General Pathology

Theme 7: Chronic Inflammation

1. Explain the process of chronic inflammation.
2. Explain the process of granulomatous inflammation.
3. Identify the morphologic patterns in acute and chronic inflammation.
4. Identify the factors that can modify the inflammatory reaction
5. Discuss the sequelae and systemic effects of chronic and granulomatous inflammation.

Chronic inflammation can be defined as inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at healing may all be proceeding simultaneously. It arises in several ways:

• It may follow acute inflammation, either because of the persistence of the inciting stimulus or because of some interference in the normal process of healing.
• It may result from repeated bouts of acute inflammation.
• Most commonly, it begins insidiously as a low-grade, smoldering response that does not follow classic acute inflammation, in one of the following settings:
  1. Persistent infection by intracellular microbes (e.g., tubercle bacilli, viral infection), which are of low toxicity but evoke an immunologic reaction.
  2. Prolonged exposure to potentially toxic exogenous (e.g., silica and silicosis in the lung) or endogenous substances (e.g., plasma lipid components and atherosclerosis)
  3. Immune reactions, particularly those perpetuated against the individual's own tissues (e.g., autoimmune diseases)

• Infiltration with mononuclear cells, which include macrophages, lymphocytes and plasma cells, a reflection of a persistent reaction to injury.
• Tissue destruction, largely induced by the inflammatory cells.
• Attempts at repair by connective tissue replacement — proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis.

Processes of Chronic Inflammation

Although it is triggered at the time of injury, the immune response takes several days to develop because the nonsensitized lymphocytes that initially respond to antigens must pass through several division cycles before increased numbers of effector lymphocytes become manifest in the tissues. Simple uncomplicated acute inflammation usually resolves upon removal of antigen prior to any apparent tissue manifestation of the immune response.

Macrophages (monocytes) are recruited to the lesion from the blood by such chemotactic factors as C5a and TGFß. Local activation occurs under the influence of multiple cytokines, particularly g interferon and IL-4. Macrophages in turn release a variety of factors that perpetuate the developing immune response, including cytokines (IL-1, IL-6 and TNFa), complement components, prostaglandin and various growth factors such as FGF (fibroblast growth factor), PDGF (platelet-derived growth factor) and TGFß (transforming growth factor). Multiple proteases and hydrolases contribute to the phagocytic and microbicidal effect.

Granulomatous Inflammation

Granulomatous inflammation is a distinctive chronic inflammatory reaction in which the predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance. In the focus of inflammation (granuloma), microscopic aggregations of macrophages are transformed into epitheloid cells surrounded by collar of mononuclear leykocytes, principally lymphocytes and occasional plasma cells. Such epitheloid cells often fuse to form giant cells comprising of a large mass of cytoplasm with 20 or more small nuclei arranged peripherally in a horseshoe shape (Langhan's Giant Cell) or haphazardly (body-type).

• Granulomatous inflammation is encountered in a relatively few but widespread chronic immune and infectious diseases, such as tuberculosis, sarcoidosis and syphilis.
  Aetiology of Granulomatous disease
  1. Unknown • sarcoidosis (Crohn's disease) — affects many organs
  2. Infection • bacteria/parasites/fungi — TB, leprosy
  3. Inorganic foreign particles • silica, talc, abestos, oils, Berylium
  4. Organic foreign particles • pollens, grass seeds, mushroom spores
• Granulomatous inflammation is characterized by granulomas — focal collections of epithelioid macrophages that are surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells. Epithelioid cells may coalesce to form multinucleate giant cells. Central necrosis may also be present in some granulomas.
• There are two types of granulomas:
  1. Foreign body granulomas, incited by relatively inert foreign bodies.
  2. Immune granulomas, formed by immune T cell-mediated reactions to poorly degradable antigens. Lymphokines, principally IFN-g from activated T cells, cause transformation of macrophages to epithelioid cells and multinucleate giant cells. The prototype for the immune granuloma is that caused by the bacillus of tuberculosis. In this disease, the granuloma is referred to as a tubercle and is classically characterized by the presence of central caseous necrosis.

Inflammatory responses often have certain features that point to their possible cause and create distinctive morphologic patterns:

• Serous inflammation implies a modest increase in vascular permeability. It is marked by an accumulation of fluid, which, when it occurs in the peritoneal, pleural, and pericardial cavities, is called an effusion but can occur elsewhere (e.g., skin bum blisters).
• Fibrinous inflammation occurs when the injury causes a more marked increase in vascular permeability. The exudate contains large amounts of fibrinogen, which is converted to fibrin as a result of activation of the coagulation system. When a serosal surface is involved, such as the pericardium or pleura, it is referred to as fibrinous pericarditis or pleuritis.
• Suppurative or purulent inflammation is characterized by the production of purulent exudate or pus consisting of white cells and necrotic cells. An abscess refers to a localized collection of purulent inflammatory tissue that is accompanied by liquefactive necrosis (e.g., pyogenic staphylococcal abscesses).
• Pseudomembranous inflammation is characterised by a membranous film consisting mainly fibrin and necrotic cells mixed which forms on a mucosal surface (deep tissues not affected), especially on respiratory and alimentary tracts e.g. diptheria.
• Ulcers are local defects, or excavations, of the surface of an organ or tissue that are produced by the sloughing (shedding) of inflammatory necrotic tissue.
• Granulomatous inflammation is a distinctive inflammatory reaction as noted and has relatively few possible causes.

The major systemic manifestations of acute inflammation involve a wide range of endocrine, autonomic, and behavioral responses, as follows:

• Endocrine and metabolic: Secretion of acute-phase proteins by the liver (including C-reactive protein, serum amyloid A, complement, and coagulation proteins).
• Autonomic: A redirection in blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin; increased pulse and blood pressure; and decreased sweating.
• Behavioral: Rigors (shivering), chills (search for warmth), anorexia, somnolence, and malaise.

• The principal manifestation of fever is an elevation of body temperature, usually by 1 to 4°C.
• Cytokines play a key role in signaling a fever: IL-l, IL-6, and mF-a, produced by leukocytes in response to infectious agents or immunologic reactions, are released into the circulation. IL-l acts directly and also by inducing IL-6, which has essentially similar effects in producing the acute-phase responses. IL- I and TNF interact with vascular receptors in the thermoregulatory centers of the hypothalamus, inducing local prostaglandin E₂ production, resulting in sympathetic nerve stimulation, vaso- constriction of skin vessels, and fever.
• Leukocytosis (elevation in total white blood cell count) is a common feature of inflammatory reactions, especially those induced by bacterial infection. Extreme elevations are referred to as leukemoid reactions. The leukocytosis occurs because of the proliferation of precursors in the bone marrow and the accelerated release of cells from the bone marrow, induced by CSFs.
• Most bacterial infection induce neutrophilia (an increased number of polymorphonuclear leukocytes in the blood), but some viral infections (e.g., mononucleosis, mumps and German measles) produce a leukocytosis because of an absolute increase in the number of lymphocytes (lymphcytosis). In other disorders, there is an absolute increase in the number of eosinophils creating an eosinophilia (e.g., bronchial asthma, hay fever and parasitic infestations). Certain infections (typhoid fever and infections caused by viruses, rickettsiae and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia). Leukopenia is also encountered in infections that overwhelm patients debilitated by disseminated cancer.

Factors Modifying the Inflammatory Reaction