Intro to Inflammation Flashcards
Inflammation
the response of vascularized tissues to infections and damage that brings cells and molecules of host defense from circulation to the sites where they are needed to eliminate offending agents (and repair damaged tissues)
Causes of acute inflammation
1) infection
2) physical injury (cuts, burns)
3) Foreign bodies (splinters, sutures)
4) Immune reaction (allergy, hypersensativity)
Acute inflammation steps
local tissue damage
vasodilation
erythema (rubor)
increase in temp (calor)
Increased capillary permeability, fluid accumulation (edema, pain)
continues chemotaxis
Edema
Neutrophils
Active phagocytes in tissue
Attracted to tissue by chemotactic factors such as complement, clotting proteins
Kill by ROS, granule contents
Release interleukin 8 (a chemokine that attracts inflamm response)
Macrophage
Ingest microbes and damaged cells
Produce IL-6, TNF-α, and IL-1
Produce growth factors that aid in repair
Neutrophil
Macrophage
Leukocyte responses
Note that there are different receptos. Release of cytokines when microbe binds leads to amplification of inflamm response
Macrophage effector function
Macrophage can either be involved in repair or inflammation and tissue injury
For repair it releases growth factors (platelet derived and fibroblast gf)
In inflammaiton they release ROS and nitrogen species
also release chemokines
Inflammatory cytokines funciton to
mobilize neutrophils
activate the vascular endothelium
chemotactic
On sensing microbial products, macrophages secrete a variety of pro-inflammatory cytokines
IL6
Fever. Induces acute-phase protein production by hepatocytes
TNF-α
Avtivates vasculat endothelium and increases vascular permeability, which leads to increased entry of complement anc cells to tissues and increased fluid drainage to lymph nodes.
Causes fever. Mobilization of metabolites. Shock.
IL-1ß
Activates vascular endothelium. Activates lymphocytes. Local tissue destruction. Increases access of effector cells.
Causes fever, production of IL-6.
CXCL8 (IL-8)
Chemotactic factor recruits neutrophils and basophils to site of infection
IL-12
Activated NK cells
IL 6
Fever
Induces acute phase protein production by hepatocytes
TNF-α
Activates vascular endothelium and increases vascular permeability, which leadds to increased entry of complement and cells to tissues and increased fluid drainage to lymph nodes
Fever
Mobilization of metabolites
Shock
IL-1ß
Activates vascular endothelium
Activates lymphocytes
Local tissue destruction
Increaes access of effector cells
Fever
Production of IL-6
CXCL8 (IL8)
Chemotactic factor recruits neutrophils and basophils to site of infection
IL12
Activates NK cells
Acute phase proteins
IL-1 IL-6 and TNF go to liver
Liver makes:
Fibrinogen
Serum amyloid A
C reactive protein
C3
Haptoglobin
Eosinophils release
cytokines and chemokines
leukotrienes
prostaglandins
Basophils release
histamine
heparin
Mast cells release
Histamine
TNF-α in allergic response and pathogen invasion
Eosinophils
Basophils
Mast cells
Histamine leads to
Blood clots
Gastric acid secretion
Blood vessels to dialate
Bronchoconstriction
Increased permeability of capillaries
Adrenaline release
Swelling and inflammation
Frequent heart beat
Endothelium
Express adhesion molecules for leukocutes
Increased by TNF-α and IL-1
Proliferate during inflammation to handle increased flow
Produce proinflammatory cytokines and to induce chemotaxis and stimulate angiogenesis for tissue repair
Leukocyte migration
Cytokines can up regulate selectins which allow leukocutes to slow down, roll, and enter ECM
Chemotaxis
Chemical signals that cause immune cells to migrate to a site of infection or injuty
There is a chemotactic gradient. Brings immune cells to site and causes migration into tissues
Vasodilation and vascular permeability
The redness and heat of inflammation
Vasodilation happens- immune cells and proteins can leak into tissue
Nitric Oxide
Macrophages produce this.
