The type of emigrating leukocytes varies with: 1- The age of the inflammatory response

1. The type of emigrating leukocytes varies with: 1- The age of the inflammatory response 2- The type of stimulus. In acute inflammation, the predominant cells are neutrophilsduring the first 6-24 hours, replaced by monocytes in 24-48 hours. Exceptions: 1.Viral infection lymphocytes predominate 2. Hypersensitivity reaction eosinophils predominate

2. Leukocyte Activation Leukocytes at the site of infection or tissue necrosis must be activated to perform their function Stimuli for activation include: Microbes Products of necrotic cells Chemical Mediators

3. Leukocyte activation results in many enhanced functions: 1- Phagocytosis of particles, an early step in the elimination of harmful substances. 2- Production of substances that destroy phagocytosed microbes and remove dead tissues; these leukocyte products include lysosomalenzymesand reactiveoxygen and nitrogenspecies. 3- Production of mediators that amplify the inflammatory reaction, including arachidonic acid metabolites and cytokines.

4. Phagocytosis • Opsonins: components of the microbes and dead cells, or host proteins that coat microbes and target them for phagocytosis; these have specific surface receptors on leukocytes helping leukocytes to bind and ingest most microorganisms and dead cells, a process called opsonization). • The most important opsonins are: • antibodies of the immunoglobulin G (IgG) class • breakdown products of the complement protein C3 • plasma carbohydrate-binding lectins called collectins, which bind to microbial cell-wall sugar groups.

5. Engulfment • Leukocytes express receptors for opsonins that facilitate rapid phagocytosis of the coated microbes. These receptors include the Fc receptor for IgG (called FcγRI), complement receptors 1 and 3 (CR1 and 3) for complement fragments, and C1q for the collectins. • Binding of opsonized particles triggers engulfment, In engulfment, pseudopods are extended around the object, eventually forming a phagocytic vacuole. The membrane of the vacuole then fuses with the membrane of a lysosomal granule, resulting in discharge of the granule's contents into the phagolysosome

6. Killing and Degradation of Microbes • The key steps in this reaction are the production of microbicidal substances within lysosomes and fusion of the lysosomes with phagosomes, thus selectively exposing the ingested particles to the destructive mechanisms of the leukocytes. • The most important microbicidal substances are reactive oxygen species (ROS) and lysosomalenzymes. Phagocytosis stimulates an oxidative burst characterized by a sudden increase in oxygen consumption, glycogen catabolism (glycogenolysis), increased glucose oxidation, and production of ROS. • Reactive nitrogen species, particularly NO, act in the same way as ROS

7. Leukocytes-Induced injury Underlying Human disease Enzymes and ROS may be released into the extracellular environment. The mechanisms that function to eliminate microbes and dead cells (the physiologic role of inflammation) are also capable of damaging normal tissues (the pathologic consequences of inflammation). Acute Disorders Acute respiratory distress syndrome (Neutrophil) Acute transplant rejection (Lymphocytes, Abs & complement.) Asthma (esonophil, IgE) Septic shock ( cytokines) Vasculitis (Ab, complement, Neutrophils)

8. Chronic disorders Arthritis (lymphocytes, macrophages, Ab) Asthma ( esinophils, other WBC, IgE) Atherosclerosis (Macrophage, lymphocytes) Chronic transplant rejection (Lymphocyte, cytokines) Pulmonary fibrosis (Macrophages, Fibroblasts)

9. CHEMICAL MEDIATORS OF INFLAMMATION • Mediators may be produced: 1- locally by cells at the site of inflammation 2- circulating in the plasma (typically synthesized by the liver) as inactive precursors that are activated at the site of inflammation • Most mediators induce their effects by binding to specific receptors on target cells • Different mediators may have similar actions, in which case they may amplify a particular response, or they may have opposing effects, thus serving to control the response • The actions of most mediators are tightly regulated. Once activated and released from the cell, mediators quickly decay (e.g., arachidonic acid metabolites), are inactivated by enzymes (e.g., kininase inactivates bradykinin), are eliminated (e.g., antioxidants scavenge toxic oxygen metabolites), or are inhibited (complement-inhibitory proteins)

10. The principal chemical mediators of inflammation

12. Principal Inflammatory Actions of Arachidonic Acid Metabolites (Eicosanoids)

13. Role of Mediators in Different Reactions of Inflammation

14. Morphologic Patterns of Acute Inflammation This is modified by Severity of the inflammatory response Its specific cause The type of tissue involved

15. Types of Acute inflammation 1. Serous inflammation - Accumulation of transudate - Examples Skin blisters (burns, viral infection) Fluid in serous cavity = effusion

16. 2. Fibrinous inflammation - More severe injury - Fibrinous exudate - Examples: Meningitis, Pericarditis, pleuritis - Outcomes a. resolution b. organization

17. 3. Suppurative ( purulent) Inflammation Purulent exudate(pus) - Consists of neutrophils, necrotic cells & edema fluid Mostly caused by pyogenic microorganisms such as Staphylococci Abscess: Focal collection of pus caused by seeding of pyogenic bacteria into a tissue or secondary infection of necrotic foci. It has a central necrotic region rimmed by a layer of preserved neutrophils & dilated blood vessel and fibroblastic proliferation Abscess with time become completely walled off & eventually replaced by connective tissues.

18. 4. Ulceration Ulcer: Local defect or excavation of the surface of an organ or tissue produced by necrosis of cells & sloughing of inflammatory necrotic tissue. Ulcers occur only on surfaces. Sites : Mucosa of mouth, stomach, intestine Skin of lower extremities -Examples Peptic ulcer of stomach or duodenum

19. Outcome of Acute Inflammation The Outcome of acute inflammation depends on: The nature of intensity of injury. The site & tissue affected The ability of the host to respond

20. The outcomes of acute inflammation are: 1. Resolution - To restore morphological & functional normality. - It occurs when: • Injury is limited or short-lived. • There is no or minimal tissue damaged • Tissue is capable of regeneration.

21. 2. Progression to chronic inflammation It occurs when the offending agent is not removed It depends on the extent of the initial injury It depends on the capacity of the affected tissue to regrow. 3. Scarring or Fibrosis It occurs when Tissue destruction is intense Inflammation occurs in tissue that don’t regenerate Inflammation is associated with extensive fibrinous exudates

22. 4. Abscess formation - Abscesses may form when: There is extensive neutrophilic infiltrate Infection by certain bacteria or fungi - The usual outcome is scarring.