Chronic Inflammation - SRS Flashcards
What are the principle cell types we should think of when we hear chronic inflammation?
Lymphocytes and Macrophages
Identify the cell on the left
B-cell (plasma cell)
Identify the cell on the right
T Cell (reactive)
What are three causes of chronic inflammation?
- Persistent infections
- Delayed type hypersensitivity
- granulomatous reactions
What disease are we looking at here?
Histoplasmosis
What are the structures surrounding the two eosinophilic centers?
Granulomas
What is the disease? What type of inflammation?
Rheumatoid arthritis - hypersensitivity disease, autoimmune
This tissue sample is taken from a patient with rhuematoid arthritis. What is the circular structure shown here?
Caseous granuloma
Prolonged exposure to toxic agents, exogenous or endogenous can lead to chronic inflammation. Give and example of each.
Silicosis - inhaled silica over a long period of time causes inflammatory lung disease. (Exogenous)
Atherosclerosis - Chronic inflammation induced at least in part by excessive production and tissue deposition of endogenous cholesterol and other lipids. (Endogenous)
Your patient, who is a sand blaster comes in and you obtain the following imaging/samples. Diagnosis? Type of inflammation?
Silicosis - chronic inflammation, exogenous agents
What are the stand out features of each of these four images taken from the brain?
What diagnosis does this indicate?
Top left - Red blobs
Top right - neurons with eosinophilic inclusions
Bottom left - Amyloid plaques
Bottom right - neurofibrillary tangles
Alzheimer’s disease
What is amyloidosis?
Accumulation of misfolded Beta pleated sheets
What are the three morphologic features of chronic inflammation?
- Infiltration with mononuclear cells (macros, lymphos, plasma cells)
- Tissue destruction by persistent offending agent or by inflammatory cells.
- Attempts at healing by CT replacement of damaged tissue, accomplished by angiogenesis and fibrosis
What is the red arrow indicating in this sample from a lung?
What kind of inflammation is this?
What do the black arrows indicate?
Lymphocytes in a germinal center
Chronic inflammation
Interstitial fibrosis (black arrows)
This is lung tissue, what type of inflammation do we see here?
Acute inflammation
Neutrophils present
Macrophages are the dominant cells in most chronic inflammatory reactions. How do they contribute to the reaction? (3)
- By secreting cytokines and growth factors that act on various cells
- By destroying foreing invaders and tissues
- Activating other cells notably T lymphocytes
What are macrophages derived from?
Hematopoietic stem cells in bone marrow
Early Development
progenitors in the embryonic yolk sac
Fetal liver
If you see a mononuclear cell in a peripheral blood smear, what would you call it? When does it’s name change and to what?
Monocyte
Once diapedesed, it is a macrophage.
How are macrophages activated in the classical pathway?
(4)
- Microbial products such as endotoxin binding TLR’s
- T cell derived signals
- IFN-y
- Crystals and particulate matter
What are classically activated macrophages also called?
M1
M1’s produce what substances?
NO
ROS
Upregulate lysosomal enzymes
cytokines
How is alternative macrophage activation accomplished?
Induced by cytokines other than INF-Y such as…
- IL-4
- IL-13
What are alternatively activated macrophages also known as?
M2’s
What is the principle function of M2’s?
What do their secretions do?
Tissue repair and anti-inflammatory effects. They secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis.
What kind of macrophage reaction produces liver cirrhosis?
Exaggerated M2 reaction
What are these two purple stained cells?
Reactive B-Cells
What is this cell?
Give the classical description you should expect to encounter.
Activated B-Cell - Plasma cell
- Eccentric Clock faced nuclei
- With a perinuclear Hoff body
- and basophilic cytoplasm
Where are Dohle bodies found?
Activated neutrophils
We have a patient with multiple myeloma, who we do a bone marrow biopsy on. We see plasma cells with little eosinophilic globules in them. What are these globules called?
These pink globules are called Russel Bodies. They are immunoglobulin.
In what conditions are you likely to see this cell?
What do the granules contain?
- Immune reactions mediated by IgE
- Parasitic infections
- Peripheral Vascular Diseases
- Cancer
Granules of eosinophils contain major basic protein
What does major basic protein do, and how?
It is a highly cationic protein that is toxic to parasites (and causes lysis of mammalian cells)
What kind of infection would this sample be typical of?
Parasitic - note the presence of eosinophils, plasma cells and multinucleated giant cells.
What type of receptor is expressed on this cell’s surface?
What does this receptor do?
FceRI - binds the Fc portion of the IgE antibody and leads to degranulation of the mast cell, releasing histamine and prostaglandins.
