14. Chronic Inflammation and Healing Flashcards
What is chronic inflammation?
Describe acute inflammation.
Inflammatory response of prolonged duration, whose extended time course is provoked by persistence of the causative stimulus to inflammation in the tissue. Active inflammation, tissue destruction and healing attemps occur simultaneously.
What is 2 things is chronic inflammation the result of a balance between?
Give an example of a chronic inflammatory process.
What happens if the damaging stimulus is:
a) neutralised or eradicated?
b) not neutralised or eradicated?
Continuing tissue damage and eradication of the damaging stimulus vs. healing and scar formation.
Active chronic peptic ulcer of the stomach (pic).
a) no further tissue damage, repair respose progresses to complete scarring
b) balance between tissue damage and repair maintained as stalemate, depending on local/systemic factors within the tissue
When does chronic inflammation occur and how does it begin?
What aetiological agents produce chronic inflammation?
List the key effector cells of chronic inflammation, and how they differ from the key effector cells of acute inflammation.
May follow acute inflammation, often begins insidiously as low grade response (e.g. in TB and RA). Insidious arises under persistant infections (e.g. TB), prolonged exposure to potentially toxic agents, and autoimmune disease.
Infectious organisms that avoid/resist host defences e.g. TB, syphilis, or which have the ability to persist due to location (joint infections, pleura etc.) Autoimmune disease e.g. RA. Irritant non-living foreign material e.g. suture. Unknown e.g. Crohn’s, IBD
B and T Lymphocytes, plasma cells, macrophages (histiocytes, monocytes), fibroblasts. Key cells of acute: polymorphonuclear lymphocytes; key of chronic: mononuclear cells.
Macrophages are part of the basic immune mechanism. Where are they derived from? What stimulates them?
List 5 functions of macrophages.
What are the 2 types of lymphocyte?
Derived from blood monocytes. Stimulated by chemokines and chemotactic agents released by T-cells.
Digestion/killing cells. Digestion of ECM. Stimulation of fibroblasts and CT. Angiogenesis. Recruitment of other inflammatory cells.
B-cells: humoral immunity, produce and secrete Ab. T-cells: CD8 and CD4 cells. Lymphocytes can activate and be activated by macrophages/other inflammatory cells.
Describe the histological appearance of inflammation.
What is granulomatous inflammation?
What is an ulcer?
Mixed inflammatory cell infiltrate composed of lymphocytes, plasma cells and macrophages. Healing by fibrosis, granualtion tissue, angiogenesis and scar tissue. Cell death, necrosis, apoptosis, abscess formation. (pic 1)
Distinctive chronic inflammatory reaction with a predominant cell type - the activated macrophage, which has an epithelioid appearance. Granuloma is a collection of epithelioid macrophages, sometimes forming multinucleate giant cells, surrounded by lymphocytes and fibrous rim, sometimes with central necrosis. E.g. RB, Crohn’s. (pic 2)
Macroscopic break in epithelial surface
What causes TB? What is the histological appearance, and what stain is used?
List some other granulomatous diseases.
Another type of chronic inflammatory condition is autoimmune disease. Describe this and give examples.
Mycobacterium tuberculosis. Caseating granulomatous inflammation (often have Langhan’s type (nuclei arranged in horseshoe shape) multinucleate giant cells) (pic). Ziehl Neelsen stain.
Bacterial: leprosy, syphilis, cat-scratch disease. Parasitic: schistosomiasis. Fungal: cryptococcus. Inorganic dusts: silicosis. Unknown: sarcoidosis, Crohn’s
Occurs when breakdown of immunological tolerance (ability of body to distinguish self from non-self), allowing body to mount immunological reaction against own tissues. Often production of autoAb to attack self antigens. Outcome = chronic inflammation, fibrosis and tissue damage. E.g. RA, Hashimoto’s thyroiditis
List the outcomes of tissue loss and destruction.
Define the following:
a) regeneration
b) resolution
c) restitution
d) repair
What 2 things is wound healing a combination of?
What is a wound?
Inflammation (in all cases), regeneration, repair with fibrosis, persistence of cavity/gap, permanent loss.
a) replacement of injured cells with cells of same type
b) complete return to normal structure and function after injury
c) return to normality due to a combination of regeneration and resolution
d) replacement of lost tissue by fibrous (scar) tissue
Regeneration and repair.
Circumscribed injury caused by an external force, sometimes associated with disruption of structure/function
What are the 4 phases of wound healing?
List some of the general features of wound healing.
List some of the features of haemostasis.
List the vessel changes and cellular changes that occur during inflammation.
Hemostasis (stop bleeding), inflammation (new framework for angiogenesis), proliferation/granulation (pulls wound closed), remodelling/maturation (final proper tissue)
Wound + blood escape, haemostasis/clotting, inflammation, macrophage remove debris, cells regenerate if possible, microvessels grow/angiogenesis, fibroblasts move in, proliferate and lay down collagen, scar.
