2.13 - Inflammation

Question 1

What is inflammation?

Answer 1

• inflammation is a non-specific response to cellular injury
• designed to remove the cause and consequence of the initial inflammatory signal (the injury) and repair inflamed tissue
• complex and tightly regulated process
• initiated by cellular damage (non-apoptotic cell death) leads to release of damage associated molecular patterns (DAMPs) or body detects pathogen associated molecular patterns (PAMPs)
• inflammation is seen in every disease and in every tissue/area of the body

Question 2

What are the four main signs of acute inflammation?

Answer 2

1. redness (rubor)
2. heat (calor)
3. pain (dolor)
4. swelling (tumor)
   extra:
5. loss of function (functio laesa)

Question 3

What are the causes of inflammation?

Answer 3

• pathogens
• allergens
• auto-antigens
• physical damage
• extreme temperatures
• non-apoptotic cell death

Question 4

Examples of diseases where inflammation is seen

Answer 4

• infection
• autoimmunity
• hypersensitivity
• trauma
• fibrotic disease
• cancer

Question 5

What is acute inflammation?

Answer 5

• inflammation is a rapid, non-specific response to cellular injury
• change in local blood flow –> structural changes in the microvasculature –> recruitment/accumulation of immune cells and proteins

Question 6

First stage of acute inflammation - steady state

Answer 6

• this is what any viable, vascularised tissue looks like
• epithelium, interstitium (mast cells and macrophages at epithelium/interstitium border), vascular endothelium (containing leukocytes, neutrophils, erythrocytes)
• e.g. skin

Question 7

Second stage of acute inflammation - damage

Answer 7

1. inflammatory signals - non-apoptotic cell death occurs and detection of foreign material e.g. bacteria
2. immune cells are activated by recognising DAMPs/PAMPs, especially mast cells, which rapidly degranulate and release vasodilators e.g. histamine and nitric oxide
3. vascular changes - increased permeability, dilation, reduced flow, plasma leakage into interstitium

Question 8

What are the benefits of increased vascular permeability and leakage?

Answer 8

• rapid movement of antibodies to site of inflammation specific to intruding pathogen
• recruiting proteins into tissue site which allows for increased activation of immune cells and source of protein for tissue repair
• recruitment of leukocytes
• formation of physical barrier

Question 9

What are some soluble mediators released at an injury?

Answer 9

• histamine - mast cells, basophils, platelets - vasodilation, increased vascular permeability, endothelial activation
• prostaglandins - mast cells, leukocytes - vasodilation, pain, fever
• cytokines - macrophages, endothelial cells, mast cells - endothelial activation (adhesion molecules), fever, malaise, pain, anorexia, shock
• chemokines - leukocytes, activated macrophages - chemotaxis, leukocyte activation
• complement - plasma (produced in liver) - leukocyte chemotaxis and activation, vasodilation (mast cell stimulation), opsonisation

Question 10

Third stage of acute inflammation - immune cell recruitment

Answer 10

• recruitment and inflammation signals at the site of damage e.g. chemokines produced
• chemokines diffuse out to form a gradient
• leukocytes in vasculature expressing complementary chemokine receptors migrate towards the chemokine source
• e.g. chemokine CXCL8 (IL-8) works on receptors CXCR1&CXCR2 (g-coupled 7-TM proteins) on neutrophils
• neutrophils are often the first cell type recruited to site of inflammation

Question 11

How does neutrophil extravasation (leakage) work?

Answer 11

1. chemo-attraction: cytokines act on endothelial layer to promote upregulation of adhesion molecules e.g. selectins
2. rolling adhesion: carbohydrate ligands in a low affinity state on neutrophils bind selectins and migrate along the blood vessel e.g. PSGL1 (selectin P ligand) binds P and E selectins
3. tight adhesion - chemokines promote low to high affinity switch in integrins e.g. LFA-1, Mac-1 –> enhance binding to ligands e.g. ICAM-1
4. transmigration - cytoskeletal rearrangement and extension of pseudopodia to move cell into interstitium - mediated by PECAM interactions on both cells

Question 12

What is neutrophil function at the site of inflammation?

Answer 12

1. pathogen recognition e.g. use of TLR4 and CD14 to identify lipopolysaccharides (LPS) present in gram-negative bacteria
2. pathogen clearance - phagocytosis, netosis (in extreme circumstances, neutrophils form neutrophil nets which trap bacteria)
3. cytokine secretion - recruitment and activation of other immune cells

Question 13

What happens in phagocytosis?

Answer 13

• large particles engulfed into membrane bound vesicles (phagosomes)
• phagosome fuses with lysosome (vesicles containing enzymes e.g. elastase and lysozyme) –> phagolysosome
• reactive oxygen species (ROS) - phagocyte NADPH oxidase
• antimicrobial peptides - e.g. defensins

Question 14

What is resolution of acute inflammation?

