Chronic Inflammation Causes Symptoms And Treatment

Chronic Inflammation — Types And General Features

Chronic inflammation is defined as a long-lasting inflammatory response in which tissue destruction and inflammation occur at the same time.

Chronic inflammation may occur by one of the following 3 ways:

• Chronic inflammation following acute inflammation: When the tissue destruction in acute inflammation is extensive, or the bacteria survive and persist in small numbers at the site of acute inflammation, it may progress to chronicity for example, Acute osteomyelitis progressing to chronic osteomyelitis, pneumonia terminating in lung abscess.

Read And Learn More: General Pathology Notes

• Recurrent attacks of acute inflammation: When repeated bouts of acute inflammation occur, it may culminate into chronicity of the process for example,In recurrent urinary tract infection leading to chronic pyelonephritis, repeated acute infection of gallbladder leading to chronic cholecystitis.
• Chronic inflammation starting de novo: Inflammatory response is chronic from the beginning when either the infection occurs with microbes of low pathogenicity (for example,Infection with Mycobacterium tuberculosis), or inflammation is due to immune-mediated injury (for example, In autoimmune diseases).

General Features And Types Of Chronic Inflammation:

Though there may be differences in chronic inflammatory response depending upon the tissue involved and causative organisms, there are some basic similarities amongst various types of chronic inflammation.

The following general features characterise any chronic inflammation:

Read And Learn More: General Pathology Notes

1. Mononuclear Cell Infiltration:

Chronic inflammatory lesions are infiltrated by mononuclear inflammatory cells like phagocytes and lymphoid cells. Phagocytes are represented by circulating monocytes, tissue macrophages, epithelioid cells and sometimes, multinucleated giant cells. The macrophages comprise the most important cells in chronic inflammation.

These may appear at the site of chronic inflammation from:

• Chemotactic factors and adhesion molecules for continued infiltration of macrophages
• Local proliferation of macrophages, and
• Longer survival of macrophages at the site of inflammation.

The blood monocytes on reaching the extravascular space transform into tissue macrophages. Besides the role of macrophages in phagocytosis, they may get activated in response to stimuli such as cytokines (lymphokines) and bacterial endotoxins.

On activation, macrophages release several biologically active substances, for example, Acid and Neutral proteases, oxygen-derived reactive metabolites and cytokines. These products bring about tissue destruction, neovascularisation and fibrosis.

Other chronic inflammatory cells include lymphocytes, plasma cells, eosinophils and mast cells. In chronic inflammation, lymphocytes and macrophages influence each other and release mediators of inflammation.

2. Tissue Destruction Or Necrosis:

Tissue destruction and necrosis are central features of most forms of chronic inflammatory lesions. This is brought about by activated macrophages which release a variety of biologically active substances e.g. proteases (elastase, collagenase, lipase), free radicals (reactive oxygen species, nitric oxide), cytokines (IL-1, IL-8, TNF-α), angiogenesis growth factor etc.

3. Proliferative Changes:

As a result of necrosis, the proliferation of small blood vessels and fibroblasts is stimulated resulting in the formation of inflammatory granulation tissue. Eventually, tissue repair by fibrosis and collagen takes place.

Major differences between acute and chronic inflammation: 

Systemic Effects Of Chronic Inflammation:

Chronic inflammation is associated with the following systemic features:

• Fever:  Invariably there is mild fever, often with loss of weight and weakness.
• Anaemia:  As discussed in Chapter 11, chronic inflammation is accompanied by anaemia of varying degrees.
• Leucocytosis:  As in acute inflammation, chronic inflammation is also accompanied by leucocytosis but generally there is relative lymphocytosis in these cases.
• ESR: ESR is elevated in all cases of chronic inflammation.
• Amyloidosis:  Long-term cases of chronic suppurative and destructive inflammation may develop secondary systemic (AA) amyloidosis.

Types Of Chronic Inflammation:

Based on etiologic agent and morphologic type of inflammatory response by the host, chronic inflammation is traditional of 2 types:

• Chronic Non-specific Inflammation:
  • When the irritant substance produces a non-specific chronic inflammatory reaction with the formation of granulation tissue and tissue repair by fibrosis, it is called chronic non-specific inflammation for example, Chronic osteomyelitis, chronic ulcer, lung abscess, anal fistulous tract etc.
  • Chronic suppurative inflammation is a variant form of non-specific chronic inflammatory response that combines features of chronic and acute inflammation, characterised by tissue destruction and infiltration predominantly by polymorphs with the formation of abscess (i.e. Chronic suppuration) for example, Actinomycosis.
  • Examples of chronic nonspecific inflammation in different organs are discussed in respective chapters of systemic pathology.
• Chronic Granulomatous Inflammation:
  • In this, the etiologic agent causes a characteristic morphologic tissue response by the formation of granulomas for example, Tuberculosis, leprosy, syphilis, actinomycosis, sarcoidosis etc.
  • Granuloma is defined as a circumscribed, tiny lesion, about 1 mm in diameter, composed predominantly of a collection of modified macrophages called epithelioid cells, and rimmed at the periphery by lymphoid cells.
  • The word ‘granuloma’ is derived from granule meaning circumscribed granule-like lesion, and -oma which is a suffix commonly used for true tumours but here it indicates a localised inflammatory mass or collection of macrophages.

