Pathology CJRebojo

Inflammation
Transcribed from Dr. Chichioco’s Lecture
TRANSUDATE EXUDATE PUS
- Reaction of vascularized living tissue to local injury
❖ Characterized • An ULTRAfiltrate of • A filtrate of blood • A purulent exudate
• Clinically by: blood plasma plasma mixed with rich in:
✓ Heat, Swelling, Redness, Pain, and Loss of Function permeability of inflammatory and • Leukocytes
• Pathologically by: endothelium is cellular debris (mostly
✓ Vasoconstriction followed by Vasodilation usually NORMAL • Permeability of Neutrophils)
✓ Stasis endothelium is • Prenchymal Cells
✓ Hyperemia usally altered
✓ Accumulation of Luekocytes
↓ Protein Content ↑ Protein Content
✓ Exudation of Fluids
✓ Deposition of Fibrin
• Followed by: 3. Leukocyte Exudation
- The process of repair, the reproduction of new capillaries and
fibrolblasts, organization, and cicatrization
❖ Etiology
‣ Microbial Infections → Pneumonia, Skin Infections, Etc.
‣ Physical Agents → Burns, Trauma--like cuts, Radiation
‣ Chemicals → Toxins and Caustic Substances (like battery acid)
‣ Others → Immunologic Reactions (rheumatoid arthritis)
❖ 4 Cardinal Clinical Signs of Inflammation (by Celsus 1 A.D.)
• Rubor = Redness
• Tumor = Swelling
• Calor = Heat
• Dolor = Pain
• Virchow added a 5th = Loss of Function

INFLAMMATION

ACUTE CHRONIC
❖ Divided into 4 steps:
Time Course < 48 hours > 48 hours a. Margination, Rolling, and Adhesion
b. Diapedesis (tranmargination across the endothelium)
Cell Type Polymorphonuclear Mononuclear Cells c. Migration towards a Chemotactic Stimulus
Leukocytes (PMN) (Macrophages, d. Phagocytosis
Lymphocytes, Plasma - Recognition and Attachment
Cells) - Engulfment
- Killing or Degradation
• Oxygen Dependent
ACUTE INFLAMMATION ✓ Myeloperoxidase Dependent (most important!)
✓ Myeloperoxidase Indepdendent
- Changes which take place usually within the first few minutes to • Oxygen Independent
several hours to days after an injury ❖ Defects in Leukocyte Function
- Most commonly involves PMN’s as mediators • Margination and Adhesion
❖ 3 Key physiologic events: ‣ Etoh, steroids, AR leukocyte adhesion deficiency
1. Changes in Vascular Flow and Caliber (hemodynamic • Emigration toward a chemotactic stimulus
changes) ‣ Drugs
• Vasoconstriction → transient and inconstant ‣ Chemotaxis Inhibitors
• Vasodilation → first arterioles then capillaries • Phagocytosis
• Slowing of the Circulation → outpouring of albumin rich fluid ‣ Chronic Granulomatous Disease (CGD)
into the extravascular tissues results in the concentration of
RBCs in small vessels and ↑ blood viscosity Chemical Mediators of Inflammation
• Leukocyte margination →PMNs become oriented @ the ‣ Vasoactive Amines (Histamine and Serotonin)
periphery of vessels and start to stick • Plasma Proteases:
✓ Time Scale: Minor Damage (15-30 minutes); Major Damage ✓ Kinin System
(a few minutes) ✓ Complement System
2. Changes in Vascular Permeability (vascular leakage) ✓ Coagulation-Fibrinolytic
• In normal tissue from arteriole to venule ‣ Arachidonic Acid Metabolites
• Elicited by Histamine, Leukotrines and other chemical • via Cyclooxyenase → by Prostaglandin
mediators • via Lipooxygenase → by Leukotrines
• ↑ Intravascular Hydrostatic Pressure + ↓ Colloid Osmotic ‣ Platelet Activating Factor (PAF)
Pressure = edema (either a transudate or exudate) ‣ Cytokines (IL-1, TNF, IL-8, IL-12)
‣ Nitric Oxide (vasodilator, cytotoxin)
‣ Lysosomal Constituents of Leukocytes
‣ Oxygen derived free radicals
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 Pathology CJRebojo

