MCB Lecture 62 & 63 Tissue Injury, Chronic Inflammation Flashcards
When can normal function be regained?
When is function not regained?
Normal function is regained when the tissue is regenerated, or if the scar is small
Function is lost when there is extensive fibrosis
What are the two outcomes of tissue injury?
Regeneration of tissue
Scarring, replacement by connective tissue
What are the requirements for regeneration?
- The tissue must be made up of labile or stable cells
- Underlying structure of the organ must not be lost
When does scarring occur?
Scarring occur when the underlying tissue is lost, or when the cells are not capable of proliferation
Which compound regulates cell cycle?
Cyclins
When will a cell enter G0?
When growth factors are removed
What does FACS analysis tell us about the effect of removing growth factors from cells?
Normal: most cells in S phase, DNA content more than 1
Remove GF: cells enter Go, DNA content = 1
Apoptotic stumulus: cells die, DNA content less than 1
What are the three different classifications of cells based on proliferative capacity?
Labile
Stable
Permanent
What is labile tissue?
Eg. ?
These cells never enter Go and are always replicating
These tissues are capable of regeneration
For example: epithelium of skin and GIT, hematopoetic cells
What is stable tissue?
Eg. ?
This tissue leaves the cell cycle, but can re-enter if required to do so.
For example: parenchyma of most solid organs (liver, kidney), endothelium, smooth muscle
What is permanent tissue?
Eg. ?
These cells enter Go and cannot exit
These tissue can never be regenerated
These cells are do terminally differentiated
For example: neurons, cardiac and skeletal muscle
What changes occur in cells during proliferation?
Increase in cell size
Increase in mitosis
Protection against apoptosis
What are the triggers of proliferation? (3)
- Growth factors
- Hormones
- Cytokines
What is the mechanism of growth factors causing proliferation?
Growth factors initiate a signal transduction pathway, leading to the transcription of genes such as cyclins that push the cell into the cell cycle.
- prevent apoptosis
- increase protein synthesis
What are the outcomes of growth factor signalling?
Migration
Angiogenesis
Proliferation
Differentiation
Which cytokine results in proliferation?
IL-2
What are the two basic classes of cells in an organ?
Parenchyma and stroma
What is parenchyma?
Give some examples
These are the function cells of an organ
Eg. Hepatocytes, myocytes, neurons
What is stroma?
What is it made up of?
The stroma is the support structure for the parenchyma
It is made up of connective tissue
What are the two forms of stroma?
Basement membrane
Interstitial matrix
Describe the possibility of tissue regeneration in the kidney
There is limited capacity for regeneration, and the underlying structure must be intact
The proximal ducts undergo hypertrophy and hyperplasia when the other kidney is removed
Describe tissue regeneration in the liver
The liver has good regenerative capacity if the underlying structure is maintained.
5-10% of the tissue may be regenerated in 4-6 weeks
What is steatosis?
This is when there are some fibrous hepatic nodules due to moderate alcohol intake. The nodules can be regenerated
What are the steps in repair by connective tissue?
- Angiogenesis
- Migration and proliferation of fibroblasts
- ECM deposition by fibroblasts
- Remodeling
When does repair by connective tissue occur?
If the tissue can not be regenerated, or if the underlying structure is lost
What is the aim of angiogenesis?
To bring the blood supply back to the damaged tissue
Describe the mechanism of angiogenesis
- Vasodilation and increased permeability of the existing vasculature
- Migration of endothelial cells
- Proliferation of endothelium
- Inhibition of proliferation and remodelling
- Recruitment of peri endothelial cells
What are the features of the new vasculature produced in angiogenesis
Leaky, as the tight junctions haven’t properly formed yet
Describe the migration and proliferation of fibroblasts during tissue regeneration
- Macrophages and endothelium produce growth factors: PDGF and FGF-2
- The growth factors stimulate recruitment and proliferation of fibroblasts
What is the function of fibroblasts in tissue regenerative by connective tissue?
To synthesise and secrete ECM, especially collagen
What are the stages of tissue repair?
