Inflammation and Repair - part 2 (Kumar Ch. 3)

Question 1

True or False

Chronic inflammation is always preceeded by acute inflammation

Answer 1

False
**It may follow acute inflammation or may begin insidiously, as a low-grade, smoldering response without any manifestations of a preceding acute reaction.

Question 2

Causes of chronic inflammation

Answer 2

1. Viral infections
2. Chronic infections
3. Persistent injury
4. Autoimmune diseases

Question 3

Morphologic features of acute inflammation

1. vascular changes
2. edema
3. predominantly neutrophilic infiltration

Answer 3

Morphologic features of chronic inflammation

1. Infiltration with mononuclear cells (macrophages, lymphocytes and plasma cells)
2. Tissue destruction
3. Angiogenesis and fibrosis

Question 4

Role of macrophages in chronic inflammation

**The dominant cells in most chronic inflammatory reactions are macrophages

Answer 4

1. Secrete cytokines and growth factors that act on various cells
2. destroy foreign invaders and tissues
3. activate other cells (T lymphocytes)

Question 5

mononuclear phagocyte

system

Answer 5

1. Kupffer cells (liver)
2. sinus histiocytes (spleen and lymph)
3. Microglial cells (central nervous system)
4. Alveolar macrophages (lungs)

Question 6

Classical macrophage activation (M1)
Induced by:
1. microbial products such as endotoxin, which engage TLRs and other sensors
2. T cell–derived signals
3. IFN-γ
4. immune responses
5. foreign substances

Answer 6

effects:

1. produce NO and ROS
2. upregulate lysosomal enzymes
3. secrete cytokines that stimulate inflammation

Question 7

Alternative macrophage activation (M2)
Induced by:
cytokines other than IFN-γ (IL-4 and IL-13)

Answer 7

effects:

1. tissue repair
2. secrete growth factors that promote angiogenesis
3. stimulate collagen synthesis

Question 8

REMEMBER

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

Answer 8

Although the major function of these lymphocytes is as the mediators of adaptive immunity, which provides defense against infectious pathogens, these cells are often present in chronic inflammation

Question 9

three subsets of CD4+ T cells that secrete different types of cytokines and elicit different types of inflammation.

Answer 9

• TH1 cells produce the cytokine IFN-γ, which activates macrophages by the classical pathway.
• TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.
• TH17 cells secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils (and monocytes) into the reaction.

Question 10

TH1 and TH17 - involved in defense against many types of bacteria and viruses and in autoimmune diseases
TH2 - mportant in defense against helminthic parasites and in allergic inflammation
Eosinophils - abundant in immune reactions mediated by IgE and in parasitic infections (major basic protein)

Answer 10

Mast cells - widely distributed in connective tissues and participate in both acute and chronic inflammatory reactions.
neutrophils - although characteristic of acute inflammation, many forms of chronic inflammation, lasting for months, continue to show large numbers of neutrophils

Question 11

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

Answer 11

Granulomatous inflammation

**Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate

Question 12

two types of granulomas, which differ in their pathogenesis

Answer 12

1. Foreign body granulomas - incited by relatively inert foreign bodies, in the absence of T cell–mediated immune responses.
2. Immune granulomas - caused by a variety of agents that are capable of inducing a persistent T cell–mediated
   immune response.

Question 13

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

Answer 13

These changes are reactions to cytokines whose production is stimulated by bacterial products such as LPS and by other inflammatory stimuli. 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 14

The acute-phase response consists of several clinical and pathologic changes:

Answer 14

1. Fever
2. Acute-phase proteins
3. Leukocytosis

Question 15

The ability of tissues to repair themselves is determined, in part, by their intrinsic proliferative capacity. Based on this criterion, the tissues of the body are divided into three groups

Answer 15

1. Labile (continuously dividing) tissues
   - hematopoietic cells, stratified squamous epith, the cuboidal epithelia of the ducts draining exocrine organs, columnar epithelium of the gastrointestinal tract and transitional epith of urinary tract
2. Stable tissues
   - Cells of these tissues are quiescent (in the G0 stage of the cell cycle) and have only minimal proliferative activity in their normal state
   - these cells are capable of dividing in response to injury or loss of tissue mass
   - liver, kidney, and pancreas
3. Permanent tissues
   - neurons and cardiac muscle cells

