Gen Path 16 and 17: Inflammation and Vascular Response

Inflammation

1. Reaction of vascularized, living tissue to local injury

2. Designed to:

   1. Eliminate the injurious stimulus

   2. Repair associated tissue damage

Pain, swelling, redness, heat, loss of function

Five cardinal signs of inflammation

Defensive

Inflammation is an evoked, ___ response that does not occur spontaneously or proactively.

Stereotypical

1. Inflammation is a ___ phenomenon

   1. Limited number and type of inflammatory responses

   2. Different stimuli can elicit the same response

Intensity, magnitude, duration

Although cellular response is stereotyped, inflammation can vary significantly in ___, ___, and ___.

Innate immune response, immunologic status of host, type of agent involved

What factors do inflammatory responses depend on?

Increasing temperature to inhibit microbial replication, providing wound healing factors, restricting movement of joints to allow for healing, killing microbes, degrading foreign materials, diluting/inactivating biological and chemical toxins

Beneficial aspects of inflammation

Recognition of inflammatory stimulus, acute vascular response, acute cellular response, chronic cellular response, resolution

What are the five phases of inflammation?

Microbes, foreign bodies, mechanical action, physical action, chemical substances

Exogenous substances inducing tissue injury

Autoimmune reactions, intracellular signals released from injured or dying cells

Endogenous substances inducing tissue injury

Pathogen-associated molecular patterns (PAMPs)

1. Highly-conserved microbial ligands

2. Recognized as “non-self” by host cells

   1. Macrophages, leukocytes, mucosal epithelium

3. Binding triggers release of inflammatory mediators

4. Unique to microbes, not components of host

Pattern recognition receptors (PRRs), inflammatory mediators

1. PAMPs are recognized by ___ on or within host cells

2. Binding results in downstream induction of ___

Damage-associated molecular patterns (DAMPs)

1. Endogenous molecules released from damaged or dying cells

2. Their presence extracellularly alerts nearby cells to the presence of tissue injury

3. Bind PRRs for downstream induction of inflammatory mediators

Pathogen-associated molecular patterns (PAMPs)

What are these all examples of?:

1. Double-stranded RNA (viruses)

2. Lipopolysaccharide/LPS (gram-negative bacteria cell wall)

3. N-formylmethionine (bacterial proteins)

4. Lipoteichoic acids (gram-positive bacteria)

5. Flagellin (bacterial protein)

6. Glucans and chitin (fungal cell wall)

Exogenous, non-self, endogenous, damaged self

PAMPs are ___ molecules that differentiate “self” from “___,” while DAMPs are ___ molecules that differentiate “healthy self” from “___.”

Mast cells

1. First responders

   1. Already present in tissue

   2. Often close to the site of injury

      1. Situated around vessels and close to peripheral nerves

   3. Contain preformed vasoactive mediators within granules

      1. Histamine

      2. Serotonin

PRRs (e.g. TLRs), FcE (binds IgE), complement receptors

Mast cell receptors

Mast cells

Functions of which type of cell?:

1. Degranulate in response to receptor binding, physical trauma, temperature extremes, etc.

2. Release histamine and serotonin

   1. Vasodilation

   2. Increased vascular permeability

Histamine, serotonin

What do mast cells release?

Resident tissue macrophages, epithelial cells

Other cells involved in the initial recognition of the inflammatory stimulus

Resident tissue macrophages

1. Recognize inflammatory stimuli and initiate inflammatory response via binding of PRRs

2. Already present in tissue

   1. Do not need to be recruited from distant sites

Epithelial cells

May secrete cytokines when injured or recognize inflammatory stimuli via PRRs

Platelets

1. Active role in inflammation and coagulation

2. Aggregate and accumulate at sites of endothelial injury

3. Activated by collagen to release inflammatory mediators

   1. Vasoactive amines (serotonin, histamine)

   2. Complement activators

   3. Platelet activating factor

   4. Coagulation factors

Bradykinin

1. Released from damaged vascular endothelium

2. Causes vasodilation

Prostaglandins and leukotrienes

1. Produced by many cell types in response to PRR activation

2. Cause vasodilation and increased vascular permeability

Platelet-activating factor (PAF)

1. Produced by many cell types in response to PRR activation

2. Causes increased vascular permeability and smooth muscle contraction

Concurrently

Following initial changes to the microvasculature, the acute vascular and cellular responses occur ___.

