The Acute Inflammatory Process

Question 1

What is Inflammation initiated by?

Answer 1

Inflammation is initiated by cells already present in the tissue - mainly macrophages, dendritic cells, histiocytes and mast cells.

Surface receptors on these cells recognise the characteristic molecular products associated with cell damage or the presence of pathogens.

Question 2

What are the inflammatory mediators responsible for the process of inflammation? Give examples.

Answer 2

• Eicosanoids: prostaglandins, leukotrienes
• Chemokines: Interleukin-8
• Cytokines: TNF-alpha, Interleukin-1, Interferon Gamma-Y.
• Enzymes: tryptase, lysozyme
• Nitric Oxide

Question 3

What does Mast cell degranulation result in?

Answer 3

Mast cell degranulation releases mediators that cause vasodilation and increase vascular permeability including:
(i) The monoamine histamine
(ii) The peptide brady kinin
(iii) prostaglandins
(iv) leukotrienes

Which are all also involved in activating nociceptor nerve endings mediating the pain associated the inflammation.

Question 4

What role do mast cells play in the pain associated with inflammation?

Answer 4

mast cell degranulation releases histamine, bradykinin, prostaglandins and leukotrienes which are involved in activating nociceptor nerve endings.

Question 5

How does the inflammatory process address immediate threat of microbial invasion?

Answer 5

Increased vascular permeability allows large molecules normally restricted to the plasma to enter the tissues.

Exuded plasma contains components required to address the immediate threat of microbial invasion: antibodies, complement and lysozyme.

Question 6

What does exuded plasma contain?

Answer 6

antibodies, complement and lysozyme

Platelets, coagulation factors, pasmin and kinins required for wound healing.

Question 7

What are cytokines?

Answer 7

Cytokines are a family of polypeptides (5-20 kDa) involved in local cell signalling by interacting with cell surface receptors.

Question 8

What happens when macrophages are exposed to the products of tissue damage or microbes?

Answer 8

Macrophages are activated to secrete a range of cytokines that amplify the inflammatory response.

Question 9

What is the role of tryptase and where is it secreted from?

Answer 9

tryptase is also produced by mast cells.

Tryptase enhances vascular permeability and degrades many signalling molecules.

It also has potentially detrimental effects such as stimulating fibroblast and smooth muscle cell proliferation.

Question 10

What are TLRs (Toll-like receptors) found and what is their role?

Answer 10

Toll-like receptors (TLRs) are found on the surface of initiate immune cells.

TLR activation enables host to recognize a large number of pathogen-associated molecular patterns (PAMPs) and subsequent intracellular signalling.

Question 11

What are TLRs specific to?

Answer 11

Lipopolysaccharide from Gram-negative bacteria

Lipoproteins from Gram positive organisms

Bacterial DNA

Question 12

What does TLR binding result in?

Answer 12

Binding of ligand to toll-like receptors leads to activation of NF-kB and mitogen activated protein (MAP) kinase pathways

These ultimately stimulate gene promoter regions and regulate the transcription of genes encoding pro-inflammatory mediators such as:

TNF-alpha, interleukins and inducible nitric oxide synthase (iNOS).

Question 13

What is NF-kB? What does it do (4)?

Answer 13

NF-κB (nuclear factor kappa light chain enhancer of activated B cells) is a family of highly conserved transcription factors

NF-kB is a major transcription factor associated with innate and adaptive immune responses.

NF-κB induces the expression of various pro-inflammatory genes,

including those encoding cytokines and chemokines,

and also participates in inflammasome regulation.

In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells.

Question 14

What is the protypical pro-inflammatory cytokine?

Answer 14

Tumour Necrosis Factor - alpha

Question 15

What is the role of TNF-alpha?

Answer 15

TNF-alpha is released primarily by macrophages after injury and modulates a variety of immunological and metabolic events locally and systemically.

Question 16

What are the local effects of TNF-alpha? (3)

Answer 16

• TNF-alpha is a potent activator of neutrophils and mononuclear phagocytes
• Serves as growth factor for fibroblasts and angiogenesis factor.
• Induces apoptosis which is important for the resolution of the inflammatory process.

Question 17

What are the systemic effects of TNF-alpha?

Answer 17

• TNF-alpha induces pyrexia
• Stimulates production of acute-phase protein secretion by the liver.

Question 18

How can TNF-alpha endanger the sickest patients?

Answer 18

• causes activation of coagulation cascade
• myocardial suppression
• induction of systemic vasodilators with resultant hypotension, catabolism and hypoglycemia

Question 19

What are the physiological effects of IL-1?

