L5-8: Inflammation Flashcards
Pathogenesis of atherosclerosis
- Endothelial injury, which causes (among other things) increased vascular permeability, leukocyte adhesion, and thrombosis
- Accumulation of lipoproteins (LDL and its oxidised forms) on the vessel wall.
- Monocyte adhere to the endothelium and migrate into the intima where they transform into macrophages and foam cells.
- Platelet adhesion can ultimately cause thrombosis.
- Factor release from activated platelets, macrophages and vascular wall cells induce smooth muscle recruitment either from the ‘media’ or circulating precursors.
- Smooth muscle then proliferates and ECM production occurs.
- Lipid accumulates extracellularly as well as within cells
Necrotic centre is composed of
cell debris, cholesterol crystals, foam cells, calcium
Fibrous cap is composed of
smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularasiation
Inflammatory markers of AMI
troponin and creatine phosphokinase
How can the infarct be modified?
- Restoration of blood flow via thrombolysis (streptokinase or tissue plasminogen activator that activates fibrinolytic enzymes and dissolves thrombus), balloon angioplasty (physical intervention via catheters to break apart blockage), or coronary arterial bypass graft
Cell source of reperfusion injury
cytoplasmic xanthine oxidase is activated by white blood cells which creates ROS/free radicals
Timeline evolution of infarct site
Day 3-4: monocyte infiltration
Day 7-10: phagocytosis of necrotic cells
Day 21: ‘Repair’ (collagen)
>Day 60: Scar tissue
myocytes survive infarct event if reperfusion occurs within
20 minutes
DEFINE: emphysema
irreversible enlargement of airspaces, distal to terminal bronchiole
Histone deacetylase inhibitors (HDACi) mode of action and role
inhibit HDACs which condense chromatin
Exudative phase of ARDS
Acute state
Interstitial /alveolar oedema, sloughing type 1 cells
Hyaline membrane formation
Features of acute vs. chronic inflammation
Onset: acute - minutes or hours; chronic - days
Cellular infiltrate: acute - mainly neutrophils; chronic - monocytes/macrophages, lymphocytes
Tissue injury/fibrosis: acute - usually mild, self-limited; chronic - severe
Sequence of events in an inflammatory reaction
- Brief arteriolar vasoconstriction followed by vasodilation - increased blood flow. Increased intravascular pressure causes an early transudate (protein-poor filtrate of plasma) into the interstetium.
- Increased vascular PERMEABILITY, enabling plasma proteins and leukocytes to leave circulation, forming oedema.
- RECRUITMENT of leukocytes from microcirculation, accumulation and activation of leukocytes
T or F:
Most mediators have long half-lives.
False, most mediators have short half-lives.
Mechanisms of vasodilation and vascular leakage/oedema in acute inflammation
Pressure balance between hydrostatic pressure (blood pressure) and colloid osmotic pressure (exerted by proteins such as albumin to draw water into circulatory system) is disrupted by fluid and protein leakage due to vasodilation and stasis. Exudate forms with a high protein content. This is followed by a transudate (low protein content)
Key mediators of vasodilation
- Nitric oxide (NO): short-acting soluble free radical produced by endothelial cells, macrophages which causes vascular smooth muscle relaxation and vasodilation, kills microbes in activated macrophages and counteracts platelet adhesion, aggregation and degranulation
- Amines e.g. histamine - vasodilation and venular endothelial cell contraction, junctional widening; released by mast cells, basophils, platelets in response to injury
Vascular permeability mechanism
- Histamines, bradykinins, leukotrienes cause an immediate but transient response in the form of endothelial cell contraction that widens endothelial intercellular gaps. Cytokine mediators (TNF, IL-1) induce endothelial cell junction retraction through cytoskeleton reorganisation and breakdown of junction proteins.
- Can also be caused by immediate direct endothelial cell damage (necrosis, detachment) or maybe caused by delayed damage as in thermal, UV injury or some bacterial toxins.