Answer 14

1. pathogen recognition - immune cells (e.g. neutrophils) and antimicrobials (e.g. antibodies) will recognise infections/particulates
2. short half-life - neutrophils (especially activated) have a rapid half-life, inflammatory mediators like histamine are turned over rapidly
3. macrophages - clear apoptotic cells, produce anti-inflammatory mediators to suppress inflammation
4. repair/wound healing

Question 15

What is exudate?

Answer 15

• fluid, proteins and cells that have seeped out of a blood vessel
• forms a separation between healthy and inflamed tissue to prevent inflammatory stimuli and pathogens from migrating into healthy tissue and causing further damage

Question 16

What types of antigen are there?

Answer 16

• foreign antigen - derived from molecules not found in body
• self antigen - derived from molecules produced by our bodies
• immunogen - independently capable of driving an immune response in the absence of additional substances
• hapten - small molecule that does not act as an antigen but when bound to a larger molecules can create an antigen

Question 17

What is chronic inflammation?

Answer 17

• similar to acute inflammation in the initial insult, same neutrophil recruitment, foreign antigens present in both, but there are differences:
• persistent inflammatory stimuli - persistent/prolonged infection (e.g. TB, hep B/C), persistent toxic stimuli (e.g. allergens, pollutants), unclearable particles (e.g. silica), autoimmunity (e.g. self antigens)
• distinct immune cell infiltrate - inflammatory macrophages, T cells (and other lymphocytes), plasma cells that secrete antibodies
• a vicious cycle of damage and repair - no clearance of inflammatory agent, bystander tissue destruction (cells keep secreting inflammatory molecules to try and destroy pathogen), concurrent repair processes (fibrosis and angiogenesis)

Question 18

What is the role of macrophages in chronic inflammation?

Answer 18

• macrophages can be recruited as monocytes to site of inflammation but there are also tissue resident macrophages there
  The good:
• phagocytic
• cytotoxic
• anti-inflammatory (e.g. TGF-B, IL-10)
• wound repair
  The bad:
• cytotoxic - produce inflammatory molecules
• inflammatory - keep recruiting T cells, neutrophils etc if left unchecked
• pro-fibrotic - normally promote collagen formation for wound repair but excessive promotion = too much collagen produced

Question 19

What is the role of T cells in chronic inflammation?

Answer 19

• pro-inflammatory e.g. TNF, IL-17, IFN-y
• cytotoxic e.g. granzymes, perforin
• regulatory e.g. TGF-B

Question 20

What is the role of B cells in chronic inflammation?

Answer 20

• generate plasma cells that secrete antibodies
• protective, clearing infection
• inflammatory, driving reactions against self
• can either be local to inflammatory site, or operate remotely (secrete antibodies into lymph/circulation that can migrate to site of infection)

Question 21

What is granulomatous inflammation?

Answer 21

• chronic inflammation with distinct pattern of granuloma formation
• triggered by strong T cell responses
• form against resistant agents (e.g. mycobacterium, tumour)
• granuloma - aggregation of activated macrophages, a barrier designed for clearance of foreign material by macrophages
• granulomas form around persistent threats

Question 22

Examples of diseases characterised by chronic inflammation

Answer 22

• rheumatoid arthritis
• asthma
• inflammatory bowel disease
• glomerulonephritis
• hepatitis
• psoriasis
• multiple sclerosis

Question 23

Examples of diseases associated with granulomatous inflammation?

Answer 23

• TB
• leprosy
• foreign body granuloma
• tumour reactions
• sarcoidosis
• Crohn’s disease (type of IBS)

Question 24

Acute vs chronic inflammation

Answer 24

• immediate onset that lasts a few days VS delayed onset that may last weeks/months/years
• vasodilation, increased vascular permeability, leukocyte response VS persistent inflammation, ongoing tissue injury, attempts at healing
• neutrophils predominate VS monocytes/macrophages predominate
• histamine release VS ongoing cytokine release
• prominent necrosis VS prominent scarring
• outcomes include: complete resolution, progression to chronic inflammation VS scarring, loss of function

Question 25

What are the positive outcomes of inflammation?

Answer 25

• clear inflammatory agent
• remove damaged cells
• restore normal tissue function

Question 26

What are the negative outcomes of inflammation?

Answer 26

• excess tissue damage
• scarring - could reduce motility
• loss of organ function –> organ failure

Question 27

What negative consequences could there be of wound healing?

Answer 27

• leads to extracellular matrix (e.g. collagen) deposition
• when excess collagen cannot be removed, it forms a scar
• wound healing in sensitive tissues could lead to loss of tissue function e.g. in heart
• broncho-pneumonia can be caused by collagen deposition as part of wound healing as thin epithelial walls that allow gas exchange in lung are replaced with collagen filled scarred areas that do not allow for gas exchange