Posts Tagged ‘ inflammation ’

Chronic Inflammation

For the rest of this article please visit www.jameswatts.co.uk/vetsci/learn were you can download it for free!

Introduction

Chronic inflammation is inflammation which has been of prolonged duration. It is the simultaneous occurrence of active inflammation, tissue destruction and attempts at repair.

Chronic inflammation can either follow on from acute inflammation or it can begin insidiously (a lack of symptoms, the patient is unaware of the onset of the disease with a subtle and cumulative harmfulness) e.g. tuberculosis

Chronic inflammation arises with the following conditions:

  • Persistent infections such as those from mycobacteria or certain fungi/parasites. This may cause type IV hypersensitity (delayed-type) but has low toxicity. This is a granulomatous inflammation
  • Prolonged exposure to exogenous or endogenous (potentially toxic) agents
  • Autoimmunity where auto-antigens evoke a self-perpetuating immune reaction which results in chronic inflammation

The histological features of chronic inflammation:

  • Tissue section infiltrated with mononuclear cells (macrophages, lymphocytes, plasma cells)
  • There is tissue destruction which has been mainly induced by inflammatory cells
  • There are attempts at repair of this tissue, characterised by; connective tissue replacing the damaged tissue, proliferation of small blood vessels (angiogenesis – formation of new blood vessels) and fibrosis
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Types of Inflammation

An extensive list of the types of inflammation you may encounter and the part of the body which they affect. If you have any additions or notice any which are incorrect then please comment at the end of this post!

This was brought to you by www.jameswatts.co.uk

Types of Inflammation

  • Adenitis – Inflammation of the adenoids
  • Adnexitis – Inflammation of the adnexa uteri
  • Alveolitis – Inflammation of the alveoli
  • Angiitis – Inflammation of  blood or lymph vessels
  • Appendicitis – Inflammation of the appendix
  • Arthritis – Inflammation of the joints
  • Balanitis –  Inflammation of the glans penis
  • Blepharitis – Inflammation of the eye
  • Bronchiolitis –  Inflammation of the bronchioles
  • Bronchitis – Inflammation of the bronchi of the lungs
  • Bronchoalveolitis – Inflammation of the bronchioles of the lungs
  • Bursitis – Inflammation of a bursa
  • Cellulitis – Inflammation of subcutaneous or connective tissue
  • Cholangitis –  An inflammation of the bile duct
  • Cholecystitis –  An inflammation of the gallbladder
  • Colitis – Inflammation of the colon
  • Conjunctivitis – Inflammation of the conjunctiva
  • Cystitis –  Inflammation of the urinary bladder
  • Dermatitis – Inflammation of the skin
  • Diverticulitis – Inflammation of the diverticulum
  • Encephalitis – Inflammation of the brain
  • Endocarditis – Inflammation of the endocardium and possibly the heart valves
  • Endocervicitis – Inflammation of the mucous membrane of the uterine cervix
  • Enteritis – Inflammation of the intestines, generally the small intestine
  • Enterocolitis – Inflammation of the mucous membranes of the small intestine and of the colon
  • Epicondylitis – Inflammation of the elbow or knee
  • Gastritis –  Inflammation of the lining of the stomach
  • Gastroenteritis – Inflammation of the mucous membranes of the stomach and intestine
  • Gingivitis – Inflammation of the gums or gingivae
  • Glomerulonephritis – Inflammation of the glomeruli
  • Glossitis – Inflammation of the tongue
  • Hepatitis – Inflammation of the liver
  • Ileitis – Inflammation of the ileum
  • Iritis – Inflammation of the iris
  • Keratitis – Inflammation of the cornea
  • Keratoconjunctivitis – Inflammation of the cornea and the conjunctiva
  • Laryngitis – Inflammation of the larynx
  • Lymphangitis – Inflammation of the lymph glands
  • Mastitis – Inflammation of a breast or udder
  • Mastoiditis – Inflammation of the ear
  • Meningitis – Inflammation of the meninges
  • Myocarditis – Inflammation of the myocardium
  • Myositis – Inflammation of the muscles
  • Nephritis – Inflammation of the kidney
  • Neuritis – Inflammation of one or more nerves
  • Oesophagitis – Inflammation of the oesophagus
  • Oophoritis – Inflammation of the ovaries
  • Osteomyelitis – Inflammation of the bone
  • Otitis – Inflammation of the ear
  • Pancreatitis – Inflammation of the pancreas
  • Parotitis – Inflammation of one or both parotid glands
  • Pericarditis – Inflammation of the pericardium, the membrane that surrounds the heart
  • Peritonitis – Inflammation of the peritoneum
  • Pharyngitis – Inflammation of the pharynx
  • Phlebitis – Inflammation of a vein
  • Polyneuritis – Inflammation of multiple nerves
  • Proctitis – Inflammation of the anus and the lining of the rectum
  • Prostatitis – Inflammation of the prostrate
  • Pyelonephritis – Inflammation of the urinary tract which has reached the kidney
  • Retinitis – Inflammation of the retina
  • Rhinitis – Inflammation of the mucous membranes of the nose.
  • Salpingitis – Inflammation of the fallopian tube
  • Sinusitis – Inflammation of the paranasal sinuses
  • Spondylitis – Inflammation of the spine
  • Stomatitis – Inflammation of the mucous membrane lining of the mouth
  • Synovitis – Inflammation of the synovium
  • Tendinitis – Inflammation of a tendon
  • Tenosynovitis – Inflammation of the fluid-filled sheath (the synovium) that surrounds a tendon
  • Thyroiditis – Inflammation of the thyroid gland
  • Tonsillitis – Inflammation of the tonsils
  • Tracheitis – Inflammation of the trachea
  • Urethritis – Inflammation of the urethra
  • Uveitis – Inflammation of the middle layer of the eye – the uvea
  • Vaginitis – Inflammation of the vagina
  • Vasculitis – Inflammation of the wall of blood vessels
  • Vulvovaginitis – Inflammation of the vulva and vagina

