2. Intro
• Chronic inflammation is a response of prolonged duration (weeks or
months) in which inflammation, tissue injury, and repair coexist, in
varying combinations
• It may follow acute inflammation, as described earlier, or may begin
insidiously
• Sometimes progressive, process without any signs of a preceding
acute reaction.
3. Causes of Chronic Inflammation
• Persistent infections by microorganisms that are difficult to eradicate,
such as mycobacteria and certain viruses, fungi, and parasites
• Chronic inflammation plays an important role in a group of diseases
that are caused by excessive and inappropriate activation of the
immune system
• Prolonged exposure to potentially toxic agents, either exogenous or
endogenous
4. Morphologic Features
• In contrast to acute inflammation, which is manifested by vascular
changes, edema, and predominantly neutrophilic infiltration,
Chronic inflammation is characterized by the following:
• Infiltration with mononuclear cells
• Tissue destruction
• Attempts at healing
5. Cells and Mediators
• The dominant cells in most chronic inflammatory reactions are
macrophages, which contribute to the reaction by secreting cytokines
and growth factors
• 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
• Circulating cells of this lineage are known as monocytes.
• Macrophages are normally diffusely scattered in most connective
tissues
8. Role of Lymphocytes
• Microbes and other environmental antigens activate T and B
lymphocytes, which amplify and propagate chronic inflammation
• These cells are often present in chronic inflammation and, when they
are activated, the inflammation tends to be persistent and severe
• Lymphocytes may be the dominant population in the chronic
inflammation seen in autoimmune and other hypersensitivity
diseases
• By virtue of their ability to secrete cytokines, promote inflammation
and influence the nature of the inflammatory reaction
10. Other Cells
• Eosinophils are abundant in immune reactions mediated by IgE and in
parasitic infections
• Mast cells are widely distributed in connective tissues and participate
in both acute and chronic inflammatory reactions
• 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 cytokines and other
mediators produced by activated macrophages and T lymphocytes
11. Granulomatous Inflammation
• Granulomatous inflammation is a form of chronic inflammation
characterized by collections of activated macrophages, often with T
lymphocytes, and sometimes associated with central necrosis
• The activated macrophages may develop abundant cytoplasm and
begin to resemble epithelial cells, and are called epithelioid cells
• Granuloma formation is a cellular attempt to contain an offending
agent that is difficult to eradicate
• There are two types of granulomas, Immune granulomas and Foreign
body granulomas
14. Cell and Tissue Regeneration
• 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.
• The ability of tissues to repair themselves is determined, in part, by
their intrinsic proliferative capacity
• Cell proliferation is driven by signals provided by growth factors and
from the extracellular matrix
• Growth factors are typically produced by cells near the site of damage
15. Mechanisms of Tissue Regeneration
• The importance of regeneration in the replacement of injured tissues
varies in different types of tissues and with the severity of injury
• Tissue regeneration can occur in parenchymal organs whose cells are
capable of proliferation, but with the exception of the liver, this is
usually a limited process
• Regeneration of the liver occurs by two major mechanisms:
proliferation of remaining hepatocytes and repopulation from
progenitor cells
16. Repair by Scarring
• 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
• Scarring may happen if the tissue injury is severe or chronic and
results in damage to parenchymal cells and epithelia as well as to the
connective tissue framework, or if nondividing cells are injured
18. Angiogenesis
• Angiogenesis is the process of new blood vessel development from
existing vessels.
• Induced by VEGF
• It is critical in healing at sites of injury, in the development of
collateral circulations at sites of ischemia and in allowing tumors to
increase in size beyond the constraints of their original blood supply
20. Factors That Impair Tissue Repair
• Tissue repair may be impaired by a variety of factors that reduce the
quality or adequacy of the reparative process.
