Chronic inflammation

Contents Definition Causes of chronic inflammation Process Mediators Types Facts of chronic inflammation Effects Diseases

Chronic InflammationChronic inflammation is a prolonged process (weeks-months-years) in which three processes are occurring simultaneously:

– Active inflammation

– Tissue destruction

– Tissue healing (repair & fibrosis)

Causes of chronic inflammationFollowing acute inflammation

– Persistence of the inciting stimulus

– Interruption of normal healing

• Repeated episodes of acute inflammation

• Low-grade inflammatory response (without a proper acute response) due to:

– Persistent infection by intracellular microbes (TB, some viruses)

– Agents that incite a low grade immune response (some fungal infections)

– Prolonged exposure to low grade, potentially toxic exogenous or endogenous substances.

– Self-directed immune reactions

ProcessInfiltration of mononuclear inflammatory cells (macrophages, lymphocytes & plasma cells.

• Tissue destruction due to persistent injury and inflammatory cells

• Attempts at healing by connective tissue replacement involving angiogenesis and fibrosis.

• Mononuclear cell infiltration

Inflammatory mediatorsMacrophages

Macrophages the dominant players in chronic inflammation

1. Derived from circulation monocytes they enter the extravascular tissue routinely and in response to chemo attractants, after extravasation they become active phagocytic macrophages.

2. Because of the numerous biologically active products secreted by macrophages they assume a central role in chronic inflammation

3. Macrophages can be activated by cytokines produced by activated T-cells and by no immune factors

4. Macrophage products are important for host defense but they can cause tissue damage. These products include ROS, NO metabolites and various proteases.

5. Macrophages release factors that stimulate fibroblast proliferation, connective tissue production and angiogenesis (fibrosis & scar formation).

6. Macrophage accumulation persists due to continued recruitment (and division) caused by ongoing production of adhesion molecules and chemotactic agents.

Lymphocytes – Mobilized in both antibody and cell mediated responses

– Respond to microbe produced endotoxin

– Activated lymphocytes activate other immune cells particularly macrophages which can in turn influence T- and B- cells (differentiation into plasma cells)lymphocytes

EosinophilEosinophils are characteristic of IgE mediated immune responses and parasitic infections. Recruitment depends on the production of eotaxin a specific eosinophil chemo attractant. Eosinophils possess MBP (major basic protein) which is toxic to parasites & epithelial cells. Remember the role of eosinophils in inactivating histamine (histaminase).

Mast cellsMast cells (basophils) are constitutively located in connective tissue and can be recruited in both acute and chronic inflammation. They bind the Fc portion of IgE which results in degranulation (histamine) capable of inciting anaphylaxis

Types of chronic inflammation1. Chronic Nonspecific Inflammation

2. Granulomatous Inflammation

Chronic Nonspecific Inflammation1. A preponderance of mononuclear cells (macrophages, lymphs, plasma cells) often with fibrosis and vascular proliferation.

2. Fibrosis (scarring) & distortion of tissue architecture.

3. Mediated by the interactions of mono/macrophages with lymphocytes

1. Cytokines from macrophages activate lymphocytes which produce cytokines activating macrophages (+ feedback loop)

2. B-cell activation occurs via macrophage presented antigens producing antigen specific plasma cell proliferation

Granulomatous Inflammation:A distinctive form of chronic inflammation characterized by focal accumulations

of activated macrophages (granulomas). The macrophages respond to activated T-cell produced γ-IFN to become enlarged and flattened forming epithelioid macrophages & multi-nucleate giant cells.1. Foci of epithelioid macrophages are surrounded by a collar of lymphocytes elaborating factors that promote macrophage activation. Macrophages may coalesce to form giant cells (Langerhans giant cells: multinucleate giant cells with nuclei arranged at periphery (indicative of TB infection)).2. Areas of central necrosis (caseous necrosis) may be present in infectious granulomas (Tb). The necrotic tissue consists of microbe-filled macrophages killed by T-lymphocytes, cytokines, activated macrophages.3. Foreign body granulomas are elicited by ~inert foreign bodies4. Immune granulomas are formed by T-cell mediated responses to persistent antigens.5. Granulomatous inflammation is a distinctive inflammatory reaction with a few important causes both infectious or noninfectious.

