L2: Inflammation Flashcards Preview

Immunology > L2: Inflammation > Flashcards

Flashcards in L2: Inflammation Deck (29):

Definition of inflammation. Classic signs of inflammation

- A complex rxn of vascularized tissue to infection or cell injury that involves extravascular accumulation of plasma proteins and leukocytes
- Signs: redness, swelling, heat and pain


Purpose of inflammation

1.) Remove pathogenic insults
2.) Remove injured tissue
3.) Institute wound healing (or scarring or both)


Distinguish between acute and chronic inflammation. Describe in terms of time period, cell type

1.) Acute: accumulation of fluid and neutrophils, measured in hours or days
2.) Chronic: offending agent unable to be removed in acute inflammation, presence of lymphocytes and macrophages, weeks months or years


Outcomes of inflammation

1.) Resolution
2.) Abscess (neutrophils and necrotic debris)
3.) Scarring (tissue irreversibly injured)
4.) Chronic inflammation


Describe the initial steps of the acute inflammatory process following injury with the role of the mast cell

- Mast cells are found lining barriers. When injury occurs and microbe is introduced, complement is activated via the alternate, classical and / or lectin pathway
- C5a, a chemokine, is produced through the complement cascade. The trauma and C5a activate the mast cell, triggering degranulation and release of histamine
- Histamine binds to many target cell receptors on endothelium, causing contraction. This increases vascular permeability and plasma leaks into the tissues
- Endothelial cells secrete NO, which causes vasodilation, which increases blood flow causing heat and redness
- Mast cells also secreted PGD2, which is a lipid mediator that binds receptors on smooth muscle cells and acts as a vasodilator, causes pain


Secretions of mast cells and their functions

1.) Histamine: released in response to C5a and trauma, binds endothelial cells, causing contraction and therefore increased vascular permeability and plasma leakage into tissue
2.) Prostaglandin D2: released in response to C5a, binds smooth muscle cells and acts as a vasodilator, causes pain too


PGD2/PGE2 precursor. Function?

- Arachidonic acid, precursor to prostaglandins, thromboxanes, prostacyclins and leukotrienes
- PGD2 (released in response to C5a): binds SM cells, acts as vasodilator, causes pain
- PGE2 (released in response to IL-1 and TNF): binds hypothalamus affecting production of cAMP, resets temp setpoint to higher temp (fever)


Describe how injury causes activation of the coagulation cascade and how this cascade contributes to the acute inflammatory process

- Injury results in BM exposure and activation of Hageman factor (XII)
- This results in generation of bradykinin (via ez: kallikrein) amongst other things
- Bradykinin increases vascular permeability (edema) and causes contraction of SM, dilation of blood vessels and pain
- In addition, complement (specifically C5) can be cleaved by kallikrein to produce C5a, the big chemokine seen in acute inflammation


What are the mediators of vasodilation?

- Prostaglandins, NO and histamine


What are the mediators of increased vascular permeability?

- Histamine and bradykinin


What are the mediators of chemotaxis, leukocyte recruitment/activation?

- TNF, IL-1, C3a/C5a, PAMPs


What are the mediators of fever?

- IL-1, TNF, prostaglandins


What are the mediators of pain?

- Prostaglandins and bradykinins


What are the mediators of tissue damage?

- Lysosomal enzymes, ROS and NO


Role of microbe in activating the acute inflammatory cascade

- Activates complement, causing production of C3a and C5a. These stimulate chemotaxis toward the site of inflammation
- PAMPs (from microbe) activate PRR on macrophages resulting in production of TNF, IL-1 (pro-inflammatory cytokines). Together with histamine, TNF and IL-1 upregulate adhesion molecules for leukocytes on endothelium


Describe the process of neutrophil extravasation to the site of injury

1.) Stasis
2.) Rolling (aka tethering): selectins:selectin ligands
- Histamine (and TNF and IL-1) upregulates endothelial cell P-selectin. P-selectin binds to neutrophil P-selectin glycolipid-1 (PSGL-1) expressed on neutrophils. This results in a low affinity interaction between ECs and neutrophils

3.) Binding: integrin:integrin ligands
- ICAM-1 (integrin) is also upregulated on EC surface, which binds LFA-1, upregulated on the cell surface of neutrophils resulting in a high affinity interaction, causing the neutrophil to stop rolling

4.) Extravasation: PECAM:PECAM
- Both neutrophils and ECs ([] at intracellular junctions) express PECAM-1, which allows neutrophils to squeeze between the endothelial cells. Once under the ECs, they use MMPs to penetrate basement membrane. Chemokines bound to proteoglycans form a gradient towards site of injury, used by the neutrophils


Anti-inflammatory mediators released by alternatively activated macrophages

- IL-10 and TGF-beta


In an acute inflammatory cascade, what is the timing of neutrophil and macrophage arrival to the site of injury?

- Neutrophils arrive within 6-24 hours
- Monocytes/macrophages arrive 24-48 hours after


Function of macrophages in wound healing?

- Ingest cellular debris, such as dead or damaged tissue cells and also dead PMNs to aid in restoring normal tissue architecture
- Secrete TGF-beta (and IL-10), which are anti-inflammatory mediators that initiates the wound healing process by inducing migration and proliferation of fibroblasts to/at the site. Also stimulates secretion of collagen


What are conditions that predispose an individual to chronic inflammation?

1. Persistent infections: mycobacterium tuberculosis, treponema pallidum, some fungal pathogens
2. Chronic exposure to toxic agents, such as silicosis
3. Autoimmune diseases, such as RA and lupus


What are the hallmarks of chronic inflammation seen in the tissue?

- infiltration of macrophages and lymphocytes
- tissue destruction by enzymes released from macrophages: elastase, collagenase, phosphatases, lipases
- attempts at healing (angiogenesis, fibrosis)


Molecular basis for fever

- IL-1 and TNF causes production of prostaglandins such as PGE2, which affect production of cAMP in the hypothalamus, causing reset of temperature set-point to higher level


What are the advantages of fever?

- Immune system functions more effectively
- Host cells protected from deleterious effects of TNF-alpha
- Pathogens grow more poorly


What cytokines cause accelerated release of PMNs (inducing neutrophilia) from the bone marrow?

- IL-1 and TNF


Segmented vs band PMN?

- Segmented = mature, band = immature


What are acute phase proteins of the acute phase response? Clinical relevance?

- In systemic inflammation, IL-6 from macrophages acts on hepatocytes to synthesize and release acute phase proteins such as CRP and serum amyloid
- Increased levels leads to accelerated ESR, which is a measure of sedimentation of erythrocytes and can be measured in a lab.
- These proteins can function as opsonins, which facilitate phagocytosis, but also in clearance of pathogens


What is shock/sepsis?

- When TNF reaches high levels in the bloodstream, there is:
1.) systemic vasodilation with increased vascular permeability leading to hypotension
2.) systemic activation of the coagulation cascade, reducing clotting factors leading to DIC, which causes organ failure and serious bleeding
3.) death


What releases TNF and IL-1?

- Macrophages


What is the most potent complement anaphylatoxin?

- C5a
- Anaphylatoxin = protein fragments produced as part of activation of complement system, which mediate degranulation of mast cells and basophils, resulting in release of mediators that induce contraction of SM and increased vascular permeability.