• Infection
• Diabetes
• Nutritional status
• Glucocorticoids (steroids)
• Mechanical factors
• Poor perfusion
• Foreign bodies
• The type and extent of tissue injury
The inflammatory response sometimes takes a specific pattern called granulomatous inflammation (discussed later). In other cases, unresolved acute inflammation evolves into chronic inflammation, such as when an acute bacterial infection of the lung progresses to a chronic lung abscess
In autoimmune diseases, self (auto) antigens evoke a self-perpetuating immune reaction that results in chronic inflammation and tissue damage; examples of such diseases are rheumatoid arthritis and multiple sclerosis. In allergic diseases, chronic inflammation is the result of excessive immune responses against common environmental substances, as in bronchial asthma. Because these autoimmune and allergic reactions are triggered against antigens that are normally harmless, the reactions serve no useful purpose and only cause disease
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 professional phagocytes that act as filters for particulate matter, microbes, and senescent cells
They also function as effector cells that eliminate microbes in cellular and humoral immune responses
found in specific locations in organs such as the liver (where they are called Kupffer cells), spleen and lymph nodes (sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages). Together these cells comprise the mononuclear phagocyte system, also known by the older (and inaccurate) name of reticuloendothelial system
In inflammatory reactions, progenitors in the bone marrow give rise to monocytes, which enter the blood, migrate into various tissues, and differentiate into macrophages. Entry of blood monocytes into tissues is governed by the same factors that are involved in neutrophil emigration, such as adhesion molecules and chemokines. The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years. Thus, macrophages often become the dominant cell population in inflammatory reactions within 48 hours of onset. The macrophages that reside in tissues in the steady state (in the absence of tissue injury or inflammation), such as microglia, Kupffer cells, and alveolar macrophages, arise from the yolk sac or fetal liver very early in embryogenesis, populate the tissues, stay for long periods, and are replenished mainly by the proliferation of resident cells.
There are two major pathways of macrophage activation, called classical and alternative (Fig. 3.19). Which of these two pathways is taken by a given macrophage depends on the nature of the activating signals. • Classical macrophage activation may be induced by microbial products such as endotoxin, which engage TLRs and other sensors, and by T cell–derived signals importantly the cytokine IFN-γ, in immune responses. 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. These macrophages are important in host defense against microbes and in many inflammatory reactions. • 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, 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
It seems plausible that in response to most injurious stimuli, the first activation pathway is the classical one, designed to destroy the offending agents, and this is followed by alternative activation, which initiates tissue repair. However, such a precise sequence is not well documented in most inflammatory reactions
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
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. These interactions are described further in the discussion of the role of lymphocytes in chronic inflammation
These T cells greatly amplify the early inflammatory reaction that is induced by recognition of microbes and dead cells as part of the innate immune response. There are three subsets of CD4+ T cells that secrete different 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 into the reaction
Both TH1 and TH17 cells are involved in defense against many types of bacteria and viruses and in autoimmune diseases. TH2 cells are important in defense against helminthic parasites and in allergic inflammation. These T cell
Lymphocytes and macrophages interact in a bidirectional way, and these interactions play an important role in propagating chronic inflammation (Fig. 3.20). Macrophages display antigens to T cells, express membrane molecules (called costimulators) that activate T cells, and produce cytokines (IL-12 and others) that also stimulate T cell responses (Chapter 5). Activated T lymphocytes, in turn, produce cytokines, described earlier, which recruit and activate macrophages, promoting more antigen presentation and cytokine secretion. The result is a cycle of cellular reactions that fuel and sustain chronic inflammation. 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. However, the specificity and even the importance of antibodies in most chronic inflammatory disorders are unclear
Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections (Fig. 3.21). Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cells. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also injures host epithelial cells. This is why eosinophils are of benefit in controlling parasitic infections, yet also contribute to tissue damage in immune reactions such as allergies
Mast cells arise from precursors in the bone marrow. They have many similarities with circulating basophils, but they do not arise from basophils, are tissue-resident, and therefore play more significant roles in inflammatory reactions in tissues than basophils do. Mast cells (and basophils) express on their surface the receptor FcεRI, which binds the Fc portion of IgE antibody. In immediate hypersensitivity reactions, IgE bound to the mast cells’ Fc receptors specifically recognizes antigen, and in response the cells degranulate and release mediators, such as histamine and prostaglandins
Some activated macrophages may fuse, forming multinucleate giant cells
In this attempt there is often strong activation of T lymphocytes leading to macrophage activation, which can cause injury to normal tissues
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 cannot be readily eliminated, 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
Foreign body granulomas are seen in response to 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 but are not immunogenic. Epithelioid cells and giant cells are apposed to the surface of the foreign body
Granulomas are encountered in certain specific pathologic states; recognition of the granulomatous pattern is important because of the limited number of conditions (some life threatening) that cause it
In the setting of persistent T cell responses to certain microbes (e.g., M. tuberculosis, Treponema pallidum, or fungi), T cell– derived cytokines are responsible for chronic macrophage activation and granuloma formation. Granulomas may also develop in some immune-mediated inflammatory diseases, notably Crohn disease, which is one type of inflammatory bowel disease and an important cause of granulomatous inflammation in the United States, and in a disease of unknown etiology called sarcoidosis. Tuberculosis is the prototype of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified.