Acute Inflammation

From now on I intend to only include the introduction of learning articles, that way you dont have to scroll for ages to get the information you need. To view and download this 9 page article on acute inflammation, visit http://www.jameswatts.co.uk/VetSci/Learn/Learn.html

Introduction

Acute inflammation is the immediate response to an inflammatory agent (such as a pathogen or foreign material) or necrotic cells/tissue caused by cell injury and death. It undergoes many vascular changes in order to increase the amount of antibodies and leukocytes at the site of inflammation. The major contributing factors are:

  1. Alterations in the vascular flow and calibre – increasing blood flow
  2. Structural changes of the microvasculature (capillaries, arterioles and venules) – Resulting in the leakage of plasma proteins (e.g. fibrin) and the evasion of leukocytes
  3. Emigration of leukocytes from the microcirculation – Resulting in the accumulation of leukocytes in the area of injury

An Introduction to Inflammation

Introduction

Inflammation can be characterised by 5 main features (names in brackets are the Latin), these are:

  • Swelling (tumour)
  • Heat (calor)
  • Redness (rubor)
  • Pain (dolor)
  • Loss of function (functio laesa)

Inflammation is a protective response by the body towards cell injury. Cell injury may be due to; necrotic cells or tissue, the introduction of microbes (such as viruses or bacteria), toxins, hypoxia, etc. Inflammation is therefore the body’s way of attempting to remove the primary cause of inflammation and any damage that may have occurred as a result (Healing and repair). However if inflammation did not occur, then the body would be unable to deal with wounds and infections letting them go unchecked and progressively destroy the tissue. All injured organs would therefore be unable to regain function, eventually leading to mortality.

Inflammation is a complicated series of biological reactions, only taking place in vascularised tissue, simply however it works by attempting to remove, dilute or barricade the injurious/pathogenic agent or tissue. Its secondary role is to induce the healing and the repair of the damaged tissue. The result of this is an accumulation of leukocytes and fluid in the vascularised tissue.

It is also important to remember that chronic inflammation may pose problems to the body; these may be hypersensitivity reactions, autoimmune reactions or organ dysfunction due to the formation of scars/obstructions caused by fibrosis e.g. hay fever (hypersensitivity) or arthritis (autoimmune response).