What is chronic bacterial infection of bone called?
Osteomyelitis
What is unique about the cells seen in osteomyelitis?
Neutrophilic exudate can persist for many months
What is this slide showing?
What is the red arrow pointing to?
What is the black arrow pointing to?
Osteomyelitis
Red: Neutrophils
Black: Trabeculated Bone
What are the two types of granulomas?
Foreign body Granuloma
Immune Granuloma
What do you see here?
Immune granuloma
What is this?
Foreign body granuloma
Closer inspection of the granuloma shown at top, taken from lung nodules of a man with HIV revealed the following. What is this most likely?
Tuberculosis
This patient was mid 20’s, found dead in the street with a syringe stuck in his arm. His lungs had multiple white nodules, which we biopsied here. What are the clear spaces with the refractile material?
Talc granuloma - used to cut cocaine… causes a foreign body giant cell reaction
What is this?
Tuberculosis granuloma
If you see a caseating granuloma, what is the first thing to rule out?
TB
What is a non-caseating granuloma with abundant macrophages, particularly in the bowel likely to be?
Sarcoidosis
What would you call acid-fast bacilli in macrophages with noncaseating granuloma?
Leprosy
A rounded, or stellate granuloma containing central granular debris and recognizable neutrophils, with few if any giant cells would point to what?
Cat-scratch disease
What kind of granuloma would you expect to find in Crohn disease (IBD)?
Noncaseating granulomas in wall of intesting with dense chronic inflammatory infiltrate
Chronic inflammation is a prolonged host response to…
Persistent stimuli
Chronic inflammation is caused by…
- Microbes that resist elimination
- immune responses against self and environmental antigens
- toxic substances (Ex/Endogenous)
Chronic inflammation is characterized by what four things?
- Coexisting inflammation
- tissue injury
- attempted repair by scarring
- immune response
The cellular infiltrate in chronic inflammation consists of? (4)
- Macros
- Lymphos
- Plasma Cells
- Other Leukocytes
Immune granulomas are a pattern of chronic inflammation induced by?
T cell and macrophage activation in response to an agent that is resistant to eradication
What are the acute-phase reaction mediators?
TNF
IL-1
IL-6
Type I interferons
Inflammation, even if localized is associated with cytokine induced systemic reactions that are collectively called the…?
Acute-phase response
What is one of the most prominent manifestations of the acute phase response, particularly when the inflammation is infection associated?
Fever, characterized by an elevation of body temperature by 1 to 4 degrees C.
What are the substances that induce fever?
What specifically is the increase in body temperature caused by?
Pyrogens: IL-1, TNF
Prostaglandins produced in the vascular and perivascular cells of the hypothalamus
What are three of the best known acute phase proteins?
- C-reactive protein (CRP)
- fibrinogen
- Serum Amyloid A (SAA) protein
To determine if pt. is at risk for cardiovascular disease, you would measure for what?
Sensitive CRP - increases in this reveal increases in inflammation
With increased inflammation is a patient in a hyperlytic or hypercoagulant state?
Hypercoagulant - due to the production and release of fibrinogen from the liver, which is crucial to the clotting process.
Why do we see increased sedimentation rate in inflammation?
Due to the increased fibrinogen!
Fibrinogen binds RBC’s and causes them to form what?
Stacks, called rouleaux
What is an increase in hepcidin related to?
Decreases GI absorption of iron
Why does hepcidin make sense in the inflammatory response?
Prevents access to iron for various pathogens such as haemophilus
In primary hemochromatosis, what happens to your hepcidin levels? What does this lead to?
They go down, because you don’t have that enzyme.
This leads to hemosiderosis, before developing hemochromatosis.
What is hemosiderosis?
Excess iron in the storage system - Reticuloendothelial system (RE)
What is hemochromatosis?
Excess iron in the tissue
What is the arrow pointing to?
RBC’s stuck together in a stack of rouleaux
Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infections. What does the leukocyte count usually climb to?
How high can it sometimes get?
Usually 15K to 20 K cells/mL
Sometimes 40k to 100K cells/mL
What kind of shift do most bacterial infections induce in leukocyte populations?
Neutrophilia - increased levels of blood neutrophils
What kind of leukocyte population change do you see due to viral infections, such as mononucleosis, mumps, and german measels?
Lymphocytosis: Absolute increase in # of lymphos.
In some allergies and parasitic infestations and cancers, what do we see with the leukocyte population?
Eosinophilia
What do some infections, such as typhoid fever, rickettsiae and some protozoa, do to the population of leukocytes?
