Inflammation is the body’s mechanism for coping with agents that could damage it. In other words, inflammation is a protective response to rid the body of the cause of cell injury and the resultant necrotic cells that cell injury produces. Although the processes of acute and chronic inflammation are an important protective mechanism used by the body to deal with potentially damaging agents, they are potentially damaging to the body and must be closely regulated. The basic steps in acute inflammation allow white blood cells to move from the blood to the tissue location where they are required. Acute inflammation can resolve completely if the inciting agent is removed, or it can have one of several other sequelae, including chronic inflammation. This chapter will discuss general concepts of acute and chronic inflammation, specific features of acute inflammation (including cardinal signs, causes, steps, and morphology and outcomes), specific features of chronic inflammation, and repair.

General Concepts of Acute and Chronic Inflammation

Overview: The body must undergo changes locally through vasodilation and increased vascular permeability in the area of the agent inciting the inflammatory reaction to allow white blood cells to accumulate. The white blood cells must then leave the blood vessel, cross the basement membrane, and be drawn to the area where they are needed. The process by which white blood cells are drawn to the area where they are needed is referred to as chemotaxis. Acute inflammation has a rapid onset, lasts for minutes to days, and is characterized by exudation of fluid and protein from vessels and emigration of neutrophils. Acute inflammation is a protective process that is designed to rid the body of the inciting agent and set up the process of repair. Chronic inflammation has a longer time course (days to years) and involves different cell types than does acute inflammation (lymphocytes and macrophages versus neutrophils). Also, in chronic inflammation, tissue repair coexists with tissue destruction.

Cardinal signs of acute inflammation: Rubor (red discoloration), calor (heat), dolor (pain), tumor (mass effect), and loss of function.

Causes of acute inflammation: Infection, trauma, physical and chemical agents, necrosis, foreign bodies, and immune reactions.

Stages of acute inflammation (Table 2-1)

1. 
   

   Vasodilation (after a transient vasoconstriction)

   
   
   
   
   • How: Vasodilation occurs through release of mediators from cells. These mediators include histamine, prostacyclin (PGI2), and nitric oxide (NO).
     
   • Why: Vasodilation increases the hydrostatic pressure by causing slowing (sludging) of blood flow. Sludging of blood also causes margination of leukocytes along the wall of the blood vessel.
   
   
   
   
2. 
   

   Increased vascular permeability (increased leakiness of vessels)

   
   
   
   
   • How: Increased vascular permeability occurs through release of mediators from cells. These mediators include histamine and leukotrienes C4, D4, and E4.
     
   • Why: Increased vascular permeability allows fluid to cross into the interstitial tissue, which increases protein levels in the interstitial tissue, thereby decreasing osmotic pressure in the blood and increasing osmotic pressure in the interstitial tissue. These changes cause fluid to flow out of the vessel, leading to edema of the interstitial tissue.
     
   • Mechanisms of increased vascular permeability: Several mechanisms increase vascular permeability, some of which are physiologic and some of which are pathologic. Endothelial contraction and retraction are physiologic mechanisms and are due to mediators. Direct endothelial injury is a pathologic mechanism due to damaging agents not under the body’s control.
     
     
     
     • Endothelial contraction (referred to as immediate-transient response)
       
       
       
       • Mediators: Histamine, bradykinin, and leukotrienes.
         
       • Vessels affected: Postcapillary venules.
         
       • Time course: Immediate; short lived (up to 30 minutes).
       
       
     • Endothelial cell retraction
       
       
       
       • Mediators: Tumor necrosis factor (TNF) and interleukins (e.g., IL-1).
         
       • How: Structural rearrangement of cytoskeleton.
         
       • Time course: 4–6 hours (referred to as delayed response); long lived.
       
       
     • Direct endothelial injury
       
       
       
       • Mediators: Bacterial enzymes.
         
       • Vessels affected: All.
         
       • How: Endothelial cell necrosis.
         
       • Time course: Immediate (referred to as immediate-sustained response).
       
       
     • Delayed prolonged response
       
       
       
       • Due to ultraviolet light, x-ray, and mild thermal injury.
         
       • Uncertain mechanism.
       
       
     • Leukocyte-mediated damage
   
   
   
   
3. 
   

   Movement of white blood cells from blood vessels into soft tissue at the site of inflammation: The steps required are rolling, pavementing, and transmigration. Chemotaxis is the process by which white blood cells are drawn to the site of acute inflammation.

Rolling

• Basic description: Loose, intermittent contact of white blood cells with endothelium, partially due to margination of white blood cells from stasis of blood.
  
• Mediators: Sialyl-Lewis X molecules on white blood cells bind with E-selectins on endothelial cells.

Pavementing

• Basic description: Tight, constant contact of white blood cells with endothelium.
  
• Mediators: Leukocyte function-associated antigen-1 (LFA-1) and Mac-1 on white blood cells bind with intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells.

Transmigration

• Basic description: White blood cells crossing through the endothelial layer.
  
• Mediators: CD31 or platelet endothelial cell adhesion molecule (PECAM) on both white blood cells and endothelial cells.

Chemotaxis

Basic description: Process by which white blood cells are drawn to the site of inflammation.

Mediators

• Exogenous mediators: Bacterial polysaccharides.
  
• Endogenous mediators: C5a, leukotriene B4 (LTB4), and IL-8. The endogenous mediators act through various mechanisms. With most, however, the activation of G-protein receptors ultimately results in activation of GTPases, which cause polymerization of actin.

The role of leukocytes (see Table 2-1)

• White blood cells recognize foreign particles through mannose and scavenger receptors. Opsonins are particles that bind to foreign material and signal leukocytes to remove it. Types of opsonins include:
  
  
  
  1. 
     

     IgG (recognized by Fc receptor on white blood cells).

     
     
  2. 
     

     C3b (recognized by CR 1, 2, and 3 on leukocytes).

     
     
  3. 
     

     Collectins (recognized by C1q on leukocytes).

  
  
• White blood cells engulf the foreign particles (most often bacteria) using the above-mentioned receptors.
  
• Killing and/or degradation of foreign substances occurs by one of several methods:
  
  
  
  • Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (has membrane and cytoplasmic component). It uses two oxygen molecules to produce a superoxide radical (O2˙−), and the superoxide radical converts to hydrogen peroxide.
    
  • Myeloperoxidase: Converts hydrogen peroxide and halogen (Cl−) to HOCl·, which causes halogenation or lipid or protein peroxidation.
    
  • Other methods of bacterial killing include bactericidal permeability increasing protein, lysozyme, and major basic protein.