Exam 1 unit 2 Patho

What is the body’s defensive response to foreign invaders and tissue damage?

Inflammation

Can inflammation cause tissue damage

Yes, inflammation can lead to tissue damage.

Acute inflammation

Minutes, hours, days

Chronic inflammation

Days to years

What are the cardinal signs of acute inflammation? (English)

The cardinal signs of acute inflammation are redness, heat, swelling, pain, and loss of function.

The cardinal signs of acute inflammation (latin??)

Rubor, Tumour, Calor, Dolor, Functio laesa

Causes of inflammation

Infection, trauma, physical, chemical agents,

necrosis, foreign bodies, and immune

reactions.

What are the immediate and early responses to tissue injury?

Vasodilation, Vascular leakage and edema, Leukocyte emigration

What happens during vasodilation

Opens microvascular beds

• Accounts for warmth and redness

What does increased intravascular pressure cause

early transudate (protein-poor filtrate of plasma) into the interstitium (vascular permeability still not increased yet).

How does vasodilation occur?

through the release of mediators from cells. These

mediators include histamine, prostacyclin (PGI2), and nitric oxide (NO).

Vasodilation increases the hydrostatic pressure by causing…

slowing (sludging) of blood flow. Sludging of blood also causes margination of leukocytes along the wall of the blood vessels.

What is going on when vascular permeability commences

Transudate gives way to exudate (protein-rich)

• Increases interstitial osmotic pressure contributing to edema (water and ions).

1/5 mechs known to cause vascular leakiness

Histamines, bradykinins, leukotrienes (C4, D4, and E4) cause an early, brief (15-30 min.) immediate transient response in the form of endothelial cell contraction that widens intercellular gaps of venules (not arterioles, capillaries)

2/5 mechanisms known to cause vascular leakiness

Cytokine mediators (TNF, IL-1) induce endothelial cell junction retraction through cytoskeleton reorganization (4-6 hrs. post injury, lasting 24 hrs. or more).

3/5 mechanisms known to cause vascular leakiness

Severe injuries may cause immediate direct endothelial cell damage (necrosis, detachment) making them leaky until they are repaired (immediate sustained response) or may cause delayed damage as in thermal or UV injury, or some bacterial toxins (delayed prolonged leakage)

4/5 mechanisms known to cause vascular leakiness

Marginating and endothelial cell-adherent leukocytes may pile-up and damage the endothelium through activation and release of toxic oxygen radicals and proteolytic enzymes (leukocyte-dependent endothelial cell injury) making the vessel leaky

5/5 mechanisms known to cause vascular leakiness

Certain mediators (vascular endothelial growth factor, VEGF) may cause increased transcytosis via intracellular vesicles which travel from the luminal to basement surface of the endothelial cell.

What is the sequence of events that the leukocyte goes through to leave the vasculature

Margination/rolling, Adhesion/transmigration, chemotaxis/activation

After leaving the vasculature what are leukocytes free to do?

Phagocytosis and degranulation, Leukocyte-induced tissue injury

What happens to vascular permeability during inflammation?

Increased vascular permeability allows fluid (exudate) to leave the blood vessel and enter the surrounding tissue.

What is leukocyte margination?

Margination is the movement of leukocytes from the central flow column of blood toward the endothelial surface of the blood vessel.

Put the events in the correct order during leukocyte recruitment.

1. Increased vascular permeability.

2. Fluid (exudate) leaves the vessel.

3. Leukocytes marginate toward the endothelial surface.

4. Leukocytes briefly adhere and release from endothelial cells (rolling).

5. Adhesion increases, causing leukocytes to stop.

What allows leukocytes to roll along the endothelium?

Complementary adhesion molecules on endothelial cells and leukocytes form weak, transient interactions. These bonds repeatedly form and break, allowing leukocytes to roll along the endothelial surface.

What is the difference between leukocyte margination and rolling?

• Margination: Leukocytes move from the central blood flow column toward the vessel wall.

• Rolling: Leukocytes form temporary adhesion interactions with endothelial cells, causing them to slow down and roll along the endothelial surface.

What causes a rolling leukocyte to eventually stop?

Mutual adhesion between the leukocyte and endothelial surface increases and reaches a peak, resulting in firm adhesion and cessation of rolling.

Early rolling adhesion is mediated by the selectin family

E-selectin (endothelium), P-selectin (platelets and endothelium), and L-selectin (leukocytes) bind other surface molecules (i.e., CD34, Sialyl-Lewis X-modified GP) that are upregulated on endothelium by cytokines (TNF, IL-1) at injury sites.

What other molecules participate in adhesion

Endothelial: ICAM-1, VCAM-1

– Leukocyte: LFA-1, Mac-1, VLA-4

– (ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4)

Usually, down-regulated or in an inactive

conformation, but inflammation alters this

• Intercellular Adhesion Molecule (ICAM-1)

• Vascular cell adhesion molecule (VCAM-1)

• Lymphocyte function associated antigen (LFA-1)

• Very late activation antigen-4 (VLA-4)

Transmigration (diapedesis)

Occurs after firm adhesion within the systemic venules and

pulmonary capillaries via PECAM-1 (CD31), expressed on

both leukocytes and endothelium. It involves the migration of leukocytes across the endothelium to reach sites of tissue injury or inflammation.