Question 16

Regeneration of the liver occurs by two major mechanisms:

Answer 16

1. proliferation of remaining hepatocytes

2. repopulation from progenitor cells

Question 17

REMEMBER
Hepatocyte proliferation in the regenerating liver is triggered by the combined actions of cytokines and polypeptide growth factors. The process occurs in distinct stages:

Answer 17

1. priming phase - cytokines such as IL-6 are produced mainly by Kupffer cells and act on hepatocytes to make the parenchymal cells competent to receive and respond to growth factor signals.
2. growth factor phase - HGF and TGF-α act on primed hepatocytes to stimulate cell metabolism and entry of the cells into the cell cycle
3. termination phase - hepatocytes return to quiescence

Question 18

Steps in scar formation

1. angiogenesis
2. formation of granulation tissue
3. remodeling of connective tissue

Answer 18

angiogenesis - formation of new blood vessels
formation of granulation tissue - Migration and proliferation of fibroblasts and deposition of loose connective tissue, together with the vessels and interspersed leukocytes, form granulation tissue

Question 19

Steps in angiogenesis

Answer 19

1. vasodilation in response to nitric oxide and increased permeability induced by vascular endothelial growth factor (VEGF)
2. Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout
3. Migration of endothelial cells toward the area of tissue injury
4. Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells
5. Remodeling into capillary tubes
6. Recruitment of periendothelial cells
7. Suppression of endothelial proliferation and migration and deposition of the basement membrane.

Question 20

Through “cross-talk” with VEGF, this pathway regulates the sprouting and branching of new vessels and thus ensures that the new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood.

Answer 20

notch signaling

Question 21

Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation. Although the major function of these lymphocytes is as the mediators of adaptive immunity, which provides defense against infectious pathogens, these cells are often present in chronic inflammation and when they are activated, the inflammation tends to be persistent and severe.

Answer 21

Some of the strongest chronic inflammatory reactions, such as granulomatous inflammation, described later, are dependent on lymphocyte responses. Lymphocytes may be the dominant population in the chronic inflammation seen in autoimmune and other hypersensitivity diseases.

Question 22

Antigen-stimulated (effector and memory) T and B lymphocytes use various adhesion molecule pairs (selectins, integrins and their ligands) and chemokines to migrate into inflammatory sites.

Answer 22

Cytokines from activated macrophages, mainly TNF, IL-1, and chemokines, promote leukocyte recruitment, setting the stage for persistence of the inflammatory response.

Question 23

By virtue of their ability to secrete cytokines, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reaction. These T cells greatly amplify the early inflammatory reaction that is induced by recognition of microbes and dead cells as part of innate immunity.

Answer 23

There are three subsets of CD4+ T cells that secrete different types of cytokines and elicit different types of inflammation.
• TH1 cells produce the cytokine IFN-γ, which activates macrophages by the classical pathway.
• TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.
• TH17 cells secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils (and monocytes) into the reaction.

Question 24

Activated B lymphocytes and antibody-producing plasma cells are often present at sites of chronic inflammation. The antibodies may be specific for persistent foreign or self antigens in the inflammatory site or against altered tissue components.

Answer 24

In some chronic inflammatory reactions, the accumulated lymphocytes, antigen-presenting cells, and plasma cells cluster together to form lymphoid tissues resembling lymph nodes. These are called tertiary lymphoid organs; this type of lymphoid organogenesis is often seen in the synovium of patients with long-standing rheumatoid arthritis and in the thyroid in Hashimoto thyroiditis

Question 25

Granulomatous inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis

Answer 25

Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate. In this attempt there is often strong activation of T lymphocytes leading to macrophage activation, which can cause injury to normal tissues. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called epithelioid cells. Some activated macrophages may fuse, forming multinucleate giant cells.

Question 26

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.

Answer 26

Immune granulomas are caused by a variety of agents that are 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. In such responses, macrophages activate T cells to produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-γ, which activates the macrophages.