Answer 19

Identical to TNF-alpha

IL-1 will induce fever, myalgia, somnolence, vasodilation and shock, cause bone resorption, induce muscle proteolysis, and induce synthesis of acute phase proteins such as C-reactive protein, serum amyloid A, and fibrinogen by hepatocytes.

Question 20

What role does IL-6 have?

Answer 20

released by several inflammatory cells and acts systemically to:
- Induce the secretion of actue-phase proteins fro the liver.
- Serves as a growth and differentiation factor for B-lymphocytes.

Question 21

What role does IL-8 have in immune response?

Answer 21

IL-8 is produced by macrophages and is a potent chemoattractant for recruiting neutrophils to inflammatory foci.

Question 22

What is the role of IL-12 in the immune response?

Answer 22

IL-12 is produced by activated macrophages and its most important functions to simulate the production of IFN-y by T-cells and Natural Killer cells.

Question 23

What is IFN-y?

Answer 23

Interferon-Gamma is a cytokine critical to immunity, and functions as the primary activator of macrophages.

Question 24

What is the role of IL-10 in the immune response?

Answer 24

IL-10 is an example of an anti-inflammatory cytokine that down regulates the expression of other cytokines.

Question 25

How do changes to blood flow at the site of inflammation aid inflammatory processes?

Answer 25

The early hemodynamic changes at a site of inflammation establish low shear conditions that enable marginated leukocytes to engage in low-affinity selectin-mediated rolling interaction with activated endothelial cells.

Question 26

What are neutrophils?

Answer 26

The most abundant leukocytes, and the first to migrate to a site of inflammation.

Question 27

Explain neutrophil migration.

Answer 27

> Neutrophil migration beings with adhesion to the vascular endothelium facilitated by binding to selectins, but also mediated by actins of integrins and their ligands whose expression is up regulated as part of the inflammatory response

> Integrins are expressed on the surface of neurotrophils and interact with ligands present on endothelial cell membranes, particuluarly intercellualr adhesion molecule-1 (ICAM-1)

> This causes tight adherance of the neutrophil to the endothelium and allows the process of penetrating the vascualr wall to begin.

> Penetration is facilitated by adhesion molecules such as Platelet endothelial cell adhesion molecule-1 (PECAM-1) that are present on the lateral surfaces of endothelial cells as well as on neutrophils.

> The binding of PECAM-1 decreases neutrophil adhesion to ICAM-1, Loosening the adherence to the endothelial cells and promoting passage across the endothelium.

Question 28

What are selectins?

Answer 28

Selectins are one class of cell adhesion molecules (CAMs) that bind carbohydrate ligands.

Question 29

What are the 2 roles of neutrophils at the site of inflammation?

Answer 29

1. They phagocytose microbes and other materials, aided by presence of the enzyme myeloperoxidase which generates hydrogen peroxide and other powerful oxidants; also aided by lysozymes.
2. Also contain enzymes such as collagenase and gelatinase which help to breakdown damaged tissues to prepare for repair.

Question 30

How can the action of neutrophils at the site of inflammation become damaging?

Answer 30

Neutrophils contain enzymes such as collagenase and gelatinase to help breakdown tissues, and while necessary in response to acute injury it may become the cause of harmful destruction of healthy tissues in chronic inflammatory diseases.

Question 31

How are lymphocytes involved in the inflammatory process?

Answer 31

Not only involved in the acute inflammation response but also in the development of acquired immunity.

They are recruited in a similar way to neutrophils and interact with Antigen presenting cells through massive proliferation and differentiation to effector T-lymphocytes.

• Some are able to migrate to infection sites and eliminate triggering pathogens.
• Others will remain as memory cells that provide acquired immunity in readiness for future encounters with the same pathogen.
• They also secret cytokines such as TNF-alpha and IFN-y that further amplify the inflammatory response.

Question 32

Explain actue -> chronic inflamamtion

Answer 32

acute inflammation may progress to chronic inflammation if a threat is not fully eliminated or there is a chronic disease process such as autoimmunity driving it.

In these circumstances, the processes that were a necessary part of repair may be the source of long-lasting tissue damage.

Question 33

What is the innate immune system?

Answer 33

The innate immune system is the body’s first line of defense against germs entering the body. It responds in the same way to all germs and foreign substances, which is why it is sometimes referred to as the “nonspecific” immune system

Question 34

how is the innate immune system connected to inflammation?

Answer 34

Inflammation is triggered when innate immune cells detect infection or tissue injury.

Question 35

What is the difference between gram positive and gram negative bactera?

Answer 35

Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which itself is surrounded by an outer membrane containing lipopolysaccharide.

Gram-positive bacteria lack an outer membrane but are surrounded by layers of peptidoglycan many times thicker than is found in the Gram-negatives.