Local hormones I: Inflammation

• Inflammation


  The body's defence response to invasion such as pathogens (disease-causing) and allergens (non-disease), and injury due to heat, UV, chemicals etc.
• Signs of Inflammation


  • Calor — warmth (increased blood flow)
  • Rubor — redness (increased blood flow)
  • Dolor — pain (sensitisation/activation of sensory nerves — raised area stimulates the nerve fibres to send info to the brain so they become activated)
  • Tumor — swelling (increased post-capillary venule permeability, leading to leakage of plasma into the area, and in severe cases, blood flow can drop, so blood pressure can decrease)
  • Functio laesa — loss of function (pain/injury)
• Chronic inflammation


  Severe tissue damage, e.g. atherosclerosis
• Acute responses


  e.g. anaphylaxis, sepsis
• Timescale of Events in Inflammation

  1. Initially, mediators, such as histamine, are released and they're released throughout. During this time, they will switch their function from being pro-inflammatory to anti-inflammatory.

  2. During this time, there's a microvascular event: bleeding may occur, but healing also starts.

  3. Inflammatory cells — neutrophils — will start to go to site of injury and try to modulate activity. The inflammatory mediators will become activated, which causes the release of the inflammatory cells, and the behaviour of those cells is controlled so they don't cause harm (some of these cells can later on become damaging).
• Steps of inflammation


  1. Recognition of the injurious agent

  2. Recruitment of leukocytes

  3. Removal of the agent

  4. Regulation (control) of response

  5. Resolution (repair)
• When there's damage


  There's increased blood flow due to local hormones such as histamine and PGs. This means the capillary bed will begin to expand (swelling).
• The post capillary venule will begin to increase in permeability


  Disrupting some of the endothelial cells, which line the inside of blood vessels.
• If the vessels become permeable

  The blood in them will start to leak out and blood volume decreases, so blood pressure decreases.
• Local Hormones


  Chemical mediators that orchestrate the complex responses involved in inflammation, also known as 'autacoids'.
• When and where are local hormones produced and released?

  • Produced in response to a wide range of stimuli
  • Synthesis or released only as and when required
  • Local release for local action
  • Inactivated locally to minimise systemic effects
• Histamine


  A chemical mediator synthesised from the amino acid histidine, and metabolised by imidazole-N-methyltransferase and diamine oxidase.

  
• Sources of Histamine


  • Mast cells (connective tissues)
  • Basophils (blood)
  • Neurons in brain
  • Histaminergic cells in gut to mediate acid secretion

  
• Histamine storage and release

  Pre-made, 'ready-to-go' in secretory granules composed of heparin and acidic proteins and released when needed, e.g. by allergic reactions, insect stings, trauma, etc through a rise in Ca²⁺.

  
• Triple vascular response


  Redness (depends on soluble, chemical mediator, e.g. histamine, 5HT, PGs etc), flare (depends on nerve supply) and weal (depends on soluble, chemical mediator), which is the raised skin that flare surrounds.
• Histamine Receptors


  There are four types: H₁, H₂, H₃ and H₄. All G-protein-coupled receptors that produce physiological effects by activating second messenger systems.
• Stimulation of H₁ and H₂ receptors

  Produces many of the actions of histamine-mediated inflammation.
• Effects of Stimulating H₁ and H₂ Receptors

  • Cardiovascular: Dilates arterioles, decreasing TPR, which is total peripheral resistance (H₁); Increased permeability of post-capillary venules, decreasing blood volume (H₁); Increase in heart rate (H₂) — tachycardia
  • Non-vascular smooth muscle (airways, gut etc): Contraction (H₁), e.g. bronchoconstriction
  • Algesia: Pain, itching and sneezing caused by stimulation of sensory nerves (H₁)
  • Gastric acid: Increase secretion (H₂)
  • Associated exocrine secretions: Increased, due to increased blood flow
• Pathological Roles of Histamine

  The most important clinical roles are acute inflammation (H₁ effects) and stimulating gastric acid secretion (H₂).
• Histamine and Gastric Acid Secretion

  1. Mediators of acid secretion are gastrin, Ach and histamine and they can act directly on the acid secreting cells (aka parietal cells) and acid secretion occurs.

  2. They can also do this indirectly via histamine secreting cells, which produce histamine that are released and bind to the H₂ receptor. This causes acid secretion to occur.

  3. If acid secretion occurs for too long, this can lead to irritation of the gut, causing ulcers. This also can cause bleeding.

  4. However, PGE₂ can inhibit the behaviour of parietal cells so they don't release too much acid. It can also promote vasodilation and is also anti-aggregatory.

  5. PGE₂ can also stimulate cells: it can act on mucus secretion cells in the endothelium of the gut, causing them to secret mucus which protects the gut.

  6. PGE₂ can promote the secretion of bicarbonate, which is can neutralise the acid.

  
• H₁ Antagonists


  They treat acute inflammation. 'First generation' drugs like mepyramine, diphenhydramine, promethazine are sedative. 'Second & third generation' drugs like terfenadine and fexofenadine are non-toxic metabolites.
• H₂ Antagonists


  Cimetidine and famotidine, which reduce gastric acid secretion in treatment of duodenal and gastric ulcers and Zollinger-Ellison syndrome. Side effects include mental confusion, dizziness, tiredness & diarrhoea.
• 1. hydroxytamine (5-HT, Serotonin)


  A neurotransmitter derived from tryptophan, with inflammatory actions.
• Distribution of 5-HT


  • Platelets
  • Mucosal EC (enterochromaffin) cells of gastrointestinal tract
  • Brain
• Inflammatory Actions of 5-HT

  • Promotes inflammation by increasing the number of mast cells at the site of tissue injury
  • Stimulates mast cell adhesion and migration
  • Enhances inflammatory reactions of skin, lungs and gut
  • May synergise with TXA₂ to stimulate platelet activity and vasoconstriction
  • Activation of TXA₂ receptors increases 5HT-mediated responses in blood vessels

  
• Lipid Mediators of Inflammation

  Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs), collectively known as the eicosanoids.

  
• Importance of Eicosanoids


  • Molecules with powerful inflammatory actions
  • Targets of major anti-inflammatory drugs: NSAIDs, Glucocorticoids, Lipoxygenase inhibitors, Leukotriene antagonists

  
• Formation of Prostanoids


  Prostaglandins and thromboxane are generated from arachidonic acid (AA, a polyunsaturated fatty acid) produced from phospholipids, by the enzyme cyclooxygenase (COX).

  
• COX1 and COX2


  COX1 is constitutively active and responsible for 'physiological' roles of PGs/TXs. COX2 needs to be stimulated (e.g. by inflammatory cytokines) and is responsible for the role of PGs/TXs in inflammation responses.
• Actions of Eicosanoids


  • Cells specialise in making particular eicosanoids
  • Act at specific G-protein-coupled receptors
  • Exert diverse and often contradictory actions in inflammation
  • Subjected to local inactivation
• Leukotriene Receptor Antagonists


  Examples: Zafirlukast, which blocks receptor for cysteinyl LTs (LTC₄, LTD₄, LTE₄). Useful in prevention of mild to moderate asthma, early to late bronchoconstrictor effects of allergens, exercise-induced asthma and asthma provoked by NSAIDs.
• Diverse Actions of Eicosanoids