Chronic Inflammation

Question 1

Chronic Inflammation

Answer 1

Chronic inflammation is a response of prolonged duration (weeks or months) in which inflammation, tissue injury and attempts at repair coexist, in varying combinations

Question 2

Causes of Chronic Inflammation: persistent infections

Answer 2

Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria and certain viruses, fungi, and parasites.

These organisms often evoke an immune reaction called delayed-type hypersensitivity.

The inflammatory response sometimes takes a specific pattern called a granulomatous reaction.

Question 3

Hypersensitivity diseases

Answer 3

Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system. Under certain conditions immune reactions develop against the individual’s own tissues, leading to autoimmune diseases.

In these diseases, autoantigens evoke a self-perpetuating immune reaction that results in chronic tissue damage and inflammation; examples of such diseases are rheumatoid arthritis and multiple sclerosis. In other cases, chronic inflammation is the result of unregulated immune responses against microbes, as in inflammatory bowel disease. Immune responses against common environmental substances are the cause of allergic diseases, such as bronchial asthma.

Because these autoimmune and allergic reactions are inappropriately triggered against antigens that are normally harmless, the reactions serve no useful purpose and only cause disease. Such diseases may show morphologic patterns of mixed acute and chronic inflammation because they are characterized by repeated bouts of inflammation. Fibrosis may dominate the late stages.

Question 4

Causes of Chronic inflammation;: prolonged exposure to toxic agents

Answer 4

Prolonged exposure to potentially toxic agents, either exogenous or endogenous.

An example of an exogenous agent is particulate silica, a nondegradable inanimate material that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis.

Atherosclerosis is thought to be a chronic inflammatory process of the arterial wall induced, at least in part, by excessive production and tissue deposition of endogenous cholesterol and other lipids

Question 5

inflammation and other diseases

Answer 5

Some forms of chronic inflammation may be important in the pathogenesis of diseases that are not conven­tionally thought of as inflammatory disorders.

These include neurodegenerative diseases such as Alzheimer disease, metabolic syndrome and the associated type 2 diabetes, and certain cancers in which inflammatory reactions promote tumor development.

Question 6

morphologic features of chronic inflammation

Answer 6

Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells

Tissue destruction, induced by the persistent offending agent or by the inflammatory cells

Attempts at healing by connective tissue replacement of damaged tissue, accomplished by angiogenesis (proliferation of small blood vessels) and, in particular, fibrosis

Question 7

Cells and Mediators of Chronic Inflammation

Answer 7

The combination of leukocyte infiltration, tissue damage, and fibrosis characterize chronic inflammation

Question 8

Role of Macrophages

Answer 8

The dominant cells in most chronic inflammatory reactions are macrophages, which contribute to the reaction by secreting cytokines and growth factors that act on various cells, by destroying foreign invaders and tissues, and by activating other cells, notably T lymphocytes

Macrophages are tissue cells derived from hematopoietic stem cells in the bone marrow and from progenitors in the embryonic yolk sac and fetal liver during early development

Question 9

two major pathways of macrophage activation

Answer 9

classical and alternative

Question 10

Classical macrophage activation

Answer 10

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 ROS and upregulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation.

Question 11

alternative macrophage activation

Answer 11

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 and the cytokines may actually inhibit the classical activation pathway; instead, the principal function of alternatively activated (M2) macrophages is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis.

Question 12

The products of activated macrophages eliminate injurious agents such as microbes and initiate the process of repair, but are also responsible for much of the tissue injury in chronic inflammation.

Answer 12

Macrophages, like the other type of phagocyte, the neutrophils, ingest and eliminate microbes and dead tissues.
Macrophages initiate the process of tissue repair and are involved in scar formation and fibrosis.
Macrophages secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines, and others) and eicosanoids. Thus, macrophages are central to the initiation and propagation of inflammatory reactions.
Macrophages display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that is essential for defense against many microbes by cell-mediated immune responses.

Question 13

Role of lymphocytes

Answer 13

Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation.

By virtue of their ability to secrete cytokines, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reaction

Question 14

Eosinophils

Answer 14

Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells. This is why eosinophils are of benefit in controlling parasitic infections, yet they also contribute to tissue damage in immune reactions such as allergies

Question 15

Mast cells

Answer 15

are widely distributed in connective tissues and participate in both acute and chronic inflammatory reactions. Mast cells express on their surface the receptor (FcεRI) that binds the Fc portion of IgE antibody. In immediate hypersensitivity reactions, IgE antibodies bound to the cells’ Fc receptors specifically recognize antigen, and the cells degranulate and release mediators, such as histamine and prostaglandins. This type of response occurs during allergic reactions to foods, insect venom, or drugs, sometimes with catastrophic results (e.g., anaphylactic shock).

