Chapter 6: Innate Immunity: Inflammation and Wound Healing

Question 1

Human Defense Mechanisms

Answer 1

1. Innate defenses are the first line of defense, are present at birth, and
   include the surface barriers skin and mucous membranes.
2. Inflammation is the second line of defense and is activated with
   injury or infectious disease.
3. Adaptive (acquired) immunity is the third line of defense, is specific
   to particular antigens, and has memory.

Question 2

Innate Immunity

Answer 2

1. Neonates often have transiently depressed inflammatory function,
   particularly neutrophil chemotaxis and alternative complement
   pathway activity.
2. Elderly persons are at risk for impaired wound healing, usually
   because of chronic illnesses.
3. There are three layers of human defense:
   * Physiologic barriers
   * Inflammatory response
   * Adaptive (acquired) immunity
4. Physical barriers are the first lines of defense functioning to prevent
   damage to the individual and thwart the entrance of pathogens. These barriers include the skin and mucous membranes.
5. Antibacterial peptides are found in mucous secretions, perspiration,
   saliva, tears, and other secretions. They provide a biochemical barrier
   against pathogenic microorganisms.
6. The skin, mucous membranes, and the lining of the gastrointestinal
   (GI) tract are colonized by commensal or mutualistic microorganisms. These microorganisms provide protection by releasing biochemical compounds which facilitate immune responses and prevent colonization by pathogens. Within the gut, they also facilitate digestion in the GI tract.
7. The second line of defense is the inflammatory response, a rapid and nonspecific protective response to cellular injury resulting from
   any cause. It can occur only in vascularized tissues.
8. The macroscopic hallmarks of inflammation are redness, swelling,
   heat, pain, and loss of function for the inflamed tissues.
9. The microscopic hallmarks of inflammation are vasodilation,
   increased capillary permeability, and an accumulation of fluid and
   cells at the inflammatory site.
10. Inflammation is mediated by three key plasma protein systems:
    * The complement system
    * The clotting system
    * The kinin system.
    The components of all three systems are a series of inactive proteins which are activated sequentially in the presence of tissue injury.
11. The complement system can be activated by antigen–antibody reactions (through the classical pathway) or by other products, especially bacterial polysaccharides (through the lectin pathway or the alternative pathway). The lectin and alternative pathways do not require antibody activation to recruit phagocytes, activate mast cells, and destroy pathogens.
12. The most biologically potent products of the complement system
    are C3b (opsonin), C3a (anaphylatoxin), and C5a (anaphylatoxin,
    chemotactic factor).
13. The clotting system stops bleeding, localizes microorganisms, and
    provides a meshwork for repair and healing.
14. Bradykinin is the most important product of the kinin system
    and causes vascular permeability, smooth muscle contraction,
    and pain.
15. Control of inflammation regulates inflammatory cells and enzymes
    and localizes the inflammatory response to the area of injury or
    infection.
16. Carboxypeptidase, histaminase, kinase, and C1 inhibitor are inactivating enzymes. The fibrinolytic system and plasmin facilitate clot degradation after bleeding is stopped.
17. Many different types of cells are involved in the inflammatory process, including mast cells, endothelial cells, platelets, phagocytes (neutrophils, eosinophils, monocytes and macrophages, dendritic cells), lymphocytes, and natural killer (NK) cells,.
18. Most cells express plasma membrane pattern recognition receptors (PRRs) which recognize molecules produced by infectious microorganisms. These molecules include pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are transmembrane receptors and nucleotide-binding-like receptors (NLR-like), and nucleotide oligomerization domain-like (NOD-like) receptors are
    cytoplasmic receptors. They are expressed by many inflammatory cells and recognize both PAMPs and DAMPs. Upon recognition, they promote the release of cytokines and inflammatory mediators, which, in turn, eliminate damaged cells and protect against invasion by microbes.
19. The cells of the innate immune system secrete many biochemical mediators (cytokines), which are responsible for activating other cells and regulating the inflammatory response. These cytokines include chemokines, interleukins, interferons, and other molecules.
20. Chemokines induce chemotaxis (attraction) of leukocytes, fibroblasts, and other cells to promote phagocytosis and wound healing.
21. Interleukins are produced primarily by lymphocytes and macrophages. They either promote or inhibit inflammation by activating the growth and differentiation of leukocytes especially lymphocytes.
22. The most important pro-inflammatory interleukins are interleukin-1
    (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα). IL-6 and IL 10 downregulate the inflammatory response.
23. Interferons are produced by cells that are infected by viruses. Once released from infected cells, interferons can stimulate neighboring healthy cells to produce substances that prevent viral infection.
24. The most important activator of the inflammatory response is the mast cell, located in connective tissue near capillaries. Mast cells initiate inflammation by releasing biochemical mediators (histamine and chemotactic factors) from cytoplasmic granules. They also synthesize other mediators (prostaglandins, leukotrienes, and platelet-activating factor [PAF]) in response to stimuli. Basophils, found in blood, function in a manner that is similar to mast cells.
25. Histamine is the major vasoactive amine released from mast cells. It increases vascular permeability through dilation of capillaries and retraction of endothelial cells lining the capillaries.
26. The endothelial cells lining the circulatory system (vascular endothelium) regulate circulating components of the inflammatory system, maintaining normal blood flow. They function in this capacity by preventing spontaneous activation of platelets and other elements of the clotting system.
27. During inflammation, the endothelium expresses receptors that
    stimulate leukocytes to exit the vessel. The endothelium also retracts
    to allow fluid to pass into the tissues.
28. Platelets interact with the coagulation cascade to stop bleeding. They release mediators which facilitate and control inflammation.
29. The polymorphonuclear neutrophil (PMN), the predominant phagocytic cell in the early inflammation, exits the circulation, through retracted endothelial junctions, by diapedesis. On exiting, it moves to the inflammatory site by chemotaxis.
30. Eosinophils release products that control the inflammatory response, and they are the principal cells that destroy parasitic organisms.
31. The macrophage, the predominant cell in the late inflammatory response, is highly phagocytic. Additionally, it is responsive to cytokines, which promote wound healing.
32. Dendritic cells function as messengers between the innate and acquired (adaptive) immune systems. They process antigens at the site of inflammation and transport the antigen to lymph nodes and spleen, where they present these antigens to the resident T cells. The result of this process is the formation of antibodies.
33. Phagocytosis is a multistep cellular process, which usually results in the destruction of pathogens and foreign debris. The steps include recognition and attachment, engulfment, formation of a phagosome, formation of a phagolysosome, and eventual destruction of the pathogen or foreign debris. Phagocytic cells engulf microorganisms, enclosing them within phagocytic vacuoles (phagolysosomes). The vacuoles contain toxins (especially metabolites of oxygen) and/ or enzymes that kill and digest the microorganisms.
34. Opsonins are molecules which enhance phagocytosis by coating the antigen. This activity results in a stronger attraction between the microorganism and the phagocyte (“marking” the organism). It also enhances the affinity with which the phagocyte binds to the microorganism. Examples include antibodies and the complement component C3b.

