U N I T VI

Textbook of Medical Physiology, 11th Edition

Chapter 33:
Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System, and Inflammation
Slides by Robert L. Hester, Ph.D.

GUYTON & HALL

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Leukocytes / White Blood Cells

- mobile units of the bodys protective sys.

Granulocytes (65%)
neutrophils, eosinophils, basophils formed in bone marrow

Monocytes (5%)
tissue macrophages formed in bone marrow

Lymphocytes (30%
formed in lymph tissue
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Genesis of Blood Products

CFU-T T-Cell

B-Cell CFU-B

Pluripotent Stem Cell

Lymphoid Stem Cell

CFU-Eosin

eosinophil

basophil CFU-Bas neutrophil CFUGM monocyte macrophage platelets CFU-MEG

Myeloid Stem Cell

BFU-E
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erythrocyte

Leukocytes Classification
Granulocytes
Neutrophils Eosinophils Basophils

Non- Granulocytes
- Monocytes - Lymphocytes

Polymorphonuclear
Neutrophils Eosinophils Basophils

Mononuclear
- Monocytes - Lymphocytes

Phagocytes
Neutrophils, monocytes Macrophages, eosinophils
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Non-phagocytes
- Lymphocytes - Basophils - Plasma cells

Life Span Granulocytes

4-8 hours circulating in the blodd 4-5 days in tissues

Monocytes
10-20 hours in the blood as macrophages months unless destroyed

Lymphocytes
weeks to months continual circulation throughout the body

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Phagocytic Cells
Polymorphonuclear Neutrophils
non-dividing, short-lived dominant number in bloodstream

Monocytes/Macrophages
long-lived cells do not circulate present in tissue, particularly in lungs,

spleen, liver, lymph nodes tissue macrophage system

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Actions of Phagocytic Cells

1. Margination neutrophils stick to the capillary walls of the inflamed area 2. Diapedesis squeeze through capillary walls 3. Ameboid Motion movement through tissues

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Actions of Phagocytic Cells

4. Chemotaxis move toward source of chemical subs

- depends on concentration gradient of these subs

a. toxins viral or bacterial

b. degenerative products of inflamed tissues

c. reaction products of complement complex d. reaction products caused by plasma clotting 5. Phagocytosis
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Actions of Phagocytic Cells

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Figure 33-2; Guyton & Hall

Phagocytosis

most important function of PMNs and macrophages cellular ingestion of the offending agent Selectivity to prevent ingestion of own normal cells

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Char. of Natural Tissue Structures

1. Smooth surfaces which resists phagocytosis 2. Protective coatswhich resists phagocytosis 3. Immune sys develops Ab against infectious agents which adheres to its membrane and makes it susceptible to phagocytosis (opsonization)

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Polymorphonuclears

1 PMN can engulf 3-20 bacteria Mature cells that can already engulf bacteria Lysosomes contain proteolytic enzyme Peroxisomes contain oxidizing agents (O2, H2O2, OH-) Myeloperoxidase- catalyses H2O2 + Cl2 hypochlorite

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Polymorphonuclears

1. Attaches itself to the foreign particle 2. Projects pseudopodia around it and fuse together 3. Invaginates phagocytic vesicle (phagosome)

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Macrophages

End-stage product of monocytes that enter the tissue from the blood 1 macrophage : 100 bacteria Can engulf bigger particles that PMNs Can extrude the residual products and survive and function for many more months

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Macrophages

Lysosomes contain proteolytic enzymes and lipases Peroxisomes Myeloperoxidase

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Phagocytosis
1. 2. 3. 4. Chemotaxis Attachment Ingestion Digestion

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Opsonization

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Phagocytosis

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Phagocytosis

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Phagocytosis
2. Engulfment 1. Binding

3. Phagosome formation
Acidification proteolysis

MHC II

Antigen presentation

4. Lysosome fusion

5 Membrane disruption
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Reticuloendothelial System
= Monocyte-macrophage system 1. Monocyte 2. Mobile macrophages 3. Fixed tissue macrophages 4. Specialized epithelial cells in the bone marrow, spleen and lymph nodes

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Tissue Macrophages
Skin & subcutaneous tissue histiocytes Lymph nodes Alveolar tissues Liver sinusoids Kupffer cells
Very effective particulate filtration system

Spleen red pulp and venous sinuses Bone marrow Brain microglia

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Inflammation
Characterized by --

1. Vasodilation increase local blood flow 2. Increased capillary permeability allows fluid into interstitial space 3. Clotting of interstitial fluid due to excessive amount of fibrinogen and other proteins leaking from the capillaries 4. Migration of granulocytes and monocytes into tissues 5. Swelling of cells

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Inflammation

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Inflammation
Substances involved

bradykinin, histamine, serotonin, prostaglandins complement, coagulation factors, lymphokines (released by sensitized T cells) Walling off effect of inflammation 1st result of inflammation blocked by fibrin clot delays spread of bacteria/toxic products

