Inflammation and Repair

Inflammation

Response of vascularized tissue to infections and tissue damage that brings cells and molecules of host defense from the circulation to sites where they are needed to eliminate the offending agents

Beneficial host response with possible tissue damage

Without this wounds will not heal and infections not checked

Signs of Inflammation

Pain

Swelling

Heat

Redness

Loss of function

Inflammatory Reaction Steps

Recognition

Recruitment

Removal

Regulation

Repair

Recognition

Of microbes and necrotic cells by the host cellular receptors and circulating proteins

Recruitment

Of leukocytes and plasma proteins from circulating to affected site

Removal

Of the offending agent by leukocytes and proteins

Sentinel Cells - macrophages, dendritic cells & mast cells

Sentinel Cells

Macrophages, dendritic cells & mast cells

Regulation

Of reaction is controlled

Repair

Of damaged tissue

Sequence of Events in Inflammation

Macrophages and other cells in tissue recognize microbes and damaged cells

Sentinel cells in tissues liberate moderators

This triggers the vascular and cellular reactions of inflammation

Influx of plasma proteins accompanies edema

Aphthous Major

Multiple, deep ulcers heal with scarring

Edema

Excess of fluid in surrounding tissues

Caused by vasodilation and increased vascular permeability increasing swelling

Causes of Inflammation

Infections and microbial toxins

Tissue necrosis regardless of the cause of cell death

Foreign bodies alone or due to the trauma elicit a response

Immune reactions (hypersensitivity) - usually protective but ends up damaging the tissue

Cellular Receptors for Microbes

Epithelial Cells

Macrophages

Leukocytes

Dendritic cells

Express this

Toll-Like Receptors (TLRs)

Microbial sensors

Recognize products of bacteria (endotoxins and bacterial DNA)

Stimulate production of cytokines, membrane proteins

Sensors of Cell Damage

Inflammasome

Circulating Protiens

Inflammasome

Multi-protein cytoplasmic complex

• products of dead cells

• Uric acid and extracellular ATP

• Crystals and some microbial products

• Induce production of interleukin-1 (IL-1)

Circulating Proteins

Plasma proteins recognize microbes in blood

Acute Reaction

COVID-19 and cytokine storm

Results in hyper-activation of the immune system and the uncontrolled release of cytokines

Chronic Reaction

Asthma is caused by eosinophils and IgE antibodies

Slow, systemic, and persistent immune response where the body sends white blood cells to attack healthy tissue, lasting months or years

Candidiasis

Common infectious complications from impaired inflammatory response

Oral fungal infection

Under-Active Inflammation

Results in increased susceptibility to infections

Seen with leukemia, drugs that suppress the immune system, such as corticosteroids and some genetic disorders

Main Components of Inflammation

Vascular reaction and cellular response

Both are activated by mediators

Acute Inflammation Components

Vasodilation

Vascular permeability

Emigration of leukocytes

Vasodilation

Increased blood flow

Relaxation and dilatation of small vessels

Engorgement of capillary beds resulting in redness and warmth

Caused by histamine

Vascular Permeability

Increase

Transudate: mostly fluid

Exudate: fluid and proteins (fibrinogen, immunoglobulin, complement, and cellular debris

Transduate

Low protein content

Little to no cellular material

Low specific gravity

Exuduate

Fluid and proteins (fibrinogen, immunoglobulin, complement, and cellular debris)

Extravascular fluid

Fibrinous - high protein with few cells

Purulent - high protein with many cells

Sanguineous - high protein with blood

Fibrinous Exudate

High protein with few cells

Purulent Exudate

High protein with many cells

Sanguineous Exudate

High protein with blood

Emigration of Leukocytes

From circulation to site of infection or damage

Neutrophil predominant

Induction of Inflammation

Cytokines and inflammatory mediators produced at the site of infection or necrosis

Purulence

Inflammatory exudate with neutrophils and dead cell debris with microbes

Hydrostatic Pressure

Pushing

Osmotic Pressure

Pulling

Mechanisms of Vascular Permeability

Short and rapid Endothelial contraction

Rapid and elicited by histamine, bradykinin, leukotrienes, and other chemical mediators