Facts of chronic inflammation

1. 3 Processes occurring simultaneously1. Acute inflammation

2. Tissue destruction

3. Tissue healing

2. Can occur:1. After inadequate acute inflammation (Incomplete)

2. Repeated acute inflammation (Interminable)

3. Low grade inflammatory response (Improper)

3. Cellular response:1. Acute (PMNs)

2. Chronic (macrophages, lymphocytes, plasma cells, eosinophils, mast cells)

3. Tissue destruction

4. Granuloma formation (giant cells, epitheliod cells)

5. Connective tissue response (fibrosis& angiogenesis)

6. Lymphatic system involvement

• Lymphatics in chronic Inflammation• Lymph vessels & nodes filter and monitor the extravascular fluid that fails to return to the post-capillary vasculature. They represent a second line of defense in conjunction with the mononuclear phagocytic system to agents not contained by local responses.

• Lymphatics in Inflammation

• Lymphatics are endothelial lined vessels with scant supporting structures that return extravasated plasma to the intravascular space. During inflammation lymph flow increases dramatically draining edema fluid, WBCs and cell debris.

• In severe injury/infection offending agents may be transported via the lymphatics leading to lymphangitis (vessel inflammation) and lymphadenitis (nodal inflammation).

• Severe infections that breach the lymphatic defense mechanisms can access the vascular system (bacteremia). Hepatic, splenic and marrow based phagocytes are another line of defense. Hematogenous spread with resulting foci of metastatic infection are the result of prodigious infections due to agent capabilities, size of insult or impaired response mechanisms.

Effect of chronic inflammation• The systemic changes associated with inflammation are collectively termed the acute phase response, when severe it is termed systemic inflammatory response syndrome (SIRS). It represents a systemic response to cytokines produced by the infectious agent itself and/or the inflammatory response.

1. Fever: a temperature elevation of 1-4°C produced by pyrogens. Pyrogens stimulate prostaglandin synthesis in the hypothalamus which through a 2nd messenger system results in a resetting of the temperature set point. ASA inhibits this response by blocking cyclooxygenase activity which blocks prostaglandin production

2. Acute-phase proteins are plasma proteins mostly hepatic in origin whose production can be increased several hundred fold in response to an inflammatory stimulus.

– A. C-reactive protein

– B. Serum amyloid A protein

– C. Fibrinogen

3. 2.A.+B. bind to microbial cell walls and act as opsonins and fix complement.

3. Leukocytosis is a common but not requisite feature of inflammation. It occurs by the accelerated release of WBC precursors from the marrow; as more mature forms are depleted immature forms appear in the peripheral blood (“left-shift”). Prolonged infection results in marrow proliferation through increased production of CSF (colony stimulating factor). Bacterial infections typically produce increases in PMNs while viral infections promote lymphocyte proliferation. Parasitic infections are associated with eosinophila

Sepsis (an overwhelming bacterial infection) the large number of microbes and endotoxin result in the production of large amounts of cytokines particularly TNF & IL-1. This results in the precipitous onset of septic shock (DIC, hypoglycemia and cardiovascular collapse) leading to MOSF.

• Systemic Effects of Inflammation1. Cardiovascular response:

1. ↑ HR & BP

2. ↓ sweating redirection of peripheral blood flow

2. Constitutional responses:1. Rigors

2. Chills

3. Anorexia

4. Somnolence

5. Malaise

• Consequences of Defective or Excessive Inflammation• Defective inflammation

– Increased susceptibility and vulnerability to infection

– Delayed healing, inflammation is an essential part of healing in removal of damaged and necrotic tissue and stimulation of reparative processes.

• Excessive inflammation

– Allergic reactions of all types

– Autoimmune disorders

– Cancer

– Atherosclerosis/ischemic heart disease

– Some neurodegenerative disorders

• Granulomatous inflammation

• Distinctive chronic inflammation type

• cell mediated immune reaction (delayed)

• Aggregates of activated macrophages epithelioid cell multinucleated giant cells (of Langhans type x of foreign body type)

• NO agent elimination but walling off

• Intracellulary agents (TBC)

• Granulomatous inflammation

Diseases related to chronic inflammationAsthma

Chronic peptic ulcer

Tuberculosis

Rheumatoid arthritis

Chronic periodontitis

Ulcerative colitis and Crohn's disease

Chronic sinusitis

Chronic active hepatitis