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Cardinal Signs of Inflammation

1. Rubor redness 2. Calor warmth or heat 3. Tumor swelling 4. Dolor pain 5. Functio lassa loss of function * Intensity of the inflammatory process is usually proportional to the degree of tissue injury

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Feedback Control of the Macrophage and Neutrophil Response

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Figure 33-6; Guyton & Hall

Cell-mediated Response to Inflammation (Lines of Defense)

1st = Tissue macrophages
already present in tissue rapid enlargement sessile macrophage break loose from their attachments & become mobile

2nd = Neutrophil invasion

margination, diapedesis, chemotaxis stimulation of bone marrow to release stored leukocytes, 4-5 hours

3rd = Macrophage proliferation

invasion by circulating monocytes (at least 8 hours to increase size)

4th = Stimulation of granulocyte and monocyte production

growth factors produced by tissue macrophages (TNF, IL-1, CSF) takes 3-4 days
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NORMAL PRODUCTION
Production Marrow pool

INFECTION
Increased Production Decreased marrow pool

Bone Circulating and marginated pools

Bone Increased circulation Increased margination

Blood vessel Transmigration Tissue

Blood vessel Tissue

Increased Transmigration Site of inflammation

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Pus Formation

Pus
cavity excavated in the inflamed tissues contains necrotic tissues, dead PMNs, dead macrophages & tissue fluid gradually autolyze & absorbed into surrounding tissues & lymph

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EOSINOPHILS

~ 2% of total white blood cells weak phagocytes exhibit chemotaxis active against parasites, allergic reactions

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EOSINOPHILS
Attach themselves to parasites by special surface molecules & release substances that kill the parasites 1. release hydrolytic enzymes from their granules (modified lysosomes) 2. release highly reactive forms of O2 3. release highly larvacidal polypeptides (major basic proteins)

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EOSINOPHILS

Allergic Reaction
mast cells & basophils release eosinophil chemotactice factor eosinophil detoxify some of the inflammationinducing subs released by the mast cells and basophils phagocytize and destroy the Ag-Ab complexes to prevent spread

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BASOPHILS
~ 0.5% of total white blood cells basophils similar to mast cells release primarily histamine, some bradykinin, heparin, serotonin, slow-reacting subs of anaphylaxis release due to binding of IgE

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Leukopenia
- Bone marrow produces very few WBC - Body is unprotected against infectious agents - Causes: 1. Decreased production 2. Increased neutrophil destruction - due to a. Irradiation (x-ray or gamma ray) b. exposure to chemicals (benzene, anthracene) c. exposure to drugs (chloramphenicol, thiouracil, barbiturate hypnotics)

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Drugs that can cause Neutropenia

Analgesics Acetaminophen Aminopyrine Dipyrone Antibiotics Cephalosporins Chloramphenicol Doxycycline Gentamicin Penicillins Streptomycin Sulfonamides Vancomycin Anticonvulsants Captopril Hydralazine Methyldopa Cardiovascular drugs Procainamide Propranolol Quinidine Diuretics Acetazolamide Spironolactone Bumetanide Methazolamide Chlorothiazide Chlorthalidone Hydrochlorothiazide Hypoglycemic agents

Carbamazepine Mephenytoin
Brompheniramine Cimetidine Tripelennamine

Primidone Trimethadione
Antihistamines

Chlorpropamide Tolbutamide
Phenothiazines Chlorpromazine Clozapine Desipramine Chlordiazepoxide Clozapine Desipramine Thioridazine Trifluoperazine Trimeprazine Neuropharmacologic agents Metoclopramide Prochlorperazine Promazine Miscellaneous drugs Allopurinol Colchicine D-Penicillamine Ethanol Levamisole Levodopa

Anti-inflammatory drugs Fenoprofen Ibuprofen Indomethacin Antimalarials Amodiaquine Dapsone Hydroxychloroquine

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Pyrimethamine Quinine

Leukemias

Uncontrolled production of WBC Bizarre, undifferentiated, abnormal WBC Cancerous mutation Acute (more aggressive) or chronic

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Leukemias

Types
1. Lymphocytic Leukemias usually beginning in a lymph node or lymphatic tissue and spreading to other areas 2. Myelogenous Leukemias from bone marrow then spread

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Effects of Leukemias

1. metastatic growth of leukemic cells in abnormal body areas bone, spleen, lymph node, liver 2. infection 3. severe anemia 4. bleeding tendency 5. * excessive use of metabolic substrates by the cancerous cells

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U N I T VI
Textbook of Medical Physiology, 11th Edition

Merry Christmas and A Prosperous New Year to Everybody!

GUYTON & HALL

Copyright 2006 by Elsevier, Inc.