The Inflammatory Response

As said before, an inflammatory response will only occur in vascularised connective tissue. A typical inflammatory response will involve the utilisation of plasma, circulating cells (leukocytes), blood vessels (endothelial cells) and other cells/extracellular matrix in the connective tissue.

The inflammatory response is mediated by chemical factors which are derived from the plasma or from the cells. The chemical mediators are triggered by an inflammatory stimulus which could include anything from a splinter (foreign material) to necrotic cells. Necrotic tissue/cells are able to contribute to inflammation (as opposed to triggering the inflammatory system) by producing their own inflammatory mediators. The chemical factors involved in the whole process both amplify the inflammatory response and impact on its progression.

The inflammatory response will only stop when the initial stimulus is removed and all the chemical mediators which arose as a result are inhibited (or dissipated).

Components of Inflammation

Some of the main components of inflammation include:

Connective tissue layer:

  • Mast cells – Resident cells of tissues which contain many granules rich in histamine and heparin. They play an important protective role as well, being intimately involved in wound healing and defence against pathogens.
  • Fibroblasts – A type of cell which synthesizes the extracellular matrix and collagen and also plays a critical role in wound healing.
  • Macrophages – Resident large phagocytes (Some also circulate in the blood stream)

The Circulating Cells:

  • Polymorphonuclear Leukocytes (Neutrophils)
  • Lymphocytes
  • Monocytes
  • Eosinophils
  • Basophils
  • Platelets

The Extracellular Matrix:

  • Collagen and Elastin fibres – These are structural fibrous proteins
  • Proteoglycans
  • Adhesive glycoproteins (Fibronectin, laminin, non-fibrillar collagen, tenascin and others)

The Extracellular Matrix (ECM)

The ECM is a network of locally secreted and assembled proteins, such as collagen and elastin. It forms in the spaces surrounding cells and linkage occurs between cells and the ECM by adhesive glycoproteins (such as Fibronectin, laminin, non-fibrillar collagen, tenascin and others). It also consists of proteoglycans which are usually attached to the proteins. They have a net negative charge that attracts water molecules, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store growth factors within the ECM.

The function of the ECM is to sequester molecules such as water (using the mechanism described above), it also acts as a reservoir for growth factors and a substratum for cells to adhere, migrate and proliferate.

Terms Associated With Inflammation

The inflammatory response can be classified as either:

  • Acute inflammation – Typically these are of relatively short duration, from a few minutes to a few days. The main characteristics of acute inflammation are; exudation (see below) of fluid and plasma proteins (oedema) and the emigration of leukocytes (predominantly neutrophils)
  • Chronic inflammation – Chronic inflammation is of longer duration and is associated with:
    • The presence of lymphocytes and macrophages
    • Proliferation of blood vessels
    • Fibrosis
    • Tissue necrosis

Definitions:

  • Exudation – The escape of fluid, proteins and blood cells from the vascular system into the interstitial tissue or body cavities
  • Exudate – Inflammatory extravascular fluid which contains; a high protein concentration, much cellular debris and a specific gravity (density in relation to water) of >1.012. The specific gravity of >1.012 is due to the increased permeability of small blood vessels in the area of injury.
  • Transudate – This is fluid with a low protein content (of which the main constituent is albumin) and it has a specific gravity of <1.012 due to the ultrafiltrate of blood plasma which results in a hydrostatic imbalance across the vascular endothelium. Permeability of the endothelium is not altered.
  • Oedema – Excess fluid in the interstitial or serous cavities (The fluid can be either transudate or exudate)
  • Pus – Inflammatory exudate rich in leukocytes (predominantly neutrophils) and cell debris.

Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

Introduction

NSAIDs are non-narcotic analgesics (An analgesic reduces or removes the sensation of pain), they are also anti-pyretic (fever) and anti-inflammatory. These effects are produced by the inhibition of the fatty acid cyclooxygenase (COX) which inhibits prostaglandin synthesis.

