1.1.1 Pre-Midterm Histology - Inflammation

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List the two major categories of inflammation

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Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes ) from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue.

chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.

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List the cardinal signs of inflammation and briefly explain how they are produced

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Dolor (pain)
Calor (heat)
Rubor (redness)
Turgor (swelling)
Functio laesa (loss of function)

Redness and heat are due to increased blood flow at body core temperature to the inflamed site; swelling is caused by accumulation of fluid; pain is due to release of chemicals that stimulate nerve endings. Loss of function has multiple causes.

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Define and compare/contrast hypertrophic scar vs. keloid

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Hypertrophic scars occur when the body overproduces collagen, which causes the scar to be raised above the surrounding skin. Hypertrophic scars take the form of a red raised lump on the skin.

Keloid scars are a more serious form of scarring, because they can carry on growing indefinitely into a large, tumorous (although benign) neoplasm.

Hypertrophic scars are often distinguished from keloid scars by their lack of growth outside the original wound area, but this commonly taught distinction can lead to confusion. All keloid scars are hypertrophic but "only a small percentage of large scars" are keloid.

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Describe the morphological differences between ulceration and erosion

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An ulcer is an erosion of more than 0.5 cm.

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Describe the histological appearance and general functions (in chronic inflammation) of plasma cells, lymphcytes, monocytes/macrophages, fibroblasts and eosinophils

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Inflammatory cells kill organisms and secrete a wide variety of soluble factors that regulate the inflammatory and healing processes.

Plasma cells (P) are identified by their purplish cytoplasm and eccentric 'clock face' nuclei. Plasma cells are differentiated B lymphocytes that produce antibodies.

Lymphocytes (L) have dark, round nuclei with a very thin rim of basophilic cytoplasm. These include both helper and cytotoxic T cells as well as B cells.

Macrophages (Ma) have oval or kidney-bean-shaped nuclei and pale cytoplasm – phagocytic and antigen-presenting.

Eosinophils (E) have bilobed nuclei and brightly eosinophilic cytoplasmic granules. When stimulated, eosinophils release granule contents, including major basic protein - effective in killing parasites.

Fibroblasts secrete extracellular matrix including collagen. After the injurious stimulus has been removed these cells progressively disappear from the tissue over weeks/months.

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Name the bacterial infection usually associated with chronic ulceration of the stomach and duodenum

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Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach

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Define the terms "Hematemesis" and "Melena"

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Hematemesis: The vomiting of blood. The source is generally the upper gastrointestinal tract.

Melena: The black, "tarry" feces that are associated with gastrointestinal hemorrhage. The black color is caused by oxidation of the iron in hemoglobin during its passage through the ileum and colon.

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Describe the typical outcome of chronic inflammation

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Tissue destruction, fibrosis, necrosis

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Describe the definitive features of a granuloma

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Activated epithelioid macrophages and multinucleate giant cells derived from macrophages

Epithelioid macrophages form circumscribed granulomas (clusters) surrounded by lymphocytes, macrophages, fibroblasts and varying degrees of fibrosis

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Describe the formation of epithelioid macrophages and giant cells

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Formed in response to a persistent irritant where several macrophages, along with other WBCs, fuse into a larger cell, sometimes appearing like epithelium. Their purpose is to isolate the irritant.

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Compare and contrast granulation tissue vs. granuloma

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Granulation tissue is an intermediate stage of acute healing which is later replaced by collagen.

A granuloma is a permanent answer to a persistent irritant.

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Compare and contrast foreing body giant cells and Langhan's giant cells

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A foreign-body giant cell is a collection of fused macrophages (giant cell) which are generated in response to the presence of a large foreign body. This is particularly evident with implants that cause the body chronic inflammation and foreign body response.

The nuclei are arranged in a disorganized manner. This is in contrast to a Langhans giant cell, where the nuclei are arranged on the border.

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Define Lipoma

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Benign tumor composed of adipose tissue

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Define Liposarcoma

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A malignant tumor that arises in fat cells in deep soft tissue, such as that inside the thigh or in the retroperitoneum.

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Fibroblasts

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Fibroblasts are the most common cell type found in connective tissue. The term "fibroblast" is commonly used to describe the active cell type, whereas the more mature form, which shows less active synthetic activity, is commonly described as the "fibrocyte". Fibroblasts are elongated, spindle-shaped cells with many cell processes. They have oval, pale-staining, regular nuclei with prominent nucleoli. Abundant rough endoplasmic reticulum and active Golgi bodies are found in the cytoplasm.
Fibroblasts synthesize collagen, reticular and elastic fibers and the amorphous extracellular substance (including the glycosaminoglycans and glycoproteins).