Bleeding, vasoconstriction, endothelial cell activation, platelets adhere, become activated and aggregate, coagulation cascade forms fibrin clot
Vessel: vasodilation, oedema
Cellular: migration, phagocytosis, neutrophils and macrophages
What is regeneration? Describe the 3 types of cells and give examples.
What is the regnerative ability of the 3 types?
Replacement of injured cells by parenchymal cells of the same type via proliferation. Cell Types: labile (cells continue to proliferate throughout life to replace those constantly destroyed e.g. skin, gut mucosa, marrow), stable (cells that turn over at low level normally, but can rapidly replicate if required e.g. kidney, liver, bone), permanent (either incapable of mitotic division or organised proliferation e.g. cardiac muscle, neurones, striated/skeletal muscle).
Labile = almost complete. Stable = moderate, no restoration of destroyed tissue architecture. Permanent = almost none.
What do most tissues require for regeneration?
Which are the only 3 tissues that can regenerate all consitiuents?
When does repair occur?
What forms granulation tissue?
An intact basement membrane; if not, fibrosis occurs.
Liver, bone, bone marrow.
If regeneration can’t take place b/c cells are permanent or tissue framework is disrupted. Replacement of injured cells by granlation tissue and ultimately a fibrous scar.
Angiogenesis, fibroblasts, myofibroblasts, macrophages. (pic)
What is angiogenesis and what are the stages?
Granulation tissue also contains fibroblasts and macrophages - what do these do?
What happens during remodelling with time?
Formation of new BV IRT chemical stimuli (imp for wound healing and tumour growth). Stages: Enzymatic degradation of basement membranes of parent vessels. Migration of endothelial cells towards stimulus. Proliferation of endothelial cells into cords. Maturation and lumen formation (initially leaky).
Fibroblasts: synthesise extracellular matrix and collagen. Proliferate and chemotactic in response to mediators e.g. collagen, macrophage chemokines
Macrophages: clear debris, secrete growth factors, stimulate endothelial cells and fibroblasts
Macrophages remove debris, increased amounts of collagen laid down, vessels disappear, fibrous tissue, collagen cross-linking, contraction of myofibroblasts, fibrous scar.
Differentiate between primary and secondary intention (healing).
Primary: clean linear wound e.g. laceration. Initial bleeding, inflammation. Edges can be brought together easily. Epithelial cells proliferate and meet on surface whilst granulation tissue forms in underlying clot. Little fibrous scar. Primary union.
Secondary: Open wound with tissue loss and jagged edges e.g. chronic ulcer, brun, abscess. Edges can’t be approximated, more bleeding, inflammation, more granulation tissue, granulation tissue on surface as epithelium takes time to cover, same process but wound contraction. Larve scar. HEALING OCCURS FROM BELOW
Describe the process of fracture healing. (NOT FOR ICA)
Usual: bleeding, clot, periosteal disruption, inflammation, granulation tissue, then:
Cartilage formed in granulation tissue from chondrocytes, bridges gap (provisional callus). Calcification and ossification by osteoblasts (fibrocartilagenous -> bony callus). Remodelling by osteoclasts/blasts. Woven bone becomes lamellar (as before). Only situation where granulation tissue leads to regeneration, every other time repair with fibrosis.
What 3 things are involved in the control of repair?
What are some local and systemic factors affecting healing?
Growth factors (e.g. FGF, EFG - activation and proliferation of fibroblasts, angiogenesis, epithelial cell regeneration), cell-cell/cell-matrix interactions (e.g. contact inhibition - cells stop growing when contact each other), extracellular matrix synthesis and collagenisation (fibronectin, proteoglycans)
Local: infection, foreign material, inadequate blood supply (e.g. DM), necrotic tissue burden, injury extent, mobility, previous radiotherapy
Systemic: age, nutrition, obesity, diabetes mellitus, metabolic disease, CT disorder, medication (chemo, corticosteroids)
Can be divided into exo/endogenous.
List some complications of repair.
List some systemic and organ-specific autoimmune diseases.
Dehiscence (falls apart, organ may protrude through). Hypertrophic scar (keloids)(due to increase in size of cells UNLIKE hyperplasia which is number). Infection. Incisional hernia (e.g. bowel escapes into hernia area). Skin discolouration.Loss of function(e.g. heart failure).Contractures(may inhibit movement/function).Stretching(e.g. aneurysm).Adhesions (may lead to obstruction e.g. bowel).
Systemic: RA, scleroderma, systemic lupus erythematosus, polymyositis, 10 sjogrens syndrome
Organ-specific: T1 diabetes mellitus, Goodpasture’s syndrome, multiple sclerosis, Grave’s disease, Hashimoto’s thyroiditis, Vitiligo, Myasthenia gravis, autoimmune pernicious anaemia, autoimmune Addison’s disease