Granulation tissue -> scar formation
Compare granulation tissue with scar tissue
Granulation:
Proliferating fibroblasts
Vascularised
Loose ECM
Scar tissue:
Inactive fibroblasts
A vascular
Dense collagen and connective tissue
What is occurring during remodelling?
What does this result in?
- Switch from type III collagen to type I
- Collagen is no longer degraded
This results in increased tensile strength of the wound
What are the two types of cutaneous wound healing?
Healing by first intention
Haling by second intention
Describe what happens in healing by first intention in the first 24 hours
- Scab formation
2. Inflammation
What sort of wounds result in healing by first intention?
What are the features of these wounds?
Surgical wounds
Paper cuts
They are very clean, small wounds
There is no necrotic tissue or inflammation
What are the features of healing by second intention?
Everything is larger: the wound, the clot, inflammation and granulation tissue
Describe wound contraction
When does it occur?
This is when the some of the cells in gap the specialised granulation tissue contract like smooth muscle cells (myofibroblasts)
This occurs in healing by the second intention
Wound size reduced by 5-10% in 4-6 weeks
What are the aims of successful healing?
To regain function
Rapidly resolve the injury
Transient scar
What factors affect successful healing?
Nutrition Location of the scar Effect of contraction Persistence of foreign bodies Infection
What are some complications of healing that can occur?
Wound dehiscence
Contraction
Keloid formation
Describe wound dehiscence
This is when the wound opens us due to poor suturing, nutrition, mechanical forces or infection
What is keloid formation?
This is hypertrophy of the scar tissue, causing a raised mass of scar tissue due to excess collagen
What problems can occur with contractions of myofibroblasts ?
The limb contracts
What are the features of chronic inflammation? (Give histology cal features too)
Inflammation lasts weeks, to months to years
Injury, inflammation and healing all occur at the same time
- mononuclear cells
- tissue damage
- repair by fibroblasts
- fibrosis
What are the two broad categories of cause of chronic inflammation?
Primary chronic inflammation
Unresolved acute inflammation
How can acute inflammation lead to chronic inflammation?
Excessive cellular exudate
Excessive necrosis
Persistent causal agent
What are peptic ulcers?
What is it an example of ?
This is when there is damage to the epithelium of the stomach (infection or anti-inflammatory drug) that can’t be resolved
It is an example of acute infections persisting and causing chronic inflammation
Describe the histology of peptic ulcers
Epithelial interruption Necrotic debris (acellular) Non specific acute inflammation Granulation tissue Fibrosis
What is osteomyelitis?
What is it an example of?
This is when there is an unresolved infection in the bone (because the blood supply is poor)
It is an example of unresolved acute infection turning into chronic infection
What is chronic choleystitis?
This is gall stones of the liver causing inflammation and thickening of the wall and chronic infection
What is primary chronic inflammation?
This is when the injury leads directly to chronic infection
What are the causes of primary chronic inflammation? (4)
- Persistent infection
- Immune mediated
- Toxic agent
- Primary granuloma
Which cells are involved in the chronic inflammatory response?
Macrophages
Lymphocytes
Other leukocytes
Describe the two types of macrophages and how each is activated
M1: classical activation: IFN-gamma and microbicidal products
M2: alternate activation: cytokines: IL-4 and IL-13
What are the functions of macrophages in chronic inflammation?
M1: inflammation and killing
M2: inhibition of inflammation and tissue repair
What is the role of lymphocytes in chronic inflammation?
They make antibody and kill infected cells
Describe the vicious circle of T cell and macrophage activation
M1 activates lymphocytes by presenting antigen and releasing stimulatory cytokines
T cells stimulate macrophages by releasing IFN-gamma and IL-4 and IL-13
What are the macroscopic morphologies of chronic inflammation?
Chronic ulcers - peptic ulcer Chronic abscess cavities - bacterial abscesses in the lung Thickened wall - chronic choleystitis Granulomatous - sarcoidosis Fibrosis - Asbestosis of lung
What are the two classes of morphology of chronic inflammation?