Question 16

neutrophils in chronic inflammation

Answer 16

Although neutrophils are characteristic of acute inflammation, many forms of chronic inflammation, lasting for months, continue to show large numbers of neutrophils, induced either by persistent microbes or by mediators produced by activated macrophages and T lymphocytes. In chronic bacterial infection of bone (osteomyelitis), a neutrophilic exudate can persist for many months.

Question 17

Granulomatous Inflammation

Answer 17

• form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes
• sometimes associated with central necrosis.

Question 18

Two types of granulomas

Answer 18

foreign body and immune

Question 19

foreign body granulomas

Answer 19

Foreign body granulomas are incited by relatively inert foreign bodies, in the absence of T cell–mediated immune responses.
Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to preclude phagocytosis by a macrophage and do not incite any specific inflammatory or immune response. Epithelioid cells and giant cells are apposed to the surface of the foreign body. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in which it appears refractile.

Question 20

Immune granulomas

Answer 20

-caused by a variety of agents capable of inducing a persistent T cell–mediated immune response.

This type of immune response produces granulomas usually when the inciting agent is difficult to eradicate, such as a persistent microbe or a self antigen.
- macrophages activate T cells to produce cytokines, such as IL-2 –> activates other T cells, perpetuating the response, and IFN-γ, which activates the macrophages.

macrophage-activating cytokines (IL-4 or IFN-γ) transform the cells into epithelioid cells and multinucleate giant cells.

Question 21

Systemic Effects of Inflammation

Answer 21

Inflammation, even if it is localized, is associated with cytokine-induced systemic reactions that are collectively called the acute-phase response

The cytokines TNF, IL-1, and IL-6 are important mediators of the acute-phase reaction; other cytokines, notably type I interferons, also contribute to the reaction

Question 22

Fever

Answer 22

characterized by an elevation of body temperature, usually by 1° to 4°C, is one of the most prominent manifestations of the acute-phase response, especially when inflammation is associated with infection.

Substances that induce fever are called pyrogens. The increase in body temperature is caused by prostaglandins that are produced in the vascular and perivascular cells of the hypothalamus.

Question 23

acute-phase proteins

Answer 23

Acute-phase proteins are plasma proteins, mostly synthesized in the liver, whose plasma concentrations may increase several hundred-fold as part of the response to inflammatory stimuli.

Three of the best-known of these proteins are C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein.

Question 24

Fibrinogen

Answer 24

binds to red cells and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than do individual red cells. This is the basis for measuring the erythrocyte sedimentation rate as a simple test for an inflammatory response caused by any stimulus.

Question 25

elevated CRP

Answer 25

Elevated serum levels of CRP have been proposed as a marker for increased risk of myocardial infarction in patients with coronary artery disease. It is postulated that inflammation involving atherosclerotic plaques in the coronary arteries may predispose to thrombosis and subsequent infarction.

Question 26

hepcidin

Answer 26

Another pep­tide whose production is increased in the acute-phase response is the iron-regulating peptide hepcidin. Chronically elevated plasma concentrations of hepcidin reduce the availability of iron and are responsible for the anemia associated with chronic inflammation

Question 27

leukocytosis

Answer 27

common feature of inflammatory reactions, especially those induced by bacterial infections.

The leukocyte count usually climbs to 15,000 or 20,000 cells/mL, but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/mL.

Most bacterial infections –> increase in the blood neutrophil count, called neutrophilia.
Viral infections, such as infectious mononucleosis, mumps, and German measles, –> increase in the number of lymphocytes (lymphocytosis).
In some allergies and parasitic infestations, –> eosinophilia.
Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) –> decreased number of circulating white cells (leukopenia).

Question 28

Overview of tissue repair

Answer 28

restoration of tissue architecture and function after an injury

Two types of reactions:

• Regeneration by proliferation of residual (uninjured) cells
• Maturation of tissue stem cells, and the deposition of connective tissue to form a scar

Question 29

Cell and Tissue Regeneration

Answer 29

The regeneration of injured cells and tissues involves cell proliferation, which is driven by growth factors and is critically dependent on the integrity of the extracellular matrix, and by the development of mature cells from stem cells

Question 30

labile tissues

Answer 30

Labile (continuously dividing) tissues.

continuously being lost and replaced by maturation from tissue stem cells and by proliferation of mature cells.

include hematopoietic cells in the bone marrow and the majority of surface epithelia, such as the stratified squamous epithelia of the skin, oral cavity, vagina, and cervix; the cuboidal epithelia of the ducts draining exocrine organs (e.g., salivary glands, pancreas, biliary tract); the columnar epithelium of the gastrointestinal tract, uterus, and fallopian tubes; and the transitional epithelium of the urinary tract.

