Chronic inflammation Dr. Mamlook Elmagraby
Objectives of the lecture: Upon completion of this lecture, students should be able to: Define chronic inflammation with emphasis on causes, nature of the inflammatory response, and tissue changes Compare and contrast the clinical settings in which different types of inflammatory cells (eosinophils, macrophages, lymphocytes) accumulate in tissues Describe the systemic manifestations of inflammation and their general physiology, including fever, leukocyte left shift, and acute phase reactants
Overview Chronic inflammation is a prolonged process in which destruction and inflammation are proceeding at the same time as attempts at healing This type of inflammation is characterized by an insidious onset and long duration Manifestations are NOT as dramatic as those of acute inflammation Chronic inflammation is characterized by: Infiltration with mononuclear cells Tissue destruction Repair Dramatic an event sudden and striking (attracting attention by reason of being extreme or prominent)
The evolution of Chronic inflammation (Causes) Acute inflammation may progress to chronic inflammation : The persistence of the injurious agent The interference with the normal process of healing Insidiously or de novo Persistent infection Prolonged exposure to non-degradable substances Immune reactions against common environmental substances Immune reactions develop against the individual's own tissues Insidious proceeding in a gradual, subtle way, but with harmful effects Evolution the gradual development of something, especially from a simple to a more complex form
Chronic Inflammatory Cells
Macrophages Macrophages are tissue cells derived from circulating blood monocytes after their emigration from the bloodstream The dominant cells in most chronic inflammatory reactions are macrophages The products of activated macrophages eliminate injurious agents such as microbes and initiate the process of repair Excessively activated macrophages can induce considerable tissue destruction (one of the characteristics of chronic inflammation)
Maturation of mononuclear phagocytes. During inflammatory reactions, the majority of tissue macrophages are derived from hematopoietic precursors. Some long-lived resident tissue macrophages are derived from embryonic precursors that populate the tissues early in development. (B)The morphology of a monocyte and activated macrophage
Mechanisms of macrophage accumulation in tissues Mechanisms of macrophage accumulation in tissues. The most important is continued recruitment from the microcirculation Macrophage Migration Inhibitory Factor
The roles of activated macrophages in chronic inflammation. Macrophages are activated by cytokines from immune-activated T cells (particularly IFN-γ) or by nonimmunologic stimuli such as endotoxin. The products made by activated macrophages that cause tissue injury and fibrosis are indicated. AA, arachidonic acid; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; TGFβ, transforming growth factor β.
T Lymphocytes T Lymphocytes emigrate from blood vessels late in an inflammatory reaction Activation of T cells is effected by cytokines (from macrophages) and directly by antigens Once activated, lymphocytes can react with certain antigens destroying them They also secrete cytokines that stimulate macrophages
The other Cells of Chronic Inflammation: B-Lymphocytes (Plasma Cells) Eosinophils Fibroblasts and Collagen Multinucleated Giant Cells
Macrophage–lymphocyte interactions in chronic inflammation Lymphocytes and macrophages interact in a bidirectional way: Macrophages Display antigens to T cells Express membrane molecules (costimulators) produce cytokines (IL-12) that stimulate T-cell responses Activated T lymphocytes produce cytokines (IFN-γ which activate macrophages, promoting more antigen presentation and cytokine secretion) These interactions play an important role in generating sustained chronic inflammation Bidirectional functioning in two directions Interaction reciprocal action
Macrophage–lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines)and others that activate macrophages (IFN-γ) Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines such as IL-12
Histological features of chronic inflammation Infiltration of mononuclear cells Tissue destruction Granulation tissue formation (fibroblasts and small blood vessels) Increased connective tissue (fibrosis)
Outcome of chronic inflammation Resolution: restoration of normal structure and function Healing by connective tissue (fibrosis or scarring) It can continue indefinitely Some disease processes are capable of continuing indefinitely such as rheumatoid arthritis
Acute inflammatory cells – Chronic Flush, Flare & Weal Little signs Acute inflammatory cells – Neutrophils Chronic inflammatory cells –Mononuclear cell Vascular damage Neo-vascularisation More exudation No/less exudation Little or no fibrosis Prominent fibrosis Comparison between acute and chronic inflammation
A, Chronic inflammation in the lung, showing all three characteristic histologic features: collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads) (3) replacement by connective tissue (fibrosis, arrows). B, By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested
Types Of Chronic Inflammation Histological features are used for classifying chronic inflammation into two types: Chronic non-specific inflammation It is characterized by non-specific inflammatory cell infiltration e.g. chronic osteomyelitis Chronic granulomatous inflammation It is characterized by formation of granulomas e.g. tuberculosis
Systemic Effects of Inflammation
Systemic Effects of Inflammation The cytokines TNF, IL-1, and IL-6 are the most important mediators of these systemic effects These cytokines are produced by leukocytes and released systemically In severe bacterial infections, the large amounts of organisms stimulate the excessive production of these cytokines, leading to septic shock Systemic effects of Inflammation consist of several clinical and pathologic changes
Fever (An elevation of body temperature) The most prominent signs especially when there is infection Exogenous pyrogens stimulate leukocytes to release endogenous pyrogens that increase the levels of cyclooxygenases Cyclooxygenases convert AA into prostaglandins (PG) In the hypothalamus the PGE2 stimulate the production of neurotransmitters Neurotransmitters reset the temperature set point at a higher level
Acute-phase proteins Plasma proteins, synthesized in the liver, whose concentrations increase as a response to inflammatory stimuli The most common acute-phase proteins are: C-reactive protein (CRP) Fibrinogen Serum amyloid A (SAA) protein Synthesis of these molecules by hepatocytes is up-regulated by cytokines (IL-6) Many acute-phase proteins, may act as opsonins, thus promoting the elimination of the microbes
Acute-phase proteins Fibrinogen Fibrinogen binds to erythrocytes and causes them to form masses that sediment more rapidly at than do individual erythrocytes This difference in erythrocyte sedimentation is the basis for measuring the erythrocyte sedimentation rate (ESR)
Leukocytosis A common feature of inflammatory reactions (especially those induced by bacterial infection) In the beginning of inflammatory response, the leukocytosis occurs due to accelerated release of cells from the bone marrow reserve This initial leukocytosis is usually associated with a rise in the number of more immature neutrophils in the blood (shift to the left) Later, colony-stimulating factors leads to increased bone marrow output of leukocytes Bone marrow reserve a storage pool of mature neutrophils in the bone marrow, which can be released as necessary shift to the left: a marked increase in the percentage of immature cells in the circulating blood, based on the premise in hematology that the bone marrow with its immature myeloid cells is on the left, whereas the circulating blood with its mature neutrophils is on the right
Leukocytosis Most bacterial infections induce neutrophilia Viral infections induce lymphocytosis Allergic diseases and parasite infestations induce eosinophilia