Leukopenia - decreased # of circulating white cells
How do cytokines like TNF and IL-1 cause fever?
By stimulating production of prostaglandins in the hypothalamus
What stimulates the production of the acute phase proteins?
Cytokines - IL-6 and friends
What stimulates leukocytosis (production of leukocytes from precursors in bone marrow)?
Cytokines: Colony-stimulating factors
In some severe infections, such as septic shock, what do we see as far as BP, coagulation, and metabolism? What induces these changes?
- Fall in BP
- Disseminated intravascular coagulation
- metabolic abnormalities
Induced by high levels of TNF and other cytokines
What does tissue repair refer to?
Restoration of tissue architecture and function after injury
By what two ways does tissue repair occur?
- Regeneration by proliferation of residual (uninjured) cells
- Maturation of tissue stem cells
- Deposition of connective tissue to form a scar
The regeneration of injured cells and tissues involves cell proliferation, which is driven by growth factors and is critically dependent on what two things?
- The integrity of the ECM
- Development of mature cells from stem cells
What are the three tissue types covered under cell proliferation in this power point?
Labile
Stable
Permanent
What are labile tissues?
Give some examples.
Continuously dividing tissues
- Statified squamous epithelia of
- Skin
- Oral cavity
- vagina
- cervix
- Columnar epithelium of the
- GI Tract
- Uterus
- Fallopian tubes
- Cuboidal epithelia of the
- ducts draining exocrine organs (salivary glands, pancreas, biliary tract)
- hematopoietic cells in the bone marrow
What are stable tissues?
Give examples.
Cells of these tissues are quiescent (in the G0 stage of cell cycle), but are capable of dividing in response to injury or loss of tissue mass.
- Stable cells constitute the parenchyma of most solid tissues such as…
- Liver
- Kidney
- Pancreas
What are permanent tissues?
Give examples.
The cells of these tissues are considered to be terminally differentiated and nonproliferative in postnatal life.
This includes
- Most neurons
- Cardiac muscle cells
How does regeneration of the liver the liver occur?
- Proliferation of remaining hepatocytes
- repopulation from progenitor cells
The section on the left is resected, and six months later we get the image on the right. What is this called? What does this primarily happen by?
Compensatory hyperplasia.
Occurs mostly by liver cell replication, and to a lesser degree by stem cell differentiation.
In humans, resection of up to what percent of the liver can be corrected by proliferation of the residual hepatocytes?
90%
Where do liver stem cells reside?
Canals of Hering
Tissues are classified as labile, stable and permanent according to the?
Proliferative capacity of their cells
What are the three primary steps in scar formation?
- Angiogenesis
- Formation of granulation tissue
- Remodeling of connective tissue
Why are newly formed vessels leaky?
- Incomplete interendothelial junctions
- VEGF increases vascular permeability
What does Trichrome stain?
Collagen
This is stained in Trichrome, what does that make the image on the left?
On the right?
The left is granulation tissue, with faint blue/silver whisps indicating the beginnings of collagen deposition.
The right is scar tissue, with extensive staining of collagen.
What do macrophages do to help initiate scar formation?
- Clear offending agents and dead tissue
- Provide growth factors for proliferation of various cells
- Secrete cytokines that stimulate…
- fibroblast proliferation
- connective tissue synthesis and deposition
What are the seven steps of angiogenesis?
- Vasodilation in response to nitric oxide and increased permeability induced by vascular endothelial growth factor (VEGF)
- Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout
- Migration of endothelial cells toward the area of tissue injury
- Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells
- Remodeling into capillary tubes
- Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel
- Suppression of endothelial proliferation and migration and deposition of the basement membrane
What disease causes the most angiogenesis and problems in current patients?
Diabetes
What are the two steps in which connective tissue is laid down?
- Migration and proliferation of fibroblasts into the site of injury
- Deposition of ECM proteins produced by these cells.
What is the most important cytokine for the synthesis and deposition of connective tissue protiens?
Transforming growth factor-β (TGF-β)
What is this, and what cytokine is chiefly responsible for it?
Interstitial pulmonary fibrosis, excess TGF-B
(AKA - usual interstitial pneumonia)
Possible TQ here
During connective tissue remodeling, the outcome depends on a balance between synthesis and degredation of the ECM protiens. What causes the degredation of collagens and other ECM components?
Why are these things so named?
Matrix metalloproteinases (MMPs)
Called this because they are dependent on metal ions (i.e. Zinc) for their activity
If you have a zinc deficiency, what might you end up with?
Excess scarring
What does this example represent that is a major influencer of tissue repair?