In labile tissues, such as the epithelia of the intestinal tract and skin, injured cells are rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells provided the underlying basement membrane is intact.
Loss of blood cells is corrected by proliferation of hematopoietic stem cells in the bone marrow and other tissues, driven by growth factors called colony-stimulating factors (CSFs), which are produced in response to the reduced numbers of blood cells.

Question 31

stable tissues

Answer 31

• quiescent (in the G0 stage of the cell cycle)
• have only minimal proliferative activity in their normal state.

However, these cells are capable of dividing in response to injury or loss of tissue mass. Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney, and pancreas.

Question 32

Permanent tissues

Answer 32

The cells of these tissues are considered to be terminally differentiated and nonproliferative in postnatal life. The majority of neurons and cardiac muscle cells belong to this category.

Question 33

tissue regeneration in parenchymal organs

Answer 33

Tissue regeneration can occur in parenchymal organs with stable cell populations, but with the exception of the liver, this is usually a limited process. Pancreas, adrenal, thyroid, and lung have some regenerative capacity. The surgical removal of a kidney elicits in the remaining kidney a compensatory response that consists of both hypertrophy and hyperplasia of proximal duct cells. The mechanisms underlying this response are not understood, but likely involve local production of growth factors and interactions of cells with the ECM. The extraordinary capacity of the liver to regenerate has made it a valuable model for studying this process

Question 34

liver regeneration

Answer 34

The human liver has a remarkable capacity to regenerate, as demonstrated by its growth after partial hepatectomy

Regeneration of the liver occurs by two major mechanisms: proliferation of remaining hepatocytes and repopulation from progenitor cells

Proliferation of hepatocytes following partial hepatectomy. In humans, resection of up to 90% of the liver can be corrected by proliferation of the residual hepatocytes.

Liver regeneration from progenitor cells.
In situations where the proliferative capacity of hepatocytes is impaired, such as after chronic liver injury or inflammation, progenitor cells in the liver contribute to repopulation. In rodents, these progenitor cells have been called oval cells because of the shape of their nuclei. Some of these progenitor cells reside in specialized niches called canals of Hering, where bile canaliculi connect with larger bile ducts.

Question 35

Repair by Connective Tissue Deposition

Answer 35

If repair cannot be accomplished by regeneration alone it occurs by replacement of the injured cells with connective tissue, leading to the formation of a scar, or by a combination of regeneration of some residual cells and scar formation

Question 36

Steps in scar formation

Answer 36

angiogenesis
formation of granulation tissue
Remodeling of connective tissue.

Macrophages play a central role in repair by clearing offending agents and dead tissue, providing growth factors for the proliferation of various cells, and secreting cytokines that stimulate fibroblast proliferation and connective tissue synthesis and deposition

Repair begins within 24 hours of injury by the emi­gration of fibroblasts and the induction of fibroblast and endothelial cell proliferation. By 3 to 5 days, the specialized granulation tissue that is characteristic of healing is apparent

Question 37

angiogenesis

Answer 37

Angiogenesis is the formation of new blood vessels, which supply nutrients and oxygen needed to support the repair process. Newly formed vessels are leaky because of incom­plete interendothelial junctions and because VEGF, the growth factor that drives angiogenesis, increases vascular permeability. This leakiness accounts in part for the edema that may persist in healing wounds long after the acute inflammatory response has resolved.

Question 38

Formation of granulation tissue.

Answer 38

Migration and proliferation of fibroblasts and deposition of loose connective tissue, together with the vessels and interspersed leukocytes, form granulation tissue. The term granulation tissue derives from its pink, soft, granular gross appearance, such as that seen beneath the scab of a skin wound.

Question 39

Remodeling of connective tissue.

Answer 39

Maturation and reorganization of the connective tissue (remodeling) produce the stable fibrous scar. The amount of connective tissue increases in the granulation tissue, eventually resulting in the formation of a scar, which may remodel over time

Question 40

steps of angiogenesis

Answer 40

Vasodilation in response to nitric oxide and increased permeability induced by vascular endothelial growth factor (VEGF)

Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout

Migration of endothelial cells toward the area of tissue injury

Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells

Remodeling into capillary tubes

Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel

Suppression of endothelial proliferation and migration and deposition of the basement membrane

Question 41

Deposition of Connective Tissue

Answer 41

The laying down of connective tissue occurs in two steps:
Migration and proliferation of fibroblasts into the site of injury
Deposition of ECM proteins produced by these cells.

