Pathology
Inflammatory Responses
Which of the following cytokines is key in maintaining granulomatous inflammation:
Answer:
IL-1 is important in initiating granuloma formation, IL-2 can cause them to enlarge and TNF-α maintains them.Chronic Inflammation
Pathology / Inflammatory Responses
Last Updated: 12th August 2019
Causes
Chronic inflammation usually develops as a primary response to:
- Microorganisms resistant to phagocytosis or intracellular killing mechanisms e.g. tuberculosis, leprosy
- Foreign bodies, which can be endogenous (e.g. bone adipose tissue, uric acid crystals) or exogenous (e.g. silica, suture materials, implanted prostheses)
- Some autoimmune diseases e.g. rheumatoid arthritis
- Primary granulomatous diseases e.g. Crohn's disease, sarcoidosis
Inflammation becomes chronic when it occurs over a prolonged period of time with simultaneous tissue destruction and attempted repair. It may occur secondary to acute inflammation due to the persistence of the causative agent.
Mechanism
The site of chronic inflammation is dominated by:
- Lymphocytes
- Plasma cells for antibody production
- Macrophages for phagocytosis (some macrophages fuse to form multinucleate giant cells)
Macrophages in inflamed tissue are formed from the transformation of monocytes. The number of macrophages gradually increases during acute inflammation until they are the dominant cell type in chronic inflammation. These macrophages are activated by numerous stimuli, including interferon-gamma (IFNγ), which is produced by activated T-cells.
The macrophages gradually remove damaged tissue by phagocytosis and produce growth factors to aid repair through fibrosis. This results in the replacement of damaged tissue with granulation tissue, which consists of new capillaries and new connective tissue formed from myofibroblasts and the collagen that they secrete.
The prolonged presence of activated macrophages in chronic inflammation leads to the overproduction of biologically active products resulting in tissue damage and systemic effects.
| Acute Inflammation | Chronic Inflammation | |
|---|---|---|
| Response | Immediate reaction of tissue to injury | Persistent reaction of tissue to injury |
| Onset | Rapid | Slow |
| Immunity | Innate | Adaptive |
| Predominant cell type | Neutrophil | Lymphocytes, plasma cells, macrophages |
| Duration | Hours to weeks | Weeks/months/years |
| Vascular response | Prominent | Less important |
Systemic Effects of Inflammation
Both acute and chronic inflammation can produce a number of systemic effects including:
- Fever
- Neutrophils and macrophages produce pyrogens (e.g. IL-1) which act on the hypothalamus
- Constitutional symptoms
- Malaise, nausea, anorexia
- Lymphadenopathy
- Reactive hyperplasia of the mononuclear phagocyte system
- Haematological changes
- Increased erythrocyte sedimentation rate (ESR), leucocytosis and acute phase protein release (e.g. C-reactive protein, CRP)
- Weight loss
- Occurs in severe chronic inflammation such as tuberculosis
Special Types of Chronic Inflammation
- Chronic suppurative inflammation
- Follows failure of acute inflammatory response to clear an inflammatory stimulus
- Examples include:
- Persistent bacterial infection that cannot be contained, as in necrotising fasciitis where bacterial secretion of enzymes facilitates the spread of infection through the connective tissue
- Abscess formation where a wall of fibrous tissue surrounds an acute inflammatory focus, which develops a liquified centre full of pus due to presence of dead and dying neutrophils and bacteria
- Granulomatous inflammation
- Typically seen when an infective agent with a digestion-resistance capsule (e.g. Mycobacterium tuberculosis) or a piece of inert foreign material (such as suture or glass) is introduced into the tissue
- A transient acute inflammatory response occurs and when this is ineffective in eradicating the stimulus, chronic inflammation occurs; IL-1 is important in initiating granuloma formation, IL-2 can cause them to enlarge and TNF-α maintains them
- A granuloma is a collection of five or more epithelioid macrophages, with or without attendant lymphocytes and fibroblasts; epithelioid macrophages are altered macrophages which have turned themselves over to becoming giant phagocytosing and killing machines, they often fuse to become multinucleate giant cells
- Other causes include: infection (e.g. parasites, leprosy, Cryptococcus), sarcoidosis, Crohn's disease, drugs, autoimmune disease (e.g. rheumatoid arthritis), tumour related (e.g. Hodgkin lymphoma)
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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 |