Infection. Prolongs inflammation and potentially increases the local tissue injury.
List as many things that influence tissue repair as you can. What’s the most important one?
- Infection
- Diabetes
- Nutritional Status (Most important based on evidence based medicine)
- Glucocorticoids
- Mechanical factors, e.g. pressure, torsion.
- Poor perfusion (arteriosclerosis, diabetes, obstructed venous draingage)
- Foreign Bodies
- Classes of tissue types involved in the injury (labile, stable, permanent)
- Location of the injury
What is this condition? How does it impact tissue repair?
Scurvy - Vitamin C deficiency inhibits collagen synthesis and retards healing.
What lab test do we use as the number 1 predictor of postoperative outcomes?
Prealbumin test - can tune patient up nutritionally prior to the surgery
How do glucocorticoids impact tissue repair?
Their antiinflammatory effects result in weakness of scarring due to the inhibition of TGF-B production and diminished fibrosis.
In what cases might the antiinflammatory effects on tissue repair be desireable?
In corneal infections, glucocorticoids are sometimes used in conjunction with antibiotics to reduce the likliehood of opacity that may result from collagen deposition.
What is this called? What is going on here?
What is the number one surgery we see this in currently in our country?
dehiscence - the omentum is protruding through the belly.
Super common in elective gastric bypass
What type of necrosis is this?
What type of gangrene?
Coagulative
This is an example of “dry” gangrene (Wet would be infected, and lead to septicemia)
What cytokine was chiefly responsible for the development of the area indicated by the arrow?
What type of tissue is this?
TGF-B
Permanent - cardiac tissue
What is this?
Results of a subdural hematoma.
If stained with Trichrome, which of these images would light up the most?
Day 103 (far right image)
What do we see happening at day 12 here?
Formation of granulation tissue
When an injury involves only the epithelial layer, what is the principle mechanism of repair?
Epithelial Regeneration, also called primary union or healing by first intention
Wounding causes the rapid activation of coagulation pathways, which results in the formation of blood clot on the wound surface. Detail what is happening at the following intervals in the process of healing by first intention.
- 24 hours
- Day 3
- Day 5
- Second week
- End of month 1
- 24 hrs: Neutrophils seen as incision margin, migrating towards fibrin clot.
- Day 3: neutros replaced by macros. Granulation tissue progressively invades the incision space.
- Day 5: neovascularization reaches its peak as granulation tissue fills the incisional space.
- Week 2: there is continued collaged accumulation and fibroblast proliferation
- End of month 1: Scar comprises a cellular connective tissue, largely devoid of inflammatory cells and covered by an essentially normal epidermis
What is the difference between first intention and second intention?
Mostly wound size.
First intention - cuts cells only (why we use sharp scalpels)
Second intention - Cuts large volumes of tissue
What is the blue stuff in the middle?
What is missing in that section?
Scar
Missing elastin = weak tissue
What is the key aspect that determines that this injury will heal slowly?
The basement membrane has been disrupted
This image shows plump fibroblasts and lots of capillaries, what is this tissue?
Granulation tissue
If Dr. Hertz says: “You see a multinucleated giant cell surrounded by epitheliod histocytes and lymphocytes” You would call this tissue specimen a?
Granuloma
What are five key aspects of secondary healing?
- Large tissue deficit wounds
- greater mass of scar tissue
- Dermal appendages that have been destroyed in the line of the incision are permanently lost
- Wound contraction in large surface wounds
- Formation of a network of myofibroblasts
Second or first intention?
What is the disease?
Second intention
Ulcerative colitis (I guess, he wasn’t terriby specific, but I think we will see this later, Inflammatory bowel disease is probably all we need now)
At best, carefully sutured wounds have approximately what strength relative to normal skin?
70%
What is shown here?
Liver Cirrhosis
What does the arrow indicate in this liver biopsy?
Collagen deposition, this is from a cirrhotic liver
TGF-B = ???
Fibrosis and scarring
Excessive formation of the components of the repair process can give rise to?
Hypertrophic scars and keloids
What is the layman’s term for exuberant granulation?
Proud flesh
What race is this most often associated with?
What is this called?
Keloid - Mostly african americans
What are the main phases of cutaneous would healing?
Inflammation
Formation of granulation tissue
ECM remodeling
Cutaneous wounds can heal by primary union or secondary union. How is secondary different?
More extensive scarring and wound contraction
Wound healing can be altered by many conditions such as?
- Infection
- Diabetes
- Type of injury
- Volume of injury
- Location of injury
- Tissue types involved
Excessive production of ECM in the skin can lead to what?
Keloids
