CHRONIC & ACUTE INFLAMMATION

Inflammation is a non specific, localized immune reaction of the organism, which tries to localize the pathogen agent. Many consider the syndrome a self-defense mechanism.

It is the reaction of tissues to injury, characterized ; • a) clinically by heat, swelling, redness, pain, and loss of function; • b)pathologically by vasoconstriction followed by vasodilatation, stasis, hyperemia, accumulation of leukocytes, exudation of fluid, and deposition of fibrin; • c) or the processes of repair, the production of new capillaries and fibroblasts, organization, and cicatrization. Etiology: Exogenous causes Physical agents –Mechanic agents: fractures, foreign bodies, sand, etc. –Thermal agents: burns, freezing Chemical agents: toxic gases, acids, bases Biological agents: bacteria, viruses, parasites Circulation disorders: thrombosis, infarction, hemorrhage Enzymes activation – e.g. acute pancreatitis Metabolic products deposals – uric acid, urea

Cardinal Signs Celsus described the local reaction of injury in terms that have come to be known as the cardinal signs of inflammation.

These signs are: – rubor (redness) – tumor (swelling) – calor (heat) – dolor (pain) – functio laesa, or loss of function (In the second century AD, the Greek physician Galen added this fifth cardinal sign) Duration of the process

Time course – Acute inflammation: Less than 48 hours – Chronic inflammation: Greater than 48 hours (weeks, months, years)

Cell type – Acute inflammation: Polymorphonuclear leukocyte (PMN) – Chronic inflammation: Mononuclear cells (Macrophages, Lymphocytes, Plasma cells)

Distribution of the lesion • focal means in a single spot or region • multifocal means similar lesions are scattered in many spots • diffuse indicates that the lesion is distributed evenly throughout most or all of the examined tissue

Location and presence of inflammation • Terms combine the organ name as a root with the suffix “itis” – tonsillitis, apendicitis, dermatitis, hepatitis, placentitis, nephritis (kidneys), mastitis (mammary glands), orchitis (testis), cholecystitis (gall bladder), etc. • a few tissues have atypical terms – pneumonia and pleurisy -itis Appendicitis Cellulitis Meningitis Pneumonitis Nephritis Myocarditis Acute inflammation: • Changes which take place usually within the first few minutes to several hours to days after an injury • Most commonly involves PMN’s as mediators

Key physiologic events: • Changes in vascular flow and caliber (hemodynamic changes) • Changes in vascular permeability (vascular leakage) • Leukocyte exudation Changes in vascular flow and caliber (hemodynamic changes) • Vasoconstriction transient and inconstant • Vasodilatation first the arterioles, and then the capillaries • Slowing of the circulation • Leukocyte margination Changes in vascular flow and caliber (hemodynamic changes) • Slowing of the circulation – outpouring of albumin rich fluid into the extravascular tissues results in the concentration of Red Blood Cells in small vessels and increased viscosity of blood. • Leukocyte margination – PMNs become oriented at the periphery of vessels and start to stick

Time scale: • Variable – minor damage--15-30 minutes – severe damage--a few minutes

SUMMARY OF EVENTS

• NORMAL HISTOLOGY : • VASODILATATION → • INCREASED VASCULAR PERMEABILITY → • LEAKAGE OF EXUDATE → • MARGINATION, ROLLING, ADHESION → • TRANSMIGRATION (DIAPEDESIS) → • CHEMOTAXIS → • PMN ACTIVATION → • PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion) → • TERMINATION → • 100% RESOLUTION, SCAR, or CHRONIC INFLAMMATION are the three possible outcomes Lymphatics in inflammation:

• Lymphatics are responsible for draining edema, Filtration (arterial end) and Reabsorption (venous end) of the capillary

EDEMA

1. Definition: accumulation of fluid in a tissue

2. Three causes: – Increased capillary filtration: hypertension etc. – Reduced capillary reabsorption: due to albumin– hypoproteinemia – Obstructed lymphatic drainage 3. Edema’s consequences: – Oxygen delivery/waste removal are impaired – Tissue death (necrosis)

Changes in vascular permeability (vascular leakage) • Starling's hypothesis • In normal tissue from arteriole to venule:

Intravascular hydrostatic pressure≅Colloid osmotic pressure

Changes in vascular permeability (vascular leakage) • In inflammation from arteriole to venule:

Intravascular hydrostatic pressure+Colloid osmotic pressure=

Edema

Related definitions:

• Edema -An excess of fluid in the interstitial tissue or serous cavities (either a transudate or an exudate) • Transudate -An ultrafiltrate of blood plasma – permeability of endothelium is usually normal. – low protein content ( mostly albumin) – specific gravity less than 1.012

• Exudate -A filtrate of blood plasma mixed with inflammatory and cellular debris. – permeability of endothelium is usually altered – high protein content – specific gravity greater than 1.020 • Pus -A purulent exudate -an inflammatory exudate rich in leukocytes (mostly neutrophils) and parenchymal cell debris.

Leukocyte extravasation

• divided into 4 steps – 1. Margination, rolling, and adhesion – 2. Diapedesis (transmigration across the endothelium) – 3. Migration toward a chemotactic stimulus – 4. Phagocytosis

Phagocytosis • 3 distinct steps –Recognition and attachment –Engulfment –Killing or degradation

Killing or degradation

• 2 mechanisms– Oxygen dependent • Myeloperoxidase dependent (the most important!) • Myeloperoxidase independent– Oxygen independent

Acute inflammation has one of four outcomes: • Abscess formation • Progression to chronic inflammation • Resolution--tissue goes back to normal • Repair--healing by scarring or fibrosis

Abscess formation: • Stedman's dictionary: "A circumscribed collection of pus appearing in an acute or chronic localized infection, and associated with tissue destruction, and frequently, swelling."-- It is usually the result of a pyogenic organism.

Abscess • It’s a localized infection with collection of bus in a cavity • Many microrganisms may be pyogenic in action and may cause abscess • Most of abscess begin as cellulites that become localized as an abscess form, the capillaries closed so the infection will kept localized • The wall of abscess cavity consist of granulation T. that contain PMNc, leukocyte, lymphocyte, fibroblast and endothelial cells which activate the local immunity of the T.

Outcomes of Acute Inflammation • Resolution of tissue structure and function with elimination of stimulus • Tissue destruction and persistent inflammation – Abscess • pus-filled cavity (neutrophils, monocytes and liquefied cellular debris) • walled off by fibrous tissue and inaccessible to circulation • tissue destruction caused by lysosomal and other degradative enzymes – Ulcer • loss of epithelial surface • acute inflammation in epithelial surfaces – Fistula • abnormal communication between organs or an organ and a surface – Scar • Causes distortion of structure and sometimes altered function • Chronic inflammation – Marked by replacement of neutrophils and monocytes with lymphocytes, plasma cells and macrophages – Accompanied by proliferation of fibroblasts and new vessels with scarring Chronic inflammation

• Chronic inflammation is prolonged (weeks or months) • Inflammation, tissue injury, and attempts at repair coexist, in varying combinations • May follow acute inflammation • May begin insidiously without any manifestations of an acute reaction (Tb, viruses, silica, asbestos, rheumatoid arthritis)

Causes of chronic inflammation

• Persistent infections – Organisms usually of low toxicity that invoke delayed hypersensitivity reaction – M. tuberculosis and T. pallidum causes granulomatous reaction

• Prolonged exposure to potentially toxic agents – Exogenous agents include silica which causes silicosis – Endogenous causes include atherosclerosis caused by toxic plasma lipid components

• Autoimmunity – Auto-antigens provoke self-perpetuating immune responses that cause chronic inflammatory diseases like RA, MS – Responses against common environmental substances cause chronic allergic diseases, such as bronchial asthma

Histologic features

• Infiltration with mononuclear cells (eg. macrophages, lymphocytes and plasma cells) due to persistent reaction to injury • Tissue destruction induced by persistent agent or inflammatory cells • Attempts at healing by connective tissue replacement of damaged tissue with angiogenesis and fibrosis Macrophages in chronic inflammation

• Mononuclear phagocytes arise from a common precursor in the bone marrow • From the blood, monocytes migrate into various tissues and differentiate into macrophages – The half-life of blood monocytes is about 1 day – The life span of tissue macrophages is several months or years • Monocytes begin to emigrate into extravascular tissues quite early in acute inflammation • In chronic inflammation, macrophage accumulation persists as a result of continuous recruitment from the circulation and local proliferation at the site of inflammation

Outcome of chronic inflammation: • Resolution/regeneration/restitution of normal structure • Repair/organization/healing by connective tissue/fibrosis/scarring • It can continue indefinitely--some disease processes are capable of continuing indefinitely such as rheumatoid arthritis..