Because NSAIDs are non-narcotic they do not cause any largely noticeable effects on the CNS (central nervous system) function. This makes them ineffective against normal nociceptive tests, these are test designed to test pain responses in living organisms and they are specifically used in the testing of new analgesic drugs. Methods usually involve the applying of pressure to a specific point of the organism. NSAIDs only raise the pain threshold when pressure is applied to a swollen and inflamed joint (this is known as analgesia via peripheral mechanisms). Therefore NSAIDs are considered anti-inflammatory agents with a mild central analgesic effect (associated with anti-pyretic action). NSAIDs are therefore primarily used in the treatment of acute or chronic conditions producing mild-moderate pain, especially involving the musculo-skeletal system. Principal utilisation occurs in the horse and dog.

Another benefit of NSAIDs non-narcotic function is that, by having an unnoticeable effect on the CNS they can therefore be used as a pre-med drug, before general anaesthetic, without fear of overloading the CNS. The use of an analgesic before the introduction of pain means that a lower dose will be required when pain is inflicted – thus reducing the chances of side effects associated with high doses. However, the type of NSAID must be selected for carefully as there may be a possibility of renal damage/toxicity. There are only a couple of NSAIDs which are believed to be renal safe.

Prostaglandins and Inflammation

NSAIDs work by inhibiting prostaglandin synthesis by targeting the COX enzyme. Prostaglandins activate the inflammatory response giving the production of pain and fever, they are produced when leukocytes reach a site of damaged tissue in an attempt to minimise tissue destruction.

Prostaglandins are involved in several other organs such as the gastrointestinal tract (inhibit acid synthesis and increase secretion of protective mucus), increase blood flow in kidneys, and leukotrienes which promote constriction of bronchi associated with asthma.

Question:

What is/are the precursor(s) of prostaglandins?

The answer may be found in the ‘Mechanisms of NSAID Action’ section.

Cyclooxygenase Enzymes (COX)

COX forms two isoforms, COX-1 and COX-2:

  • COX-1 is often thought of as being the ‘good’ COX; this is due to its involvement in tissue homeostasis. It is required to keep the body ‘normal’ – primarily the synthesis of prostaglandins responsible for protection of the stomach lining. (Constitutive physiological).
  • COX-2 therefore is thought of as the ‘bad’ COX; this is because it is produced during inflammation, by the inflammatory cells which have been activated by cytokines. (Inducible physiological).
  • There is some evidence for a COX-3, a possible variation of COX-1 which is also associated with the inflammatory response. It has been found in the CNS and is affected by paracetamol.

Mechanism of NSAID Action

The primary action of NSAIDs is the inhibition of the COX enzyme, by inhibiting this enzyme the production of prostaglandins are also inhibited. The COX enzyme synthesised prostaglandins from fatty acids such as arachidonic acid.

Most NSAIDs inhibit both major forms of the COX enzyme, however all are still considered toxic. Newer drugs which are believed to be COX-2 specific (thereby not affecting the COX-1 enzyme and allowing prostaglandins associated with normal function to continue normal operation) are relatively safer in chronic use. There are fewer side effects which is what makes them be suited to prolonged periods of use. Examples: Merck’s rofecoxib and etoricoxib, Pfizer’s celecoxib and valdecoxib.

The NSAIDs selective for COX-2 are now however under scrutiny, due to reports of cardiovascular toxicity. These include strokes and myocardial infarctions. This has resulted in the withdrawal of certain COX-2 selective drugs such as rofecoxib. Further studies are suggesting that the cardiovascular toxicity of these COX-2 selective NSAIDs may actually not be much greater than ‘trusted’ NSAIDs such as ibuprofen. However, their toxicity still remains a point of research and discussion.

Other Actions of NSAIDs

Besides from the inhibition of the COX enzyme, other actions include:

  • Inhibit superoxides (toxic) and free radicals
  • Inhibit Bradykinin production (A Peptide which dilates blood vessels, lowering blood pressure)
  • Stabilises lysosomes
  • Inhibits metalloproteinases (Proteolytic enzymes whose catalytic mechanism involves a metal)
  • Antagonises interleukin-1 (fever inducer and controlling factor of lymphocytes) and tumour necrosis factor (TNF – cytokine involved in the induction of inflammation and apoptosis, dysfunction of this factor is believed to be involved with the production of cancers.)

IC50

This is the half maximal inhibitory concentration (IC50). It is a measure of the effectiveness of a compound (typically a drug candidate) in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. It is commonly used as a measure of antagonist drug potency in pharmacological research.

