) typically have very high ESR even if they don't have inflammation. Although a low ESR is not usually important, it can be seen with polycythaemia, with extreme leucocytosis, and with some protein abnormalities.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