Resolution

• Definition: Resolution is the return of tissue to its normal state. Factors necessary for resolution: • Removal of the offending agent • Regenerative ability if cells have been destroyed • Intact stromal framework

Wound healing: • Essentially the same as repair. – Healing by first intention (aka primary union) – Healing by second intention (aka secondary union) In second intention healing • There is a big hole that needs to be filled in • The hole is filled in with abundant granulation tissue • With time the wound contracts more than a wound which healed by first intention. This occurs with the passage of time and is secondary to myofibroblasts.

Time scale for repair/wound healing: – First hours: fibrin clot forms with overlying scab – 24 hours PMNs appear at margin of incision. – 24-48 hours: Basal cells at edges proliferate and start to migrate along the cut margins of the dermis – Day 3 Macrophages replace PMNs and granulation tissue invades incision space. Epithelial cell proliferation continues. Time scale for repair/wound healing: – Day 5: Incisional space is filled with granulation tissue. Neovascularization is maximal. Collagen fibrils bridge the gap. Epidermis recovers its normal thickness. – 2 weeks: Continued proliferation of fibroblasts and accumulation of collagen. Edema, new vessels, and inflammatory infiltrates are absent – 1 month: Scar covered by intact normal epithelium. Tensile strength increases with additional time.

Wound strength over time: • At the end of one week wound strength is approximately 10% of the strength of unwounded skin • It increases rapidly over the next 4 weeks. • It peaks at about the 3rd month and achieves about 70-80% of the tensile strength of unwounded skin. Additional definitions: • Ulcer -A local defect, or excavation of the surface of an organ or tissue, which is produced by the sloughing (shedding) of inflammatory necrotic tissue. Ulceration is defined by the presence of necrotic tissue on or near a surface.

Factors That Affect Wound Healing

• Malnutrition – Protein deficiencies prolong the inflammatory phase of healing and impair fibroblast proliferation, collagen and protein matrix synthesis, angiogenesis, and wound remodeling. – Carbohydrates are needed as an energy source for white blood cells. – Fats are essential constituents of cell membranes and are needed for the synthesis of new cells. – Vitamins A and C have been shown to play an essential role in the healing process. • Vitamin C is needed for collagen synthesis. • Vitamin A functions in stimulating and supporting epithelialization, capillary formation, and collagen synthesis. The B vitamins are important cofactors in enzymatic reactions that contribute to the wound-healing process. • Vitamin K plays an indirect role in wound healing by preventing bleeding disorders. • Blood Flow and Oxygen Delivery – Pre-existing health problems – Arterial disease and venous pathology – Molecular oxygen is required for collagen synthesis. • It has been shown that even a temporary lack of oxygen can result in the formation of less stable collagen. – Wounds in ischemic tissue become infected more frequently. – PMNs and macrophages require oxygen for destruction of microorganisms.

Repair • Similar to wound healing • Definition: Damage to both parenchymal cells and stromal framework which results in the replacement of nonregenerated parenchymal cells by connective tissue which over time produces fibrosis and scarring. Granulation tissue • The early specialized vascular and fibrous tissue formed is termed granulation tissue. Grossly it looks pink and granular. Histologically one sees vessels and fibroblasts.

Components necessary for repair • Angiogenesis or neovascularization of new blood vessels • Migration and proliferation of fibroblasts • Deposition of extracellular matrix (ECM) • Remodeling or maturation and organization of the fibrous tissue

Angiogenesis • BM degradation of parent vessel • Migration of endothelial cells toward an angiogenic stimulus • Proliferation of endothelial cells behind the leading front of migrating cells. • Maturation of endothelial cells and organization into capillary tubes Angiogenesis - Formation of new blood vessels