Chapter 3: Inflammation and Repair

Question 1

The typical inflammatory reaction develops through a series of sequential steps..?

Answer 1

• Recognition of the noxious agent that is the initiating stimulus for inflammation. The cells involved in inflammation (tissue-resident sentinel cells, phagocytes, and others: macrophages, dendritic cells, mast cells) are equipped with receptors that recognize microbial products and substances released from damaged cells. These receptors are described in more detail later. Engagement of the receptors leads to the production of mediators of inflammation (amines, cytokines), which then trigger the subsequent steps in the inflammatory response.
• Recruitment of leukocytes and plasma proteins into the tissues. Since blood perfuses every tissue, leukocytes and proteins such as complement can be delivered to any site of microbial invasion or tissue injury. When pathogenic microbes invade the tissues, or tissue cells die, leukocytes (first mainly neutrophils, later monocytes and lymphocytes) and plasma proteins (complement, kinins) are rapidly recruited from the circulation to the extravascular site where the offending agent is located. The exodus of cells and plasma proteins from blood requires coordinated changes in blood vessels and secretion of mediators, described in detail later.
• Removal of the stimulus for inflammation is accomplished mainly by phagocytic cells, which ingest and destroy microbes and dead cells.
• Regulation of the response is important for terminating the reaction when it has accomplished its purpose.
• Repair consists of a series of events that heal damaged tissue. In this process the injured tissue is replaced through regeneration of surviving cells and filling of residual defects with connective tissue (scarring).

Question 2

Inflammatory reactions may be triggered by a variety of stimuli..?

Answer 2

• Infections (bacterial, viral, fungal, parasitic) and microbial toxins.
• Tissue necrosis.
• Foreign bodies (splinters, dirt, sutures) and sometimes endogenous substances: urate crystals (in gout), cholesterol crystals (in atherosclerosis), and lipids (in obesity-associated metabolic syndrome).
• Immune reactions (also called hypersensitivity).

Question 3

Several cellular receptors and circulating proteins are capable of recognizing microbes and products of cell damage and triggering inflammation..?

Answer 3

• Cellular receptors for microbes. The best defined of these receptors belong to the family of Toll-like receptors (TLRs).
• Sensors of cell damage. All cells have cytosolic receptors, such as NOD-like receptors (NLRs), that recognize diverse molecules that are liberated or altered as a consequence of cell damage. These molecules include uric acid (a product of DNA breakdown), adenosine triphosphate (ATP) (released from damaged mitochondria), reduced intracellular K+ concentrations (reflecting loss of ions because of plasma membrane injury), even DNA when it is released into the cytoplasm and not sequestered in nuclei, as it should be normally, and many others. These receptors activate a multiprotein cytosolic complex called the inflammasome, which induces the production of the cytokine interleukin-1 (IL-1). IL-1 recruits leukocytes and thus induces inflammation.
• Other cellular receptors involved in inflammation. In addition to directly recognizing microbes, many leukocytes express receptors for the Fc tails of antibodies and for complement proteins. These receptors recognize microbes coated with antibodies and complement (the coating process is called opsonization) and promote ingestion and destruction of the microbes as well as inflammation.
• Circulating proteins. The complement system reacts against microbes and produces mediators of inflammation. A circulating protein called mannose-binding lectin recognizes microbial sugars and promotes ingestion of the microbes and the activation of the complement system. Other proteins called collectins also bind to and combat microbes.

Question 4

Acute inflammation has three major components..?

Answer 4

• Dilation of small vessels leading to an increase in blood flow (vascular gross/anatomical)
• Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation (vascular micro/physiological)
• Emigration of leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent (cellular)

Question 5

2 main mechanisms are responsible for the increased permeability of postcapillary venules, a hallmark of acute inflammation..?

Answer 5

• Contraction of endothelial cells
• Endothelial injury

Question 6

Mediators of endothelial cell contraction/increased vascular permeability in acute inflammation?

Answer 6

• Histamine (and serotonin)
• Leukotrienes
• Bradykinin (kinins)
• Platelet-activating factor

Remember bold

Question 7

Different steps involved in leukocyte recruitment to sites of inflammation?

Answer 7

• Margination
• Rolling
• Adhesion to endothelium
• Migration across the endothelium and vessel wall (transmigration or diapedesis)
• Migration in the tissues toward a chemotactic stimulus

Question 8

Endothelial and Leukocyte Adhesion Molecules?

Answer 8

• Selectins: at first
• Integrins: adhesion +
• Ig (CD31): transmigration

Question 9

Chemotaxis: exogenous factors?

Answer 9

Bacterial products, including peptides with N-formylmethionine terminal amino acids and some lipids.

Question 10

Chemotaxis: endogenous factors?

Answer 10

• Cytokines, particularly those of the chemokine family (e.g., IL-8)
• Components of the complement system, particularly C5a
• Arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4)
• Also platelet-activating factor

NB: All these chemotactic agents bind to specific seven-transmembrane G protein–coupled receptors on the surface of leukocytes.