In this disease the granuloma is referred to as a tubercle. The morphologic patterns in the various granulomatous diseases may be sufficiently different to allow a reasonably accurate diagnosis
Critical to the survival of an organism is the ability to repair the damage caused by toxic insults and inflammation. In fact, the inflammatory response to microbes and injured tissues not only serves to eliminate these dangers but also sets into motion the process of repair. Repair of damaged tissues occurs by two types of reactions: regeneration by proliferation of residual (uninjured) cells and maturation of tissue stem cells, and the deposition of connective tissue to form a scar
Regeneration. Some tissues are able to replace the damaged components and essentially return to a normal state; this process is called regeneration. Regeneration occurs by proliferation of cells that survive the injury and retain the capacity to proliferate, for example, in the rapidly dividing epithelia of the skin and intestines, and in some parenchymal organs, notably the liver
Connective tissue deposition (scar formation). If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that may result in formation of a scar
In some tissues (sometimes called labile tissues), cells are constantly being lost and must be continually replaced by new cells that are derived from tissue stem cells and rapidly proliferating immature progenitors. These types of tissues include hematopoietic cells in the bone marrow and many surface epithelia, such as the basal layers of the 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
Other tissues (called stable tissues) are made up of cells that are normally in the G0 stage of the cell cycle and hence not proliferating, but they are capable of dividing in response to injury or loss of tissue mass. These tissues include the parenchyma of most solid organs, such as liver, kidney, and pancreas. Endothelial cells, fibroblasts, and smooth muscle cells are also normally quiescent but can proliferate in response to growth factors, a reaction that is particularly important in wound healing
Some tissues (called permanent tissues) consist of terminally differentiated nonproliferative cells, such as the majority of neurons and cardiac muscle cells. Injury to these tissues is irreversible and results in a scar, because the cells cannot regenerate. Skeletal muscle cells are usually considered nondividing, but satellite cells attached to the endomysial sheath provide some regenerative capacity for muscle
The most important sources of these growth factors are macrophages that are activated by the tissue injury, but epithelial and stromal cells also produce some of these factors. Several growth factors bind to ECM proteins and are displayed at the site of tissue injury at high concentrations. All growth factors activate signaling pathways that ultimately induce changes in gene expression that drive cells through the cell cycle and support the biosynthesis of molecules and organelles that are needed for cell division
In epithelia of the intestinal tract and skin, injured cells are rapidly replaced by proliferation of residual cells and differentiation of cells derived from tissue stem cells, providing the underlying basement membrane is intact. The residual epithelial cells produce the growth factors involved in these processes
The newly generated cells migrate to fill the defect created by the injury, and tissue integrity is restored
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. This process is driven by cytokines such as IL-6 produced by Kupffer cells, and by growth factors such as hepatocyte growth factor (HGF) produced by many cell types. • Liver regeneration from progenitor cells. In situations in which 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. The signals that drive proliferation of progenitor cells and their differentiation into mature hepatocytes are topics of active investigation.
The term scar is most often used in connection to wound healing in the skin, but also may be used to describe the replacement of parenchymal cells in any tissue by collagen, as in the heart after myocardial infarction.
Steps in Scar Formation
Repair by connective tissue deposition consists of a series of sequential steps that follow tissue injury (Fig. 3.24). • Within minutes after injury, a hemostatic plug comprised of platelets (Chapter 4) is formed, which stops bleeding and provides a scaffold for infiltrating inflammatory cells. • Inflammation. This step is comprised of the typical acute and chronic inflammatory responses. Breakdown products of complement activation, chemokines released from activated platelets, and other mediators produced at the site of injury function as chemotactic agents to recruit neutrophils and then monocytes during the next 6 to 48 hours. As described earlier, these inflammatory cells eliminate the offending agents, such as microbes that may have entered through the wound, and clear the debris. Macrophages are the central cellular players in the repair process—M1 macrophages clear microbes and necrotic tissue and promote inflammation in a positive feedback loop, and M2 macrophages produce growth factors that stimulate the proliferation of many cell types in the next stage of repair. As the injurious agents and necrotic cells are cleared, the inflammation resolves; how this inflammatory flame is extinguished in most situations of injury is still not well defined.