Is the vessel wall injured during leukocyte transmigration

typically no.

Know this john

Chemotaxis

is the process by which leukocytes are directed to move towards the site of infection or injury in response to chemical signals.

What substances act as chemo attractants

• Soluble bacterial products (peptides with N-formylmethionine termini)

• Complement components (particularly C5a)

• Cytokines (chemokine family e.g., IL-8)

• Products of the lipoxygenase pathway of arachidonic acid metabolism, particularly leukotriene B4 (LTB4

What are the first two steps leukocytes perform once they reach a site of injury?

1. Recognize the target (such as a microbe).

2. Attach to the target through receptors on the leukocyte.

This recognition and attachment prepare the pathogen for engulfment

What is opsonization, and why does it help phagocytosis?

Answer: Opsonization is the coating of a microbe with specific proteins called opsonins. These proteins make it easier for leukocytes to recognize and attach to the microbe.

Examples of opsonins:

• Fc portion of IgG (antibody-mediated opsonization).

• C3b (complement protein

What is engulfment during phagocytosis?

Engulfment is the process in which a leukocyte extends pseudopods around a bound particle and encloses it within a membrane-bound vesicle called a phagosome.

Describe how a phagosome forms from the initial attachment of a microbe.

• The microbe binds to receptors on the leukocyte.

• The leukocyte extends pseudopods around the bound particle.

• The pseudopods enclose the particle.

• The membrane closes, forming a vesicle called the phagosome.

What is the difference between a phagosome and a phagolysosome?

• Phagosome: Membrane-bound vesicle containing the engulfed particle.

• Phagolysosome: Compartment formed when a phagosome fuses with lysosomes, bringing digestive enzymes and other antimicrobial contents into contact with the ingested material.

What happens when a phagosome fuses with lysosomes?

Fusion produces a phagolysosome, where lysosomal contents, including digestive enzymes and antimicrobial substances, are delivered to the compartment to break down the ingested material.

What are the two major mechanisms leukocytes use to kill or degrade ingested material?

• Oxidative burst: Production of reactive oxygen species (ROS) that contribute to microbial destruction.

• Leukocyte granule contents: Release of antimicrobial enzymes and other substances that help degrade ingested material

What is an oxidative burst, and what is its purpose during phagocytosis?

An oxidative burst is a rapid increase in the production of reactive oxygen species (ROS) by an activated phagocyte. ROS contribute to killing and degrading engulfed microbes.

Important: Oxidative burst is an antimicrobial mechanism, not the process of engulfment itself

ROS formed through oxidative burst that includes":

Increased oxygen consumption

– Glycogenolysis

– Increased glucose oxidation

– Formation of superoxide ion:

» 2O2 + NADPH → 2O2- + NADP+ + H+ (NADPH oxidase)

» O-2 + 2H+ → H2O2 (superoxide dismutase, SOD

What is MPO

Myeloperoxidase, an enzyme in azurophilic granules of neutrophils that produces hypochlorous acid from hydrogen peroxide and chloride ions during the oxidative burst which is a powerful antimicrobial agent.

how can PMN’s kill microbes?

Polymorphonuclear leukocytes (PMNs) kill microbes through halogenation or lipid/protein peroxidation

when is iNOS expressed?

when macrophages are activated by cytokines (e.g., IFN-γ) or microbial products, and induces the production of NO

In macrophages, what does NO react with to generate highly reactive free radical peroxynitrite (ONOO.)

Superoxide anion (O₂•−)

What do peroxynitrites attack/damage?

lipids, proteins and nucleic acids of microbes and host cells.

What other antimicrobials are in leukocyte granules?

– Bactericidal permeability increasing protein (BPI)

– Lysozyme

– Lactorferrin

– Defensins (punch holes in membranes)

What does a loss in NADPH oxidase result in?

Chronic granulomatous disease.

What is the inheritance of chronic granulomatous disease?

the mutation for the autosomal recessive form of chronic granulomatous disease results in a defective cytoplasmic component, and the mutation for the X-linked form results in a defective membrane component

What is the affect of the mutation on the x chromosome in chronic granulomatous disease?

Inability to form H2O2 - Bacterial organisms produce H2O2—MPO may use some of the H2O2. However, many microorganisms produce catalase, which degrades the H2O2 they produce NO HOCl2!!!

What does the CYBB gene provide instructions for?

Protein called cytochrome b-245 beta chain which is a subunit of a group of proteins that form the enzyme complex called NADPH oxidase that is crucial for the immune response, helping to generate reactive oxygen species to kill bacteria.