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Macrophages<br />

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Macrophages show pronounced phagocytotic activity. Macrophages originate from monocytes (from precursor cells in bone marrow), which migrate to connective tissue and differentiate into tissue macrophages.
The main functions of macrophages are ingestion by phagocytosis of microorganisms (bacteria, viruses, fungi), parasites, particulate matter such as dust, and they also participate in the breakdown of aged cells including erythrocytes. The intracellular digestion occurs as a result of fusion of lysosomes with the phagosome (ingested body).
Macrophages are normally long-lived and survive in the tissues for several months. In some cases where a foreign body (such as a small splinter) has penetrated the inner tissues of the body, several macrophages may fuse together to form multinuclear foreign body giant cells. These large cells accumulate at sites of invasion of the foreign body and sites of inflammation.

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Mast Cells

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Mast cells are oval or round cells (20-30mm diameter) in connective tissue characterized by cytoplasm packed with large round basophilic granules (up to 2mm diameter). The granules are stained metachromatically (purple after toluidine blue staining). Two of the main components of mast cell granules are histamine and heparin. The granules of mast cells are released in inflammatory responses. Mast cells are abundant in loose connective tissue (especially adjacent to blood vessels), in the dermis, and in the lamina propria of the respiratory and digestive tracts.

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Plasma Cells

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Plasma cells are responsible for antibody production. These large cells have eccentric nuclei, basophilic cytoplasm (much rough endoplasmic reticulum associated with protein synthesis) and well-developed Golgi bodies. Plasma cells are relatively short-lived (10-20 days) and are found in sites of chronic inflammation or sites of high risk of invasion by bacteria or foreign proteins (such as the lamina propria of the intestinal and respiratory tracts).

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Leukocytes

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The white blood corpuscles are commonly found in connective tissue. They migrate from the blood vessels to the connective tissue, especially to sites of injury or inflammation.

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Describe the process of photoaging

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Both UVA and UVB radiation can cause skin damage including wrinkles, lowered immunity against infection, aging skin disorders, and cancer. Some of the possible mechanisms for UV skin damage are collagen breakdown, the formation of free radicals, interfering with DNA repair, and inhibiting the immune system.

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Describe the role of myofibroblasts in wound repair and inflammation.

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It can contract by using smooth muscle type actin-myosin complex, rich in a form of actin called alpha-smooth muscle actin. These cells are then capable of speeding wound repair by contracting the edges of the wound.
Early work on wound healing showed that granulation tissue taken from a wound, could contract in vitro (or in an organ bath) in a similar fashion to smooth muscle, when exposed to substances that cause smooth muscle to contract, such as adrenaline or angiotensin.
More recently it has been shown that fibroblasts can transform into myofibroblasts with photobiomodulation.
After healing is complete, these cells are lost through apoptosis and it has been suggested that in several fibrotic diseases (for example liver cirrhosis, kidney fibrosis, retroperitoneal fibrosis) that this mechanism fails to work, leading to persistence of the myofibroblasts, and consequently expansion of the extracellular matrix (fibrosis) and contraction.
Similarly, in wounds that fail to resolve and become keloids or hypertrophic scars, myofibroblasts may persist, rather than disappearing by apoptosis.

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Tumor Necrosis Factor

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A cytokine involved in systemic inflammation and a member of a group of cytokines that stimulate the acute phase reaction.
The primary role of TNF is in the regulation of immune cells. TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, including major depression, Alzheimer's disease and cancer.
TNF was thought to be produced primarily by macrophages, but it is produced also by a broad variety of cell types including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neuronal tissue. In the skin, mast cells appear to be the predominant source of pre-formed TNF, which can be released upon inflammatory stimulus

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List and describe the three major components of the acute inflammatory response

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Vascular dilatation - relaxation of vascular smooth muscle leads to engorgement of tissue with blood (hyperemia)

Endothelial activation - increased endothelial permeability allows plasma proteins to “leak” into tissues; expression of adhesion molecules on the endothelial surface causes neutrophil adherence; production of factors that cause vascular dilatation

Neutrophil activation and migration - expression of complementary adhesion molecules; increased motility - emigration from vessels into tissues; increased capacity for bacterial killing …

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Describe the development of acute inflammatory exudate

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Stage 1
Early vascular changes –
1. dilation of vessels (engorged capillaries, venules)
2. adhesion of neutrophils to endothelium (pavimenting)
3. fluid accumulation in interstitium

Stage 2
Migration of neutrophils - neutrophils pass through vessel walls, penetrate the endothelial basement membrane and migrate into perivascular CT.