Evolution Of Granuloma

The formation of granuloma is a type IV hypersensitivity reaction. It is a protective defence reaction by the host but eventually causes tissue destruction because of the persistence of the poorly digestible antigen for example, Mycobacterium tuberculosis, M. leprae, suture material, particles of talc etc.

The sequence in the evolution of granuloma is schematically and is briefly outlined below:

1. Engulfment by macrophages: Macrophages and monocytes engulf the antigen and try to destroy it. But since the antigen is poorly degradable, these cells fail to digest and degrade the antigen and instead undergo morphologic changes to transform into epithelioid cells.
2. CD4+ T cells:  Macrophages, being antigen-presenting cells, having failed to deal with the antigen, present it to CD4+ T lymphocytes. These lymphocytes get activated and elaborate lymphokines (IL-1, IL-2, interferon-γ, TNF-α).
3. Cytokines: Various cytokines formed by activated CD4+ T cells and cytokines produced by activated macrophages perform the following roles:

• • IL-1 and IL-2 stimulate the proliferation of more T cells.
  • Interferon-γ activates macrophages.
  • TNF-α promotes fibroblast proliferation and activates endothelium to secrete prostaglandins
    which have a role in vascular response in inflammation.
  • Growth factors (transforming growth factor-β, platelet-derived growth factor) elaborated by
    activated macrophages stimulate fibroblast growth.

Thus, a granuloma is formed having macrophages modified as epithelioid cells in the centre, with some interspersed multinucleate giant cells (Langhans’ and foreign body type), surrounded peripherally by lymphocytes (mainly T cells), and healing by fibroblasts or collagen depending upon the age of granuloma.

Morphology Of Granuloma:

In general, a granuloma has the following structural composition:

• Epithelioid cells:  These are so-called because of their epithelial cell-like appearance.  They are modified macrophages/histiocytes which are somewhat elongated cells having slipper-shaped nucleus. The nuclear chromatin of these cells is vesicular and lightly staining, while the cytoplasm is abundant, pale-staining with hazy outlines so that the cell membrane of adjacent epithelioid cells is closely apposed. Epitheliod cells are weakly phagocytic.

• Multinucleate giant cells:  Multinucleate giant cells are formed by the fusion of adjacent epithelioid cells and may have 20 or more nuclei. These nuclei may be arranged at the periphery like the horseshoe or as a ring or may be clustered at the two poles (Langhans’ giant cells), or they may be present centrally (foreign body giant cells). ‘ The former are commonly seen in tuberculosis while the latter are common in foreign body tissue reactions. Like epithelioid cells, these giant cells are weakly phagocytic.
• Lymphoid cells: As a cell-mediated immune reaction to antigen, the host response by lymphocytes (predominantly T cells) is integral to the composition of a granuloma. Plasma cells indicative of accelerated humoral immune response are present in some types of granulomas.

• Necrosis:  Necrosis may be a feature of some granulomatous conditions for example, Central caseation necrosis in tuberculosis, so called because of its dry cheese-like appearance.
• Fibrosis:  Fibrosis is a feature of healing by proliferating fibroblasts at the periphery of granuloma. The classical example of granulomatous inflammation is the tissue response to tubercle bacilli which is called tubercle seen in tuberculosis (described later). A fully-developed tubercle is about 1 mm in diameter with a central area of caseation necrosis, surrounded by epithelioid cells and one to several multinucleated giant cells (commonly Langhans’ type), surrounded at the periphery by lymphocytes and bounded by fibroblasts and fibrous tissue.

Chronic Inflammation — General Features And Type

• Chronic inflammation may result either following acute inflammation or after its recurrent= attacks or may be chronic from the beginning (for example, Tuberculosis, autoimmune diseases).
• In general, features of chronic inflammation are tissue infiltration by mononuclear cells, tissue destruction, proliferation of blood vessels and fibroblasts.
• Chronic inflammation may produce systemic features such as fever, anaemia, (AA) amyloidosis.
• Based on morphology and underlying etiologic agents, chronic inflammation is of 2 main types: chronic non-specific and chronic granulomatous type.
• Granulomatous inflammation is a special type of chronic inflammation characterised by the presence of granulomas. A granuloma is a circumscribed collection of epithelioid cells surrounded at the periphery by lymphocytes and may contain a few multinucleate giant cells.
• The formation of a granuloma is a host inflammatory response to a poorly degradable agent by eliciting delayed-type hypersensitivity (type IV reaction).
• Evolution of a granuloma involves engulfment of the invading agent by the macrophages, failure to degrade the antigen, morphologic change of macrophages to epithelioid cells, and incoming CD4+ T cells elaborate various cytokines which contribute to proliferation and activation of cells.
• A granuloma may have necrosis in the centre and eventually heals by fibrosis. Granulomatous diseases include infections (bacterial, fungal, parasitic) autoimmune inflammatory, and as a reaction to foreign bodies.