Question 3

Acute and Chronic Inflammation

Answer 3

1. Acute inflammation is self-limiting and usually resolves within 8 to10 days.
2. Local manifestations of inflammation include the classic signs of redness, heat, swelling, pain, and loss of function. They are the result of vascular changes associated with the inflammatory process, including vasodilation and increased capillary permeability.
3. The principal systemic effects of inflammation are fever, leukocytosis (increased levels of circulating leukocytes), and an increase in plasma proteins, primarily the acute-phase reactants, IL-1, and IL-6.
4. Chronic inflammation can be a continuation of acute inflammation that lasts 2 weeks or longer, or it can occur as a distinct process without significant preceding acute inflammation.
5. Chronic inflammation is characterized by a dense infiltration of lymphocytes and macrophages. Granuloma formation is a process wherein the body walls off and isolates infectious microorganisms. It serves to protect the body from further tissue damage.

Question 4

Wound Healing

Answer 4

1. Resolution (regeneration) is the return of tissue to nearly normal structure and function. Repair is healing by scar tissue formation.
2. Resolution occurs when little tissue has been lost or where the injured tissue is capable of regeneration. This type of healing is called healing
   by primary intention.
3. Tissues that have sustained extensive damage or tissue types that are incapable of regeneration heal by repair, a process which results in the formation of a scar. This process is called healing by secondary intention.
4. Resolution and repair occur in two separate phases. The reconstructive phase occurs when the wound begins to heal. The maturation phase occurs when the healed wound is remodeled. Cellular activity decreases and the blood vessels regress.
5. Dysfunctional wound healing can be secondary to ischemia, excessive bleeding, excessive fibrin deposition, predisposing disorders (e.g., diabetes mellitus), wound infection, inadequate nutrients, use of NSAIDs and steroids, or altered collagen synthesis.
6. Dehiscence is a disruption where the wound pulls apart at the suture line.
7. A contracture is a structural deformity caused by the excessive shortening of collagen in scar tissue.