- Certain mediators (VEGF) can also cause increased transcytosis via intracellular vesicles from luminal to basement membrae
Leukocyte exiting vasculature mechanism
- Margination and rolling: with increased vascular permeability, fluid leaves vessel causing leukocytes to marginate along the endothelial surface. Receptors such as L- and P-selectins produced in response to injury attach to receptors on leukocytes such as proteoglycans and integrins. This induces rolling
- Adhesion and transmigration: adhesion occurs through receptor-ligand interaction between leukocyte and endothelial cell. Endothelial cells upregulate glyproteins such as ICAM-1 in response to injury which then bind to cell surface receptors on leukocytes such as LFA-1. Transmigration occurs after firm adhesion within capillaries via PECAM-1
- Chemotaxis and activation
Clotting cascade
Begins with Hageman factor which exists in an inactive state. Activated to XIIa within platelets. XIIa activates thrombin which in turn converts soluble fibrinogen to insoluble fibrin clot.
Kinin cascade
Leads to formation of bradykinin from cleavage of precursor (HMWK) through kallikrein.
Bradykinin involved in vascular permeability, arteriolar dilation, non-vascular smooth muscle contraction (e.g. bronchial smooth muscle), increased nociception. Rapidly inactivated via kininases
Complement system
Activation of complement leads to cleavage of C3. C3a and C5a are involved in recruitment and activation of leukocytes and destruction of microbes.
Arachidonic acid metabolites and their roles in inflammation
Phospholipases derived from phospholipids that make up membrane initiate a series of events depending upon the function of various other factors down two major pathways to produce either cyclooxygenases which go on to produce prostaglandins (smooth muscle activators), or 5-lipooxygenase which produces leukotrienes involved in vascular permeability. Steroids inhibit phospholipase conversion to arachidonic acid. COX-1 and COX-2 inhibitors include aspirin which inhibit cyclooxygenase.
Inhibiting cytokine driven inflammation
Inhibitory cytokines (e.g. IL-10)
Reduce cytokine producing cells (e.g. cytostatics)
Inhibitors of signal transduction (e.g. cyclosporin)
Regulation of gene expression (e.g. glucocorticosteroids)
Reduction in circulating cytokines (e.g. Abs, soluble receptors)
Fever mechanism
Cytokine-mediated (especially IL-1, IL-6, TNF)
Acute myocardial infarction - pathogenesis at cellular level
- Cell death by necrosis and apoptosis - occurs rapidly post-ischaemia. Apoptosis inhibitors reduce infarct size.
- Reperfusion - in <20 mins myocytes surive infarct event
- No reperfusion - necrosis complete in 6-12 hours
Inflammatory markers of AMI used as diagnostic biomarkers
Troponin I
Creatine phosphokinase
Myoglobin
Modification of infarct
- Restoration of coronary blood flow through thrombolysis via streptokinase or tissue plasminogen activator (activates fibrinolytic enzymes, dissolves thrombus), balloon angioplasty, or coronary arterial bypass graft
- Reperfusion
Source of reperfusion injury
Reperfusing polymorphs (leukocytes or granulocytes) produce reactive oxygen species/free radicals due to activation of cytoplasmic xanthine oxidase
Pharmacological protection from reperfusion injury
Ischaemic pre-conditioning (RISK) and post-conditioning (SAFE) pathways confer protection by inhibiting/closing the mitochondrial permeability transition pore (mPTP). This blocks the release of cytochrome C and thus activation of apoptotic pathways.