Diffuse
Granulomatous
Describe the structure of diffuse chronic inflammation
Give an example
No granuloma
Eg. Asbestosis
Describe the Pathogenesis of asbestosis
- Asbestos fibres are inhaled and penetrate deep into the lung
- Diffuse pulmonary interstitial fibrosis forms
- Contraction of the walls leads to enlarged air spaced and honey combed effect
- Walls of visceral pleura are thick and fibrous
What are other types of diffuse chronic inflammation?
Chronic bronchitis Bronchiectisis Ulcerative colitis Rheumatoid arthritic Atherosclerosis Peptic ulcers
What is the structure of granulomatous chronic inflammation?
Give the structure of this feature
Possible zone of necrosis (caseating or non caseating)
Epithelioid cells
Lymphocytes
Macrophages
Multi nucleates giant cells
Collagen and fibroblasts around the outside
What are the different types of granulomatous lesions?
Immune mediated (caseating, non-caseating)
Foreign body
What causes the immune mediated granulomas?
Describe the structure of the granuloma
Caused by a nonfiction such as tuberculosis
The granuloma has caseous necrotic tissue in the centre
What is an example of something causing non-caseating granuloma?
What is the structure of the granuloma?
Sarcoidosis
Cause unknown
No necrotic tissue in the granuloma
Non horseshoe arrangement of nuclei in the giant cells
Where do non-caseating granulomas occur?
They occur in many different organs throughout the body, but cause the most harm in the lungs
Describe the steps leading to foreign body mediated granuloma
- Inert, foreign material enters (talc, silica, splinter, prosthesis)
- Too large to be phagocytosed
- Granuloma forms to barricade it off to prevent further damage
What are the sequelae of chronic inflammation? (4)
Give example of diseases for each
Contraction of fibrous tissue - chronic rheumatic fever Loss of parenchyma and thus function - cirrhosis of the liver Metaplasia - smoking Neoplasia - hepatocellular carcinoma (in the liver)
Describe what happens in healing by the first intention over the next 3 days
- Mitoses under the scab
- Neutrophils are replaced by macrophages, which clear the debris
- Granulation tissue forms: fibroblasts make ECM , angiogenesis
Describe what happens over the next few weeks in healing by first intention
- Scarring
- fibroblasts inactive
- vasculature decreases
- type 1 -> type 3 collagen ( strong wound)
- oedema drains
- epithelium has been regenerated
What type of morphology of chronic inflammation is chronic bronchitis?
What causes it?
Diffuse
Cigarette smoke and pollutants - exogenous toxins
What type of morphology of chronic inflammation are peptic ulcers?
What causes it?
Diffuse, chronic ulcers
Caused by persistent infection of helicobacter pylori
What type of morphology of chronic inflammation is ulcerative colitis?
What causes it?
Diffuse
Autoimmune, inappropriate immune response
What type of morphology of chronic inflammation is rheumatoid arthritis?
Diffuse, immune complexes in joints
Type III hypersensitivity
What type of morphology of chronic inflammation is sarcoidosis?
Granulomatous (non-caseating)
What type of morphology of chronic inflammation is asbestosis?
Diffuse, fibrous thickening of visceral pleura
What type of morphology of chronic inflammation is tuberculosis?
What causes it?
Granulomatous; caseating granuloma in lungs
Persistent infection of mycobacterium tuberculosis in. Alveolar macrophages
What type of morphology of chronic inflammation is foreign body?
Granulomatous, non necrotic
What type of morphology of chronic inflammation is atherosclerosis?
What causes it?
Diffuse
Caused by an endogenous toxin
What type of morphology of chronic inflammation is chronic choleystitis?
Diffuse, thickening of wall of gall bladder
Which different CD4+ t lymphocytes have a role in chronic inflammation? Differentiate between their different roles
Th1: classically activate macrophages by secreting IFN-gamma
Th2: secrete IL-4 IL-5 IL-13 for alternate macrophage activation
Allergic inflammation, protection against helminthic parasites
Th17: secrete IL-17 for leukocyte recruitment
What is a tubercle?
It is the lesion in mycobacterium tuberculosis chronic inflammation
What is chronic rheumatic fever?
This happens after a strep infection –> type II hypersensitivity.
This causes fibrosis of the mitral valves. The thick fibrous tissue contracts –> stenosis