This can be related to inhibition of COX enzymes, we can use it to find out how many times a dose required to inhibit COX-1 we need to administer in order to inhibit COX-2, i.e. COX-2/COX-1,  a lower ratio is better as it shows that the drug has a higher selectivity for COX-2 the ‘bad’ COX associated with inflammatory responses.

COX-1 Selective               Drugs                       Amount times dose required to inhibit COX-2

  • Aspirin                                                                  170
  • Piroxicam                                                             250

Less Selective COX-1 Drugs

  • Paracetamol                                                            7
  • Ibuprofen                                                                15

Equipotent

  • Naproxen                                                                  1

COX-2 Selective Drugs

  • Meloxicam                                                               <1

The Anti-Pyretic Effect of NSAIDs

NSAIDs do not affect normal body temperature only when pyrexia (fever) is present, do they alter temperature. Bacterial or endogenous (substances from within the body) pyrogens can act directly on the hypothalamus. Heat temperature is regulated in the hypothalamus by controlling temperature regulating peripheral mechanisms such as vasoconstriction/dilation, sweating, shivering and metabolic activity.

Pyrogens activate hypothalamic COX, increasing prostaglandin concentration. The effect of this is that the set body temperature (Average 37oC) is increased (Pyrexia is considered >38oC). NSAIDs counter this by inhibiting prostaglandin synthesis by the inhibition of COX enzymes. By doing this they have effectively blocked the action of the pyrogens on the CNS and return the raised set body temperature back down to normal levels (37oC).

Commonly Used NSAIDs

Some of the most commonly found NSAIDs and their properties:

Aspirin (Acetylsalicylic acid)

Aspirin is a potent anti-inflammatory drug with mild central analgesic and antipyretic actions. It is administered orally and readily absorbed from the stomach and small intestine, an acid drug is well absorbed in an acidic environment. It is metabolised by tissue /plasma esterases. Aspirin may also be used in low doses, daily to prevent platelet aggregation.

In a healthy body, thromboxane and prostacyclin (eicosanoids – fatty acid signalling molecules) are balanced. Aspirin however disrupts this balance in the favour of prostacyclin, inhibiting aggregation.

Aspirin irreversibly binds to platelet COX, however as platelets are produced every few days, the condition is not permanent, and this is why chronic dosing may be necessary.

Aspirin is toxic in cats due to their lack of the enzyme UDP-glucuronyl transferase, therefore when giving aspirin to cats the maximum stated dose is 25mg/kg daily (Compared to 25mg/kg 3-4 times a day in dogs) Toxicity effects may still appear even at lower doses e.g. vomiting, abdominal pain, anorexia and gastric ulceration.

Paracetamol

Paracetamol is a weak anti-inflammatory drug; however it does have a more potent central analgesia and anti-pyretic effects than aspirin (See IC50 table to see a smaller dose is required of paracetamol to inhibit COX-2, the COX enzyme responsible for inflammatory responses).

Due to paracetamol being well tolerated, producing less gastric irritation than aspirin and having much fewer side effects than aspirin, it has become a predominant household analgesic. Acute overdoses can cause fatal hepatic damage; early symptoms include anorexia, vomiting, diarrhoea and abdominal pain. It is the reactive metabolites of paracetamol latching onto -SH groups that cause hepatic toxicity.

The dog is more resistant to paracetamol toxicity than cats, an oral dose is recommended every 6 hours of 25-30mg/kg.

Phenylbutazone

Phenylbutazone is the most widely used NSAID in equine medicine; however it is extremely toxic in humans. It has a long  t1/2 (half-life) of 70 hours and produces severe gastric ulceration and agranulocytosis. It can be administered orally and by intravenous injection. Due to the acidity of the drug, it is readily absorbed from the stomach/duodenum. Phenylbutazone metabolites are weak acids and therefore preferably excreted in alkaline urine. Training horses may have acidic urine, and so it is recommended not to take Phenylbutazone within 8 days of competition.

Half-life in dogs of Phenylbutazone has been recorded at 3-8 hours (however this may vary dependent on the dose). Phenylbutazone can inhibit the synthesis of prostaglandin in inflammatory exudates for 12-24 hours, with the response lasting for up to three days after the final dose in the course.