Risk factors for acute myocardial infarction and mechanisms
Hypertension
Diabetes
Smoking
Hypercholesterolaemia
AMI
Acute myocardial infarction - macroscopic death of myocardium due to vascular insufficiency (VI)
COPD major
Irritants such as smoking can cause
Emphysema
Irreversible enlargment of airspaces, distal to terminal bronchiole
Types of COPD
Emphysema - alveolar wall destruction, overinflation
Chronic bronchitis - Productive cough, airway inflammation
Asthma - Reversible obstruction, bronchial hyperresponsiveness triggered by allergens
Chronic bronchitis
Persistent cough with sputum production for at least 3 months in 2 consecutive years. May progress to COPD and may overlap with emphysema. Hypersecretion of mucus and if persistent, marked increase in goblet cells in small airways
Asthma
Chronic disorder of the conducting airways, usually by immunological reaction which is marked by an episodic bronchoconstriction
Atopic asthma
triggered by environmental allergens (dusts, pollens, roach or animal dander, foods); type I IgEmediated
hypersensitivity reaction
Non-atopic asthma
typically virus-induced inflammation lowers threshold to irritants
Drug-induced asthma can be induced by
salicylate (aspirin)-induced is a typical example
Occupational asthma
exposure to fumes (plastics, organic solvents, chemical dusts)
Atopic asthma sequence of events
Type I IgE-mediated hypersensitvity reaction (immediate)
Allergen stimulates Th2 response
Class switching (IgE)
IgE binds to Fc receptors on mast cells
Subsequent exposure to allergen results in mast cell activation by Ag-induced cross-linking of IgE, degranulation and release of preformed mediators such as histamine
Mast cell mediators
ECF = eosinophil chemotactic factor NCF = neutrophil chemotactic factor PAF = platelet-activating factor
Pathogenesis of asthma
Thickened basement membrane
Increase mucus in bronchial lumen caused by mucus-secreting goblet cell hyperplasia in the mucosa and hypertrophy of submucosal glands, chronic inflammation due to recruitment of eosinophils, macrophages and other inflammatory cells, as well as hypertrophy/hyperplasia of smooth muscles
Genetics of asthma
> 100 genes implicated
Susceptibility loci on long-arm of chromosome 5 (5q):
- IL-3, IL-4, IL-5, IL-9, IL-13 (receptor), IL-14 (receptor)
- β2-adrenergic receptor
- ADAM-33 polymorphisms – matrix metalloprotease involved in bronchial hyperresponsiveness
Mammalian chitinases – polysaccharides contributing to TH2 inflammation
Management of asthma
Short-acting β2 agonist
Low-dose inhaled corticosteroid (anti-inflammatory)
Experimental models of asthma
Chronic ovalbumin-induced asthma model
Experimental therapies for asthma
Histone deacetylase inhibitors
Normal alveolar structure
Type I pneumocytes cove 95% of the alveolar surface
Type II cells synthesize surfactant and are involved in the repair of alveolar epithelium through their ability to give rise to type I cells
Pneumonia
Respiratory disorders involving acute inflammation of the lung structures, mainly the alveoli and bronchioles
Infecious pneumonia is often facilitated by which virulent organism
Streptococcus pneumoniae
Lung defences
Airway:
- Ciliated epithelial cells lining airway tract produce mucus which creates a barrier to protect from pathogens, chemicals and irritants, as well as using cilia to move trapped dust and pathogens away.
- Clara cells act as progenitor cells with stem cell-like characteristics, while also participating in xenobiotic metabolism and regulation of lung immune system
- Surfactant proteins produced by clara cells
Alveoli:
- Surfactant proteins produced by type II cells
- Opsonins
- Complement
- Resident macrophages
- Neutrophils
Impaired lung defences
Loss/suppression of cough reflex - can lead to aspiration of gastric contents
Injury to muco-ciliary apparatus
Interference with phagocytic/anti-bacterial action of
alveolar macrophages
Accumulation of secretions
Pulmonary congestion or oedema
Acute inflammation in the lung - time course
1-2 days: lung heavy, full of blood - oedema
2-4 days: lung red, heavy, full of liquid and some fibrin - stasis and congestion = RED HEPATISATION
4-8 days: lung solid, heavy, grey-white = GREY
HEPATISATION
alveoli full of fibrin & neutrophils, red cells
disintegrate
> 8 days: RESOLUTION - exudate breaks down &
is removed
Histology of the stages of bacterial pneumonia
The congested capillaries and extensive neutrophil exudation into alveoli corresponds to early red hepatisation. This is followed by early organization of intra-alveolar exudate, seen in areas to be streaming through the pores of Kohn, i.e. the spreading of inflammatory response to previously healthy alveoli. Lastly, advanced organising
pneumonia featuring transformation of exudates to fibrous masses richly infiltrated by macrophages and fibroblasts.