Sometimes, due to direct injury to endothelial cells - cells die and leave space

Stasis

Vessels with engorged RBCs due to loss of fluid

Increase vessel diameter

Increase in RBCs and increased viscosity of blood

Contraction of Endothelial Cells

Induced by histamine and other mediators

Rapid and short-lived

Increased vascular permebility

Endothelial Injury

Caused by burns and some microbial toxins

Rapid but may be long-lived

Increased vascular permeability

Angiodema

Allergic reaction, stress, temperature, pressure, vibratory reaction, or genetic condition

Complication: airway obstruction

Increased histamine release - fluid accumulation

Lymphatic Vessels

Results in redness and swelling known as lymphangitis

Lymph nodes - swollen and painful is reactive lymphadenitis

Pain Mediators

Bradykinin, PGE₂

Vasodilation Mediators

Histamine, PGD₂

Fever Mediators

IL-1

TNF

PGE₂

Tumor Necrosis Factor (TNF)

Potent, pro-inflammatory cytokine produced by macrophages & lymphocytes

Leukocyte Events

Margination

Rolling

Adhesion

Emigration or transmigration

Chemotaxis

Margination

Physical forces (stasis)

Movement of RBCs (and neutrophils) towards the endothelial wall to begin adhesion

Rolling

Selectins

Weak transient sticking

Adhesion

Family of proteins called integrins

ICAM - intercellular adhesion molecules

VCAM - vascular cell adhesion molecule

Emigration or Transmigration

PECAM-1 - platelet endothelial adhesion molecule

Chemotaxis

Movement to the site of injury

Along a chemical gradient

Chronic Inflammation Cells

Macrophages and lymphocytes

Chronic Vascular Response

Variable persistence of dilation and leakiness

Endothelial cell activated - ready ot proliferate if needed

Chronic Inflammation Repair

Macrophages - growth factors

Fibroblasts - fibrosis/scar

Endothelial cells - neovascularization

Neutrophil

Presence defines acute inflammation

First cell to emigrate

Response to necrosis and infections

Release ROS - pain

Apoptosis

Monocytes

Emigrate within 48 hours and live for months in tissue as macrophages

Macrophages

Phagocytosis

Antigen presentation

Cytokine, enzyme, and plasma protein secretion

MPO - ROS, NO, Prostaglandins

Healing and repair

Lymphocytes

Immune functions

Eosinophils

Allergic reactions to parasites

Mast Cells

Secrete histamine

Plasma Cells

Immune functions

Mediators

Substances that initiate and regulate inflammatory reactions

Prostoglandins

Secreted by mast cells and leukocytes

Vasodilation, pain, and fever

Serous Inflammation

Protein rich exudate in body cavities and spaces created by tissue necrosis

Skin blister

Increased pressure due to the buildup of fluid that causes pressure on nerve endings

Watery fluid

Fibrinous Inflammation

Diphtheria - pharyngeal region

Formation of fibrin, usually on the surfaces of organs such as the heart and lungs

Purulent Inflammation

Formation of pus, which consists of dead cells, neutrophils, and microbes

Caused by bacterial infection

Abscess is localized version of this

Ulcer

Discontinuity in an epithelium with underlying acute and chronic inflammation

Scarring

Type of repair after substantial tissue destruction or when inflammation occurs in tissues that do not regenerate

Fibroblasts

Chronic Inflammation Morphology

Infiltration with mononuclear cells (macrophages, lymphocytes, plasma cells)

Tissue destruction by persistent offending agent of inflammatory cells

Attempts at healing - CT replacement by angiogenesis and fibrosis

Classic Activation of Macorphages

Microbial actions

Phagocytosis and killing of bacteira and fungi

ROS, NO, and lysosomal enzymes

Alternative Activatation of Macrophages

Anti-inflammatory effects, wound repair, and fibrosis

IL-10 and TGF-B recruiting fibroblasts

Role of Lymphocytes

Mediators of adaptive immunity

T and B cells are activated by microbes and environmental antigens

Role in granulomatous inflammation, autoimmune and hypersensitivty diseases

CD4 T cell - secrete cytokines

Bidirectional with macrophages