Question 27

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

Answer 27

Synthesis of these molecules in hepatocytes is stimulated by cytokines, especially IL-6 (for CRP and fibrinogen) and IL-1 or TNF (for SAA).

Question 28

Acute-phase proteins have beneficial effects during acute inflammation, but prolonged production of these proteins (especially SAA) in states of chronic inflammation causes secondary amyloidosis

Answer 28

Elevated serum levels of CRP have been proposed as a marker for increased risk of myocardial infarction in patients with coronary artery disease.

Question 29

Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia.

Viral infections, such as infectious mononucleosis, mumps, and German measles, cause an absolute increase in the number of lymphocytes (lymphocytosis).

Answer 29

In some allergies and parasitic infestations, there is an increase in the absolute number of eosinophils, creating an eosinophilia.

Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia).

Question 30

Other manifestations of the acute-phase response include increased pulse and blood pressure; decreased sweating, mainly because of redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin; rigors (shivering), chills, anorexia, somnolence, and malaise, probably because of the actions of cytokines on brain cells.

Answer 30

In severe bacterial infections (sepsis), the large amounts of bacteria and their products in the blood stimulate the production of enormous quantities of several cytokines, notably TNF and IL-1. High blood levels of cytokines cause various widespread clinical manifestations such as disseminated intravascular coagulation, hypotensive shock, and metabolic disturbances including insulin resistance and hyperglycemia. This clinical triad is known as septic shock

Question 31

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

Answer 31

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.

Question 32

The laying down of connective tissue occurs in two steps: (1) migration and proliferation of fibroblasts into the site of injury and (2) deposition of ECM proteins produced by these cells.

Answer 32

These processes are orchestrated by locally produced cytokines and growth factors, including PDGF, FGF-2, and TGF-β. The major sources of these factors are inflammatory cells, particularly alternatively activated (M2) macrophages, which are present at sites of injury and in granulation tissue.

Question 33

After its deposition, the connective tissue in the scar
continues to be modified and remodeled. 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. MMPs should be distinguished from neutrophil elastase, cathepsin G, plasmin, and other serine proteinases that can also degrade ECM but are not metalloenzymes

Answer 33

MMPs include interstitial collagenases, which cleave fibrillar collagen (MMP-1, -2 and -3); gelatinases (MMP-2 and 9), which degrade amorphous collagen and fibronectin; and stromelysins (MMP-3, -10, and -11), which degrade a variety of ECM constituents, including proteoglycans, laminin, fibronectin, and amorphous collagen.

Question 34

Healing by first intention
Within 24 hours, neutrophils are seen at the incision
margin, migrating toward the fibrin clot. They release
proteolytic enzymes that begin to clear the debris. Basal cells at the cut edge of the epidermis begin to show increased mitotic activity.

Answer 34

Within 24 to 48 hours, epithelial
cells from both edges have begun to migrate and
proliferate along the dermis, depositing basement membrane components as they progress. The cells meet in the midline beneath the surface scab, yielding a thin but continuous epithelial layer that closes the wound.

Question 35

Healing by first intention
By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space

Answer 35

By day 5, neovascularization reaches its peak as granulation tissue fills the incisional space. These new vessels are leaky, allowing the passage of plasma proteins and fluid into the extravascular space. Thus, new granulation tissue is often edematous.

Question 36

Restoration of normal tissue structure can occur only if the residual tissue is structurally intact, as after partial surgical resection.

Answer 36

By contrast, if the entire tissue is damaged by infection or inflammation, regeneration is incomplete and is accompanied by scarring.

Question 37

Repair by Connective Tissue Deposition
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.

Answer 37

Steps in Scar Formation

1. Angiogenesis
2. Formation of granulation tissue
3. Remodeling of connective tissue

Question 38

Healing by first intention
During the second week, there is continued collagen accumulation and fibroblast proliferation. The leukocyte infiltrate, edema, and increased vascularity are substantially diminished. The process of “blanching” begins, accomplished by increasing collagen deposition within the incisional scar and the regression of vascular channels.

Answer 38

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. However, the dermal appendages destroyed in the line of the incision are permanently lost. The tensile strength of the wound increases with time, as described later.