Complications of acute inflammation in lobar pneumonia
- Tissue destruction and necrosis
- Spread of infection and inflammation to pleural cavity = PLEURISY
- Bacteraemic disseminatio
Contrasting features of acute and chronic inflammation in lung
- In acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.
- In chronic inflammation, collection of chronic inflammatory cells occurs, as well as destruction of parenchyma where normal alveoli are replaced by spaces lined by cuboidal epithelium. Fibrosis occurs in between lungs, reducing elasticity of the lung.
Acute Respiratory Distress Syndrome (ARDS)
Diffuse alveoli damage, high mortality- 40%-60%
Effect of wide-spread, diffuse damage to alveolar capillaries and/or alveolar epithelium and alveolar surfactant layer
Causes of ARDS
DIRECT LUNG INJURY:
a) gastric aspiration
b) pulmonary contusion, penetrating lung injury
c) ionising radiation
d) near drowning
e) inhalation injury eg. NO2, SO2, Cl2, smoke
f) reperfusion pulmonary edema after lung transplant
g) oxygen toxicity (SCUBA divers)
Surfactant proteins
Surfactant proteins line the internal layer of alveoli in the lung protect the airways from infection but their main function is to maintain alveolar integrity and reduces surface tension at the air-liquid interface -> air exchange. Also have immune function.
ARDS vs. Pneumonia
ARDS always acute onset of respiratory failure
ARDS almost always seen as a bilateral infiltrate on
CXR
Pathogensis of ARDS
Sloughed bronchial epithelium
Loss of type II cells - loss of pulmonary surfactant and thus integrity of alveoli
Apoptosis of Type 1 cells - decreased transfer of oxygen
Nearby capillaries are also damaged
Accumulation of neutrophils
Progression and Morphology of ARDS
Exudative phase (acute):
Day 1: interstitial/alveolar oedema, degenerative changes in type 1 alveolar epithelium, start of interstitial infiltrate - lymphocytes, plasma cells, macrophages
Day 2: sloughing type 1 cells bare - basement membrane
hyaline membranes begin
Day 4-5: Peak hyaline membrane formation
Day 7: Peak of interstitial inflammatory infiltrate, type 2 alveolar epithelial cells proliferate & spread along basement membrane, thrombi in alveolar capillaries & pulmonary arterioles
Organising phase (slower): Interstitial inflammation and type II hyperplasia persist Macrophages breakdown hyaline membrane & debris > day 14: interstitial fibroblasts proliferate, produce collagen
Outcomes of ARDS
- Resolution - complete recovery and restoration of normal lung function:
• Alveolar exudate and hyaline membrane resorbed
• Normal alveolar epithelium restored
• Fibroblast proliferation ceases
• Extra collagen metabolised - broken up and destroyed - End-stage fibrosis:
• Exudate associated with tissue destruction i.e. the hyaline membranes - large amount of scar tissue produced
• Lung architecture remodelled, multiple cyst-like spaces = ‘honeycomb lung’
• Spaces separated from each other by fibrous tissue, lined with type II epithelium, bronchiolar epithelium or squamous cells
Mechanisms involved in resolution of ARDS
Na/K-ATPase = Sodium pump ENaC = Epithelial Sodium Channel Aquaporins = water transport channels
ARDS treatment
- Mechanical ventilation
- Inhalation of NO – vasodilation
- High O2 concentrations - toxic
- Surfactant therapy
- Anti-inflammatory drugs - glucocorticoids
- Treatment very difficult - mortality 40 - 60%