Another View of Chemical Mediators

• Vasodilation (vascular flow w/ caliber; hemodynamic changes)
✓ Prostaglanding, Nitrix Oxide
• Increased Vascular Permeability (vascular leakage)
✓ Vasoactive Amines (Histamine, Serotonin)
✓ C3a and C5a (through liberating amines)
✓ Bradykinin (most painful)
✓ Leuktorienes C4, D4, E4
• Chemotaxis, Leukocyte Activation (leukocyte exudation)
✓ C5a
✓ Leukotrine B4
✓ Bacterial Products
✓ Cytokines (IL-8)
• Tissue Damage (a leukocyte exudation)
✓ Neutrophil and Macrophage Lysosomal enzymes
✓ Oxygen Metabolites
✓ Nitric Oxide
• Fever
✓ IL-1, IL-6, TNF MACROPHAGE (MO)
✓ Prostaglandins ❖ Functions
• Pain • Produce toxic, biologically active substances such as oxygen
✓ Prostaglandins metabolites
✓ Bradykinin • Cause influx of other cells such as other macrophages and
★ 2 Additional Points: lymphocytes
• These systems are all interrelated • Cause fibroblast proliferation and collagen deposition
• There seems to be a very good system of checks and balances • Phagocytosis
❖ Time Scale predominate cell at 48 hours after acute inflammation
❖ 3 Ways in which MOs accumulate:
CHRONIC INFLAMMATION
• Continued recruitment from the circulation --- secondary factors
• Division
- Can be due to: • Prolonged Survival
a. ↓ Vascular Supply = ↓ response and repair
b. Persistance of injurious elements Other Cells in Chronic Inflammation
c. Presence of microorganism/infection ‣ Lymphocytes
d. Malnutrition ‣ Plasma Cells
- Time Course: >48 hours (weeks, months, years) ‣ Eosinophils
- Cell Type: Mononuclear Cells (Primarily Macrophages, ‣ PMNs
Lymphocytes, Plasma Cells)
❖ Arises in various organs in 1 of 3 ways:
CHRONIC GRANULOMATOUS INFLAMMATION (GI)
• Following Inflammation
• After repeated bouts of acute inflammation (Pneumonia)
• Without prior acute inflammation (Tb, viruses, silica, asbestos, - A type of pattern of chronic inflammation defines by the presence of
rheumatoid arthritis) granulomas which are small, 0.5-2 mm collection of:
❖ Histologically includes: • “epithelioid” histiocytes/macrophages
• Lymphocytes, plasma cells, and macrophages • (Langhan’s) giant cells [coalesced histiocytes]
• Proliferation of Fibroblasts and small blood vessels • surrounded by a rim of Lymphocytes
• Increased connective tissue
• Tissue destruction
❖ Mononuclear Phagocytes (Macrophages/MOs/Histiocytes)
• The PMN is central to acute inflammation
• The MACROPHAGE is central to chronic inflammation
‣ Synonyms:
✓ Macrophages (MOs)
✓ Histiocytes
✓ Kupper Cells (etc.)
❖ Macrophage Origin:
• come from the same cell line but differ depending on their
microenvironment
• belong to the mononuclear phagocyte system (RES).
• RES consist of: bone marrow, peripheral blood, and tissue
❖ MO’s share in common:
• Mobility = SLOWER than PMNs
- Granulomas occur in response to various diseases:
• Phago- and pinocytosis
• Foreign Body
• Ability to become activated, especially by Lymphokines, T cells
• Tuberculosis (tb)
and anything that disturbs cell membrane → allows more • Fungal Infections
aggressive behavior in inflammation • Sarcoidosis
• Ability to secrete LARGE quantities of chemical mediators • Schistosomiasis
• Leprosy
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 Pathology CJRebojo

❖ 2 factors necessary for Granuloma Formation: Angiogenesis

• Presence of indigestible organisms or particles (Tb, Mineral Oil, • Basal Membrane degradation of parent vessel
Etc.) • Migration of endothelial cells toward an angiogenic stimulus
• Cell Mediated Immunity (T-Cells) • Proliferation of endothelial cells behind the leading front of migrating
cells
• Maturation of endothelial cells and organization into capillary tubes