Signs of Phenylbutazone toxicity include inappetance and depression with weight loss and oedema. The oedema (fluid retention) is due to the decreased NaCl excretion.

Dosing of Phenylbutazone should not exceed:

  • Day 1 – 4.4 mg/kg twice a day
  • Day 2-4 – 2.2 mg/kg twice a day
  • Day >5 – 2.2 mg/kg daily

Phenylbutazone is also administered in combination with other drugs for the treatment of musculoskeletal disorders e.g. Tomanol – Phenylbutazone and Isopyrin

Meclofenamic Acid (Arquel)

Meclofenamic acid is a potent anti-inflammatory, anti-pyretic analgesic. It is more potent than aspirin but similar in effect. As well as inhibiting COX enzymes it has found to be a prostaglandin antagonist, interacting with prostaglandin receptors. It therefore prevents the action of prostaglandin already present possibly exerting a more rapid reduction of inflammation.

Half-life is 6-8 hours; therapeutic levels are maintained with daily doses.

Unlike other NSAIDs onset of Meclofenamic acid is relatively slow, taking 36-96 hours for effects to begin

Prolonged administration in the horse may lead to anorexia, depression, ulceration of buccal mucosa, gastric haemorrhage or diarrhoea

Naproxen

Naproxen is a propionic acid derivative (like ibuprofen or Ketoprofen) with a tendency for reduced frequency of serious side effects at therapeutic doses. In the horse, half-life of the drug is 5 hours; double daily doses have been proven effective in soft-tissue inflammatory conditions such as myositis. In the dog however, half-life is much longer at around 70 hours, it is therefore recommended to avoid this NSAIDs due to excessive toxicity

Ketoprofen

Ketoprofen is a potent COX inhibitor which is also able to stabilise lysosomal membranes and is a Bradykinin antagonist. It is also reported to be an inhibitor of the lipoxygenase enzyme system (iron-containing enzymes which catalyse the dioxygenation [incorporation of two oxygen atoms] of some polyunsaturated fatty acids). It is around 50x more potent than Phenylbutazone, however this is not accompanied by an equivalent increase in toxicity. It is also suggested that it may be cartilage sparing, neither accelerating chondrocyte damage nor reducing proteoglycan production.

Carprofen

Carprofen is a potent anti-inflammatory drug, but is a weak inhibitor of COX. Its mode of action is not yet known but it significantly inhibits neutrophil migration. Due to weak inhibition of COX, toxicity of Carprofen its toxicity tends to be low.

Piroxicam

Piroxicam is a potent and long lasting anti-inflammatory drug. Its half-life of around 60 hours enables lower dosing (alternate days). A higher frequency of dosing will produce standard NSAID toxic effects (see below, section ‘Side Effects of NSAIDs’)

Meloxicam

Meloxicam is a similar drug, but with a shorter half-life (30-40 hours). It is thought to have greater potency for COX-2 than COX-1 therefore side-effects may be less. It is also thought to be chondroprotective (The slowing of degradation of articular cartilage)

Flunixin

Flunixin is a potent versatile anti-inflammatory drug with a short half-life in all species (2-8 hours). However its duration of action is relatively long (24-36 hours)

When to Use NSAIDs

  • Mild to moderate inflammatory lesions and associated pain
  • Acute inflammation and pain
  • Joint inflammation and pain
  • Suppression of pulmonary oedema
  • Endotoxaemia
  • Anti-thrombic

Side Effects of NSAIDs

  • Gastric irritation and ulceration – This is a main side effect of chronic NSAID use, it occurs because when NSAIDs inhibit the COX-1 enzyme, COX-1 synthesises prostaglandins associated with inhibiting acid synthesis and increasing secretion of protective mucus. SO by inhibiting COX-1, the stomach becomes unprotected from the gastric acid causing irritation and possibly ulceration in chronic use.
  • You can protect the gut by administering proton pump inhibitors (Losec), prostaglandin analogues (Misoprostol) or H2 receptor antagonists (Zantac)
  • Vomiting and diarrhoea
  • Hepatotoxicity
  • Renal papillary necrosis, chronic nephritis
  • Bone marrow disturbance
  • Skin rashes
  • Respiratory distress