Stage 3
Early formation of exudate
Neutrophils (N) are attracted to the site of tissue damage by inflammatory chemical mediators, such as complement component C5a and leukotriene B4 (LTB4), as a result they migrate actively towards higher concentrations of these agents (chemotaxis)

Several other plasma proteins are present in the tissue space – evidenced by fibrin (from plasma fibrinogen)

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Describe (in general terms) the roles of immunoglobulins, complement cascade components and fibrinogen in the acute inflammatory process

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Immunoglobulins:
Opsonization
Complement activation

Complement:
Opsonization
C3a, C5a
Membrane Attack Complex

Fibrinogen:
Fibrin framework for:
Bacterial immobilization
Neutrophil migration

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List the three components that form a typical acute inflammatory exudate

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water and the dissolved solutes of the main circulatory fluid such as sap or blood. In the case of blood: it will contain some or all plasma proteins, white blood cells, platelets and (in the case of local vascular damage) red blood cells.

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Define lung consolidation

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Consolidation is a clinical term for solidification into a firm, dense mass. It is more specifically used in reference to a region of lung tissue that, normally compressible, has filled with liquid,[1] a condition marked by induration[2] (swelling or hardening of normally soft tissue) of a normally aerated lung. Consolidation occurs through accumulation of inflammatory cellular exudate in the alveoli and adjoining ducts. Simply, it is defined as alveolar space that contains liquid instead of gas. The fluid can be pulmonary edema, inflammatory exudate, pus, inhaled water, or blood (from bronchial tree or haemorrhage from a pulmonary artery). It is clinically important in pneumonia: the signs of lobar pneumonia are characteristic and clinically referred to as consolidation.

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List the three morphological types of acute inflammation

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1. Suppurative or Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid.

2. Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows fibrinogen to pass through the blood vessels. If an appropriate procoagulative stimulus is present, such as cancer cells, a fibrinous exudate is deposited as fibrin. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function.

3. Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma.

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Describe suppurative inflammation and list at least 2 common conditions that demonstrate this type of inflammation

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Suppurative or purulent (pus-containing) inflammation
Pus is a semi-liquid containing neutrophils, fluid and necrotic tissue
An abscess is a circumscribed collection of pus

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Define pyogenic bacteria

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exudate in purulent inflammation is rich in neutrophils – this commonly results from bacterial infection. Bacteria that promote purulent inflammation are called “pyogenic” bacteria

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Describe fibrinous inflammation and list the typical locations for this type of inflammation

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The exudate in fibrinous inflammation has a high plasma protein content

Fibrinogen, a plasma protein, is converted to fibrin and deposited in tissues. It is usually associated with serous membrane-lined cavities : pleural, pericardial and peritoneal

Fibrin strands form a mat, often causing adhesion between adjacent surfaces

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Define and compare/contrast exudate versus transudate

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Transudate
Extravascular fluid with low protein content and a low specific gravity. primary cell types are mononuclear cells: macrophages, lymphocytes and mesothelia cells.

Exudate
Extravascular fluid due to vessel alteration during inflammation (increased permeability, vascular constriction then dilation). High protein content, with cell debris present and high specific gravity.

This is in contrast to transudate where the extracellular fluid is an ultrafiltrate of blood plasma and thus larger molecules such as proteins and cell debris are absent.

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Describe serous inflamation and name at least one condition that demonstrates this type of inflammatory response

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In this pattern of acute inflammation the main tissue response is accumulation of fluid with a low plasma protein and cell content (transudate)

Serous inflammation can be seen in the skin in response to a burn, and in serous membrane-lined cavities (pleural effusions are commonly classified as transudative versus exudative, providing a clue as to likely causes)

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Describe the main factors that determine the outcome of acute inflammation

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The outcomes of acute inflammation are determined by:

1) severity of tissue damage

2) capacity of stem cells within the tissue to replace the specialized cells required (regeneration)

3) the type of agent causing the damage

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Describe the process of healing by complete resolution following bacterial pneumonia or acute bronchitis

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Resolution - complete restitution of normal tissue architecture and function; can only occur when the connective tissue framework is intact and the tissue has the capacity to regenerate.
Neutrophils and necrotic tissue are removed by phagocytosis (i.e. macrophages.) Those leave the tissue via the lymphatic drainage

Examples:
a. following pneumonia, regrowth of alveolar lining cells depends on resident stem cells to divide and differentiate.
b. Recovery from sunburn (acute inflammatory response in the skin secondary to UV radiation)

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Compare and contrast acute abscess from chronic abscess

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Abscess formation - acute inflammatory response fails to destroy/remove the cause of tissue damage; continues, usually with a component of chronic inflammation.

Acute inflammation progresses producing liquefaction of tissue to form pus

An abscess cavity encapsulated by granulation and fibrous tissue is called a chronic abscess.

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List the main chemical mediators responsible for arteriolare dilation/vasodilation, increased vascular permeability and leukocyte activation and chemotaxis in the process of acute inflammation

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