Outcome of Chronic Inflammation

• Resolution/Regeneration/Restitution of Normal Structure
• Repair/Organization/Healing by connective tissue/Fibrosis/Scarring
• It can continue indefinitely -- some disease process are capable of
continuing indefinitely such as rheumatoid arthritis
Deposition of Extracellular Matrix (ECM)
RESOLUTION - The breakdown of subsequent deposition of ECM that leads to scar
formation and remodelling
- It is the return of the tissue to its normal state • Fibroblasts → lay down the ECM
❖ Factors Necessary for Resolution:
• Metalloporteinases → synthesize and degrade the ECM
• Removal of Offending Agent
• Regenerative ability if cells have been destroyed
• Intact stromal framework Remodeling or Maturation and Organization of the Fibrous
❖ Categorization of cells based on regenerative ability
Tissue
• Labile Cells - The primary component is COLLAGEN as it provides the tensile
✓ cells which continue to proliferate throughout life (gut, skin, strength.
bone marrow) - Collagen is also degraded (collagenases) and it is the balance of
• Stable Cells synthesis and degradation which leads to orderly wound formation
✓ cells which retain the capacity to proliferate throughout life but
usually do not UNLESS stimulated (liver, kidney, pancreas,
bone)
• Permanent Cells
✓ cells which cannot reproduce themselves after birth (neurons,
cardiac and skeletal muscles)
❖ Stromal Framework
- It is not enough to be able to regenerate
- There must be an adequate stromal framework

REPAIR

- aka. organization/healing by connective tissue/fibrosis/scarring

- 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
Granular Tissue
- The early specialized vascular and fibrous tissue formed
- Grossly it looks pink and granular
- Histologically: one sees vessels and fibroblasts
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 (compared to first)
✓ There is a big hole that needs to be filled in
✓ The hole is filled 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
secondar to myofibroblasts

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 Pathology CJRebojo

Fibrous Inflammation
• Serous fluid + Plasma Proteins (fibrinogen)
• Seen commonly in infections of the pleural cavity and pericardial
sac

Time Scale for Repair/Wound Healing
• First Hours: Fibrin clots forms with overlying scap
• 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
• Day 5:
✓ Incisional space is filled with granulation tissue
✓ Neurovascularization is MAXIMAL
✓ Collagen fibrils bridge the gap
✓ Epidermis covers its normal thickness
• 2 weeks:
✓ Continued proliferation of fibroblasts and accumulation of
collagen
✓ Edema, new vessels, and inflammatory infiltrate are ABSENT
• 1 month:
✓ Scar covered by intact normal epithelium
✓ Tensile strength increases with additional time
Serous Inflammation
• Marked by outpouring of a thin fluid that, depending on the site of
injury is derived from either blood serum or secretions of
mesothelial cells lining the peritoneal, pleural, and pericardial
cavities.
Suppurative or Purulent Inflammation
• Serous + Fibrous + Plus
• Especially common in Staph infections
• Acute Appdenicitis is an exampls
Ulcer
• A local defect, or excavation of the surface of an organ or tissue
• Produced by the sloughing (shedding) of inflammatory necrotic
tissue
• Defined by the presence of necrotic tissue on or near a surface
E N D (CJRebojo 2013)

Wound Strength over Time:

- At the end of 1 week → wound strength approx. 10%
- It increases rapidly over the next 4 weeks
- It peaks at about 3rd month and achieves about 70-80% of the
tensile strength of unwounded skin

PATHOLOGIC ASPECTS OF INFLAMMATION AND WOUND

REPAIR

- Systemic and Local Host Factors influence the adequacy of

inflammatory-reparative response:
• Protein Deficiency
• Vitamin Deficiency (esp Vit. C)
• Steroids
• Infection is the single most important cause of delay in wound
healing
• Rupture (wound dehisence)
- Abberations in Growth:
• Excessive amounts of Collagen → keloid
• Excessive amounts of Granulation Tissue → proud flesh
• Uncontrolled proliferation of Fibroblasts → fibromatoses

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