Inflammation and Repair

Inflammation and Repair

CHAPTER CONTENTS

OVERVIEW OF INFLAMMATION: DEFINITIONS AND GENERAL FEATURES

Inflammation is a response of vascularized tissues that delivers leukocytes and molecules of host defense from the circulation to sites of infection and cell damage. Although in common medical and lay parlance inflammation suggests a harmful reaction, it is actually a protective response that is essential for survival. It serves to rid the host of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues). The mediators of defense include phagocytic leukocytes, antibodies, and complement proteins. Most of these normally circulate in a resting state in the blood, where they are sequestered from tissues and unable to cause damage and from where they can be rapidly recruited to any site in the body when they are needed. Some of the cells involved in inflammatory responses also reside in tissues, where they function as sentinels on the lookout for threats. The process of inflammation delivers circulating cells and proteins to tissues and activates the recruited and resident cells as well as some soluble molecules, which then function to get rid of the harmful or unwanted substances. Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores. The suffix -itis after an organ denotes inflammation in that site, such as appendicitis, conjunctivitis, or meningitis.

The typical inflammatory reaction develops through a series of sequential steps:

· Recognition of the noxious agent that is the initiating stimulus for inflammation. The cells involved in inflammation (tissue-resident sentinel cells such as dendritic cells, phagocytes, and others) 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, 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 (e.g.,

complement proteins) 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 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).

Before discussing the mechanisms, functions, and pathology of the inflammatory response, it is useful to review some of its fundamental properties.

· Components of the inflammatory response. The major participants in the inflammatory reaction in tissues are blood vessels, leukocytes, and various plasma proteins. As will be discussed in more detail later, blood vessels respond to inflammatory stimuli by dilating and by increasing their permeability, enabling circulating proteins to enter the site of infection or tissue damage. In addition, the endothelium lining blood vessels changes, such that circulating leukocytes adhere and then migrate into the tissues. Leukocytes, once recruited, are activated and acquire the ability to ingest and destroy microbes and dead cells, as well as foreign bodies and other unwanted materials in the tissues.

· Acute and chronic inflammation. The distinction between acute and chronic inflammation was originally based on the duration of the reaction, but we now know that they differ in several ways. Acute inflammation is a rapid, often self-limited, response to offending agents that are readily eliminated, such as many bacteria and fungi, and dead cells. It typically develops within minutes or hours and is of short duration (several hours to a few days). It is characterized by the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils. If the offending stimulus is eliminated, the reaction subsides, and residual injury is repaired.

Chronic inflammation may follow acute inflammation or arise de novo. It is a response to agents that are difficult to eradicate, such as some bacteria (e.g., tubercle bacilli) and other pathogens (such as viruses and fungi), as well as self antigens and environmental antigens. Chronic inflammation is of longer duration and is associated with more tissue destruction and scarring (fibrosis). Sometimes, chronic inflammation may coexist with unresolved acute inflammation, for example, in peptic ulcers.

· Harmful consequences of inflammation. Protective inflammatory reactions to infections are often accompanied by local tissue damage and its associated signs and symptoms (e.g., pain and functional impairment). Typically, however, these harmful consequences are self-limited and resolve as the inflammation abates, leaving little or no permanent damage. In contrast, there are many diseases in which the inflammatory reaction is misdirected (e.g., against self tissues in autoimmune diseases), occurs against normally harmless environmental substances (e.g., in allergies), or is inadequately controlled. In these cases, the normally protective inflammatory reaction becomes the cause of the disease, and the damage it causes is the dominant feature. In clinical medicine, great attention is given to the injurious consequences of inflammation.

Listed are selected examples of diseases in which the inflammatory response plays a significant role in tissue injury. Some, such as asthma, can present with acute inflammation or a chronic illness with repeated bouts of acute exacerbation. These diseases and their pathogenesis are discussed in relevant chapters.

with antiinflammatory drugs, which ideally would control the harmful sequelae of inflammation yet not interfere with its beneficial effects. Inflammation also may contribute to a variety of diseases that are thought to be primarily metabolic, degenerative, or genetic, such as type two diabetes, Alzheimer disease, and cancer.

· Local and systemic inflammation. Most of this chapter focuses on the inflammatory response to a localized infection or tissue damage. Although even local reactions may have systemic manifestations (e.g., fever in the setting of bacterial or viral pharyngitis), the inflammation is largely confined to the site of infection or damage. In rare situations, such as some disseminated bacterial infections, the inflammatory reaction is systemic and causes widespread pathologic abnormalities. This reaction is called sepsis. Systemic inflammatory response syndrome is a sepsis-like syndrome not caused by microbial infections. It can be caused by burns, trauma, and pancreatitis.

Mediators of inflammation. The vascular and cellular reactions of inflammation are triggered by soluble factors that are produced by various cells or derived from plasma proteins and are generated or activated in response to the inflammatory stimulus. Microbes, necrotic cells (whatever the cause of cell death), and even hypoxia can trigger the elaboration of inflammatory mediators and thus elicit inflammation. Such mediators initiate and amplify the inflammatory response and determine its pattern, severity, and clinical and pathologic manifestations.