Transforming growth factor-β (TGF-β) is the most important cytokine for the synthesis and deposition of connective tissue proteins

Question 42

Remodeling of Connective Tissue

Answer 42

The outcome of the repair process is influenced by a balance between synthesis and degradation of ECM proteins

The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases (MMPs), so called because they are dependent on metal ions (e.g., zinc) for their activity

Question 43

factors that influence tissue repair: infection

Answer 43

Infection is clinically one of the most important causes of delay in healing; it prolongs inflammation and potentially increases the local tissue injury

Question 44

factors that influence tissue repair: diabetes

Answer 44

Diabetes is a metabolic disease that compromises tissue repair for many reasons, and is one of the most important systemic causes of abnormal wound healing

Question 45

factors that influence tissue repair: nutrition

Answer 45

Nutritional status has profound effects on repair; protein deficiency, for example, and particularly vitamin C deficiency, inhibits collagen synthesis and retards healing.

Question 46

factors that influence tissue repair: glucocorticoids

Answer 46

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, the anti-inflammatory 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 collagen deposition.

Question 47

factors that influence tissue repair; mechanical

Answer 47

Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart, or dehisce.

Question 48

factors that influence tissue repair: poor perfusion, foreign bodies

Answer 48

Poor perfusion, due either to arteriosclerosis and diabetes or 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

Question 49

type and extent of tissue injury

Answer 49

The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of stable and labile cells; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function. Injury to tissues composed of permanent cells must inevitably result in scarring with, at most, attempts at functional compensation by the remaining viable elements. Such is the case with healing of a myocardial infarct.

Question 50

location of injury

Answer 50

location and character of the tissue in which the injury occurs are also important.
Example, inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities) —> 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, the exudate undergoes organization: granulation tissue grows into the exudate, and a fibrous scar ultimately forms

Question 51

Healing by First Intention

Answer 51

Only the epithelial layer? repair is epithelial regeneration (= primary union or healing by first intention)

Wounding –> rapid activation of coagulation pathways, –> blood clot on the wound surface

Within 24 hours, neutrophils at the incision margin, migrating toward the fibrin clot.

By day 3, neutrophils have been largely replaced by macrophages, granulation tissue progressively invades the incision space.

By day 5, neovascularization reaches its peak as granulation tissue fills the incisional space.

During the second week, there is continued collagen accumulation and fibroblast proliferation.

By the end of the first month, the scar comprises a cellular connective tissue largely devoid of inflammatory cells and covered by an essentially normal epidermis.

Question 52

Healing by 2nd intention

Answer 52

When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring

Question 53

secondary healing

Answer 53

When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring

At first a provisional matrix containing fibrin, plasma fibronectin, and type III collagen is formed, but in about 2 weeks this is replaced by a matrix composed primarily of type I collagen. Ultimately, the original granulation tissue scaffold is converted into a pale, avascular scar, composed of spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components.** The dermal appendages that have been destroyed in the line of the incision are permanently lost. ** The epidermis recovers its normal thickness and architecture. By the end of the first month, the scar is made up of acellular connective tissue devoid of inflammatory infiltrate, covered by intact epidermis.

Question 54

Wound contraction

Answer 54

Wound contraction generally occurs in large surface wounds. The contraction helps to close the wound by decreasing the gap between its dermal edges and by reducing the wound surface area. Hence, it is an important feature in healing by secondary union.

The initial steps of wound contraction involve the formation, at the edge of the wound, of a network of myofibroblasts, which are modified fibroblasts exhibiting many of the ultrastructural and functional features of contractile smooth muscle cells. Within 6 weeks, large skin defects may be reduced to 5% to 10% of their original size, largely by contraction.

Question 55

Wound Strength

Answer 55

Carefully sutured wounds have approximately 70% of the strength of normal skin, largely because of the placement of sutures.

When sutures are removed, usually at 1 week, wound strength is approximately 10% of that of unwounded skin, but this increases rapidly over the next 4 weeks. The recovery of tensile strength results from the excess of collagen synthesis over collagen degradation during the first 2 months of healing, and, at later times, from structural modifications of collagen fibers (cross-linking, increased fiber size) after collagen synthesis ceases.

Wound strength reaches approximately 70% to 80% of normal by 3 months but usually does not substantially improve beyond that point.

Question 56

Abnormalities in Tissue Repair

Answer 56

Inadequate formation of granulation tissue or formation of a scar can lead to two types of complications: wound dehiscence and ulceration

Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids

Exuberant granulation

Contraction in the size of a wound is an important part of the normal healing process