Question 11

Neutrophilic to monocytic predominance switch time in inflammation in most cases?

Answer 11

24 hours

Question 12

Main phagocytic receptors?

Answer 12

• Mannose receptors
• Scavenger receptors
• Receptors for various opsonins

Question 13

Main opsonins?

Answer 13

• Immunoglobulin G (IgG) antibodies
• The C3b breakdown product of complement
• Certain plasma lectins, notably mannose-binding lectin and collectins

Question 14

2 antiinflammatory cytokines?

Answer 14

• Transforming growth factor-β (TGF-β)
• IL-10

Question 15

Mediators of vasodilation?

Answer 15

• Histamine
• Prostaglandins
• Platelet-activating factor
• Kinins
• Complement (mast cell stimulation)

Remember bold

Question 16

Mediators of endothelial activation?

Answer 16

• Histamine
• Cytokines (expression of adhesion molecules)

Question 17

Mediators of pain?

Answer 17

• Prostaglandins
• Bradykinin (kinins)
• Also substance P

Question 18

Mediator(s) of fever?

Answer 18

• Prostaglandins
• Also TNF, IL-1

Question 19

Mediators of leukocyte adhesion?

Answer 19

• Leukotrienes
• Platelet-activating factor

Question 20

Mediators of leukocyte activation?

Answer 20

• Leukotrienes
• Chemokines
• Complement

Question 21

Mediator(s) of direct target killing (membrane attack complex)?

Answer 21

Complement

Question 22

Mediator(s) of degranulation and oxidative burst?

Answer 22

Platelet-activating factor

Question 23

Mediator(s) of smooth muscle contraction?

Answer 23

Kinins

Question 24

2 pathways of macrophage activation and their main roles?

Answer 24

• Classical macrophage activation may be induced by microbial products such as endotoxin, which engage TLRs and other sensors; by T cell–derived signals, importantly the cytokine IFN-γ, in immune responses; or by foreign substances, including crystals and particulate matter. Classically activated (also called M1) macrophages produce NO and lysosomal enzymes, which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. The main role of these macrophages in host defense is to destroy microbes (NOS, NO, lysosomal enzymes) and promote the inflammatory response (IL-1, -12, -23, chemokines).
• Alternative macrophage activation is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells. These macrophages are not actively microbicidal; instead, their principal functions are to terminate inflammation (IL-10, TGF-beta) and promote tissue repair (GFs, TGF-beta).

Question 25

Examples of diseases with granulomatous inflammation, cause, and type of granulomatous inflammation?

Answer 25

• Tuberculosis; Mycobacterium tuberculosis; Caseating granuloma (tubercle)
• Leprosy; Mycobacterium leprae; Noncaseating granulomas
• Syphillis; Treponema pallidum; Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells are necrotic without loss of cellular outline
• Cat-scratch disease; Gram-negative bacillus; Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon
• Sarcoidosis; Unknown etiology: Noncaseating granulomas with abundant activated macrophages (naked granulomas)
• Crohn disease; Immune reaction against intestinal bacteria, possibly self antigens; Occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate

Question 26

Which is the most important cytokine for the synthesis and deposition of connective tissue proteins in tissue repair?

Answer 26

TGF-beta

Question 27

Factors that influence tissue repair?

Answer 27

• Infection is clinically one of the most important causes of delayed healing; it prolongs inflammation and potentially increases the local tissue injury.
• Diabetes is a metabolic disease that compromises tissue repair for many reasons (Chapter 24) and is one of the most important systemic causes of abnormal wound healing.
• Nutritional status has profound effects on repair; protein deficiency and vitamin C deficiency inhibit collagen synthesis and retard healing.
• Glucocorticoids (steroids) have well-documented antiinflammatory effects, and their administration may result in weakness of the scar due to inhibition of TGF-β production and diminished fibrosis. In some instances, however, these effects of glucocorticoids are desirable. For example, in corneal infections, glucocorticoids are sometimes prescribed (along with antibiotics) to reduce the likelihood of opacity that may result from scarring.
• Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart, or dehisce.
• Poor perfusion, due to peripheral vascular disease, arteriosclerosis, and diabetes or due to obstructed venous drainage (e.g., in varicose veins), also impairs healing.
• Foreign bodies such as fragments of steel, glass, or even bone impede healing by perpetuating chronic inflammation.
• The type and extent of tissue injury and the character of the tissue in which the injury occurs affect the subsequent repair. Complete restoration can occur only in tissues composed of stable and labile cells. Injury to tissues composed of permanent cells inevitably results in scarring and some loss of function.
• The location of the injury is also important. For example, inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities) develops extensive exudates. Subsequent repair may occur by digestion of the exudate, initiated by the proteolytic enzymes of leukocytes, and resorption of the liquefied exudate. This is called resolution, and in the absence of cellular necrosis, normal tissue architecture is generally restored. However, in the setting of larger accumulations, granulation tissue grows into the exudate, and a fibrous scar ultimately forms. This is called organization.