Biphasic

The vascular permeability response is ___.

Histamine

The early phase of the vascular permeability response is dependent on ___.

Cytokines, IL-1, TNF-alpha

The later phase of the vascular permeability response is dependent on ___ such as ___ and ___.

Kinins

Which type of molecule is present in both phases of the vascular permeability response?

Increased capillary hydrostatic pressure

Net effect of histamine on capillary beds

Flow, stasis

Arteriolar dilation drives increased blood ___, while venule dilation causes blood ___.

Active hyperemia (redness), tissue swelling

Effects of acute vascular response

Active hyperemia (redness)

Causes of which effect of acute vascular response?:

1. Vasodilation

2. Blood stasis

Tissue swelling

Causes of which effect of acute vascular response?:

1. Leakage of plasma proteins

   1. Increased hydrostatic pressure

   2. Increased vascular permeability

2. +/- Leakage of macromolecules and leukocytes

   1. Endothelial gaps

   2. Endothelial injury

Neutrophils

Often predominant if the response is acute and/or bacterial

Neutrophils and macrophages

1. Lesions which are subacute to chronic

   1. Relative number of macrophages tends to increase with chronicity

Eosinophils

Parasitic disease and acute hypersensitivity reactions

Lymphocytes and plasma cells

Antigenic stimulation or delayed-type hypersensitivity

Mast cells, neutrophils

Which types of cells move into an inflammatory lesion acutely?

Eosinophils, macrophages

Which types of cells move into an inflammatory lesion in the transition from acute to chronic?

Lymphocytes, fibroblasts

Which types of cells move into an inflammatory lesion chronically?

Polymorphonuclear cells (PMNCs)

1. Contain distinctly lobulated/segmented nuclei

2. i.e. granulocytes

Neutrophils, eosinophils, basophils

Which cells are granulocytes?

Polymorphonuclear cells (PMNCs) / Granulocytes

Morphology of which type of cells?:

1. Lobed or segmented nuclei

2. Granules contain enzymes and mediators of inflammation

Terminally differentiated (do not divide; short half-life); found circulating in blood and in tissues

Characteristics of PMNCs/granulocytes

Neutrophils

Characteristics of which type of cell?:

1. Key effector cell in the acute inflammatory response

2. First cell to enter an area of injury from the bloodstream

   1. Move rapidly by amoeboid motion (crawl on substrate)

3. Segmented nucleus (2-5 nuclear segments)

4. Intensely phagocytic

5. Granules are lysosomes which contain powerful degradative enzymes

6. Unstable and short-lived in circulation

   1. More persistent in tissue

Heterophils of birds and reptiles

1. Elongate red granules

2. Not as antibacterial as mammalian neutrophils

   1. Lack myeloperoxidase

   2. Both morphologic and functional difference

Heterophils of rabbits, guinea pigs, and elephants

1. Bright red granules

2. No difference in function compared to neutrophils

3. Only difference is morphology on blood smear

4. “Heterophils” based on appearance, “neutrophils” based on function

   1. Terminology is pathologist or clinician-dependent

Adherence, migration, chemotaxis

Three steps of neutrophils moving from vasculature to tissue

Adherence

1st step of neutrophils moving from vasculature to tissue

Stasis and margination

Margination

Neutrophils move towards endothelial surface as blood stasis occurs

Selectins

Endothelium expresses ___ in response to histamine, thrombin, PAF, etc.

Rolling

Part of neutrophil adherence

1. Neutrophil ligands specifically interact with endothelial selectins

   1. Sialyl Lewis X-modified glycoproteins

   2. L-selectin (variable by species)

2. “Rolling”

   1. Continued binding and unbinding slows neutrophil to an eventual stop along endothelial surface

Pavementing

Part of neutrophil adherence

1. i.e. “stable adhesion”

   1. Irreversible process

   2. Flattening of neutrophil on endothelial surface

   3. Induced by IL-1 and TNF-alpha from adjacent tissue

   4. Mediated by:

      1. Beta-2-integrins (CD11/CD18) on neutrophils

      2. ICAM-1 and VCAM-1 on endothelial cells

Migration

2nd step of neutrophils moving from vasculature to tissue

1. Neutrophils exit the vessel by diapedesis

   1. PECAM-1 in endothelial cell junctions and on leukocytes binds to itself

   2. Leukocytes squeeze through endothelial cell junctions

      1. Occurs at post-capillary venules and capillaries