Steps in Scar Formation
Cell proliferation. In the next stage, which takes up to 10 days, several cell types, including epithelial cells, endothelial and other vascular cells, and fibroblasts, proliferate and migrate to close the now-clean wound. Each cell type serves unique functions. • Epithelial cells respond to locally produced growth factors and migrate over the wound to cover it. • Endothelial and other vascular cells proliferate to form new blood vessels, a process known as angiogenesis. Because of the importance of this process in physiologic host responses and in many pathologic conditions, it is described in more detail later. • Fibroblasts proliferate and migrate into the site of injury and lay down collagen fibers that form the scar. • The combination of proliferating fibroblasts, loose connective tissue, new blood vessels and scattered chronic inflammatory cells, forms a type of tissue that is unique to healing wounds and is called granulation tissue. This term derives from its pink, soft, granular gross appearance, such as that seen beneath the scab of a skin wound. • Remodeling. The connective tissue that has been deposited by fibroblasts is reorganized to produce the stable fibrous scar. This process begins 2 to 3 weeks after injury and may continue for months or years.
Healing of skin wounds can be classified into healing by first intention (primary union), referring to epithelial regeneration with minimal scarring, as in well-apposed surgical incisions, and healing by second intention (secondary union), referring to larger wounds that heal by a combination of regeneration and scarring.
Vasodilation in response to NO and increased permeability induced by 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
Growth factors. VEGFs, mainly VEGF-A (Chapter 1), stimulates both migration and proliferation of endothelial cells, thus initiating the process of capillary sprouting in angiogenesis. It promotes vasodilation by stimulating the production of NO and contributes to the formation of the vascular lumen. Fibroblast growth factors (FGFs), mainly FGF-2, stimulate the proliferation of endothelial cells. They also promote the migration of macrophages and fibroblasts to the damaged area, and stimulate epithelial cell migration to cover epidermal wounds.
Notch signaling. Through “cross talk” with VEGF, the Notch signaling 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. • ECM proteins participate in the process of vessel sprouting in angiogenesis, largely through interactions with integrin receptors of endothelial cells and by providing the scaffold for vessel growth. • Enzymes in the ECM, notably the matrix metalloproteinases (MMPs), degrade the ECM to permit remodeling and extension of the vascular tube
Activation of Fibroblasts and Deposition of Connective Tissue 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.
TGF-β is the most important cytokine for the synthesis and deposition of connective tissue proteins.
Remodeling of Connective Tissue After the scar is formed, it is remodeled to increase its strength and contract it. Wound strength increases because of cross-linking of collagen and increased size of collagen fibers. In addition, there is a shift of the type of collagen deposited, from type III collagen early in repair to more resilient type I collagen. In well-sutured skin wounds, strength may recover to 70% to 80% of normal skin by 3 months. Wound contraction is initially caused by myofibroblasts and later by cross-linking of collagen fibers
Infection is 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 an important systemic cause of abnormal wound healing. • Nutritional status has profound effects on repair; protein malnutrition and vitamin C deficiency, for example, inhibit collagen synthesis and retard healing. • Glucocorticoids (steroids) have well-documented antiinflammatory effects, and their administration may result in weak scars because they inhibit TGF-β production and diminish fibrosis. In some instances, however, the anti-inflammatory effects of glucocorticoids are desirable. For example, in corneal infections, glucocorticoids may be prescribed (along with antibiotics) to reduce the likelihood of opacity due to collagen deposition. • Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart (dehisce). • Poor perfusion, resulting either from arteriosclerosis and diabetes or from obstructed venous drainage (e.g., in varicose veins), also impairs healing. • Foreign bodies such as fragments of steel, glass, or even bone impede healing. • The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of cells capable of proliferating; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function. Injury to tissues composed of nondividing cells must inevitably result in scarring; such is the case with healing of a myocardial infarct. • The location of the injury and the character of the tissue in which the injury occurs also are important. For example, in inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities), small exudates may be resorbed and digested by the proteolytic enzymes of leukocytes, resulting in resolution of the inflammation and restoration of normal tissue architecture. However, when the exudate is too large to be fully resorbed it undergoes organization, a process during which granulation tissue grows into the exudate, and a fibrous scar ultimately forms
Excessive Scarring Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids. The accumulation of excessive amounts of collagen may result in a raised scar known as a hypertrophic scar. These often grow rapidly and contain abundant myofibroblasts, but they tend to regress over several months