Chédiak-Higashi Syndrome

A rare genetic disorder characterized by immunodeficiency, decrease in phagocytosis because of reduced transfer of lysosomal enzymes in phagocytic vesicles partial oculocutaneous albinism, and neurological problems, platelet disorder, nerve defects, resulting from a mutation affecting lysosomal trafficking.

Types of inflammation

Serous, Fibrinous, Purulent

Serous inflammation

Relatively clear, watery fluid (few cells, transudate); seen in viral infections and burns.

Fibrinous inflammation

Finely particulate, thick fluid (much more protein and cells than serious inflammation (exudate); seen in uremic and post-myocardial infarct pericarditis.

Purulent inflammation

Appears with pus (thick, white-yellow fluid)—fluid contains neutrophils, protein and necrotic cells (an exudate); seen in bacterial and fungal infections.

Purulent fluid

is composed predominantly of neutrophils admixed with plasma proteins and cellular debris.

Outcomes of acute inflammation

resolution, abscess formation, ulcers, fistula formation, chronic inflammation and scar formation.

definition of resolution

The inciting agent is removed, and all damage done by inciting agent and inflammatory cells is repaired.

Abscess definition

Walled off collection of pus (neutrophils and necrotic debris).

definition of ulcer

Loss of mucosa and deeper tissues. If only the mucosa is lost, the term used is erosion.

definition of fistula

Abnormal connection between two organs; most commonly organs with a lumen.

Replacement of lost parenchyma with disorganized connective tissue (e.g., collagen).

Scar formation

is the continued and excessive deposition of ECM (collagen)— pathologic consequence of persistent injury and causes loss of function.

Fibrosis

Prolonged inflammation consisting of active inflammation and tissue destruction and repair, all occurring simultaneously. Chronic inflammation can follow acute inflammation, but can also occur as a low-grade asymptomatic, prolonged response to an inciting agent

Chronic Inflammation

What causes chronic inflammation

Viral, persistent microbial infection, prolonged exposure to toxins, and autoimmune dysfunction.

What cells are involved in chronic inflammation

Macrophage and lymphocyte infiltration.

Activated macrophages produce what?

1. Proteases, IL-1, TNF, arachidonic acid metabolites, NO (IL-1 and TNF activate lymphocytes).

2. Angiogenesis and growth factors,(e.g., platelet-derived growth factors [PDGF] or fibroblast growth factor [FGF]

Activated lymphocytes produce…?

1. FGF stimulates fibroblasts to

produce collagen, which results

in scarring.

2. PDGF and transforming growth

factor-β (TGF-β).

3. Interferon-γ (activates

macrophages).

All things macrophages

Circulate as monocytes and reach site of injury within 24-48 hrs. and transform. They become activated by T cell- derived cytokines, endotoxins, and other products of inflammation.

Lymphocytes (T and B cells)

Antigen-activated (via macrophages and dendritic cells)

Release macrophage-activating cytokines (in turn, macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed).

Plasma Cells

– Terminally differentiated B cells

– Produce antibodies

Eosinophils

– Found especially at sites of parasitic infection, or at allergic sites (IgE- mediated)

Granulomatous inflammation

Collection of activated macrophages (i.e., epithelioid histiocytes); can have multinucleated giant cells. Causes: mycobacteria, fungi, foreign material, sarcoidosis, and silica

Repair

The process of repair begins early. It involves regeneration of the parenchyma or replacement of damaged tissue with a scar if regeneration is not possible. The process of complete regeneration (resolution of acute inflammation) requires an organ that is composed of cells that can divide and an intact basement membrane and connective tissue scaffolding

Regeneration

is complete replacement of damaged cells, with no scar formation:

Can occur in renewal tissues (e.g., GI tract and skin)

Can occur in stable tissues (e.g., liver & kidney)

Heaing

is regeneration of cells combined with scarring and fibrosis

Important Mediators in repair

EGF, VEGF, TGF-β, PDGF, FGF

EGF

Epidermal Growth Factor, a protein that stimulates cell growth, proliferation, and differentiation by binding to its receptor EGF receptor.

VEGF

Stands for Vascular Endothelial Growth Factor, a key protein that promotes the growth of blood vessels and is crucial in the healing process. (angiogenesis)

PDGF

Promotes migration and proliferation of fibroblasts, smooth muscle cells, and monocytes.

FGF

Stimulates blood vessel formation and wound repair through macrophages, fibroblasts, and endothelial cell migration.

TGF-β

Acts as growth inhibitor of epithelial cells.

Cutaneous Wound healing steps

1. Formation of new blood vessels.

2. Migration and proliferation of fibroblasts.

3. Deposition of extracellular matrix.

4. Maturation and reorganization of fibrous

tissue. Tissue remodeling is the balance

between extracellular matrix synthesis and

degradation. Extracellular matrix is

degraded by matrix metalloproteinases,

MMPs (e.g., collagenases, gelatinases

Keloid scars

Abnormal growth of scar tissue that extends beyond the original wound site, often resulting from excessive collagen production during healing.