NO leads to reduced leukocyte adhesion to vessel wall
Vascular smooth muscle relaxation and vasodilation
Reduced adhesion of platelets
Vasodilators
Nitric oxide
histamine
prostaglandins
serotonin
Macrophages produce what vasodilator
Nitric oxide
What cells produce histamine vasodilator
Basophils and mast cells
What cells produce prostaglandins
eosinophils and endothelial cells
Endothelial cells
Vascular permeability through histamine release
Basophils and mast cells
Vascular permeability through leukotrienes
eosinophils and endothelial cells
Vascular permeability through bradykinin
endothelial cells
Vascular permeability can happen through release of
histamine
leukotrienes
bradykinin
complement components
Arachadonic acid
important in vasodilation and vascular permeability
cyclooxegenase can turn a acid into prostoglandins
Cox 1, COX 2, ASA, and indomethacin can inhibit this
Steroids inhibit phospholipids from being turned into arachadonic acid
Clotting
Sometimes good thing needed to stop bleeding. Can wall off infection. Platelets critical.
Cytokines produced by macrophaged cause dilation of local small blood vessels
Leukocytes move to periphery of blood vessel as a result of increased expression of adhesion molecules
Leukocytes extrqavasate at site of infection
Blood clotting occurs in the microvessels
Platelets
Contribute to blood clots
Release:
ROS to recruit additional platelets
Fibroblast growth factors for wound repair
Serotonin for vasodilaiton
Anti-microbial peptides
Platelets
Clotting and repair
Clotting in A is good. Bacteria contained locally. Can not escape.This can happen if we inhibit plasminogen
In B, plasminogen leads to clot dissolution and you have bacteria spreading. This can lead to larger infection.
Kinins and clotting cascades
Kininn cascade
Bradykinin can lead to vascular permeability
Thrombin can turn fibrinogen into fibrin plasmin can also lead to fibrin
D dimer
measure of fibrin degradation products
Prothrombin time
time in secronds for a fibrin clot to form
Clinical coagulation tests
When you have a clot there is some fibrin involved. As a result of this when you have clotting you can get fibrin degradation products
Prothrombin time is ther time in seconds that it takes a fibrin clot to form
D dimer is measure of fibrin degredation products
Mediators of vasodilation
(to increase blood flow to site of the infection)
histamine
nitric oxide
prostaglandins
Mediators of vascular permeability
(helping immune cells to get to tissues)
Histamine
complement
bradykinin
leukotrienes
Mediator of chemotaxis
IL-8
Chemokines
Complement
Mediators of fever
TNF-α
IL-1
IL6
Prostaglandins
Mediators of pain
prostaglandins
bradykinin
Mediators of tissue damage
ROS
NO
Morphologic patterns of acute inflammation- serous
Skin blister from burns or viral infection leads to accumulation of fluid
Morphologic patterns of acute inflammation- fibrinous
Continues vascular permeability - fibrinogen influx
Morphologic patterns of acute inflammation- purulent
Abcess cavity containing neutrophils and cellular debris surrounded by congested blood vessels
Liquefactive necrosis
Ulcer
An ulcer is formed by shedding of inflamed necrotic tissue of:
Mouth
Stomach
Intestines
Genitals
Sepsis
Systemic inflammation
Amplified whole body inflammatory response to trauma/infection
cytokine strom destorys tissues
Systemic inflammatory response syndrome (SIRS) due to infection
Multiple organ dysfunction syndrome (MODS)
Systemic inflammation
Local inflammation
Endothelial cells. TNF and IL-1 signal.
chemokines made
Increased permeability of cells
Leukocytes signaled by TNF and IL-1
Produce IL-1 IL-6 and chemokines
Systemic inflammation
Systemic protective effects
TNF-α, IL-1 , and IL-6 signal brain. Leads to fever.
IL-1 and IL6 signal liver. Leads to acute phase proteins.
TNF, IL-1, and IL-of 6 signal bone marrow. Leukocyte production
Systemic inflammtion
Systemic pathological effects
TNF signals heart. Low cardiac output.
TNF signals endothelial cells/ blood vessels
Thrombus. Increased permeability
TNF signals skeletal muscle. Insulin resistance.
Resolution of inflammation
Injury can happen and inflammtion happens.
Vascular changes, Neutrophil recruitment. Limited tissue injury.
Resolution can happen. We want this. Back to normal function.
However, we can get fibrosis or chronic inflammation which can be bad. Fibrosis is collagen deposition and loss of function.
Chronic inflammation causes
Persistant infections (ex TB, H pylori)
Immune mediated diseases
autoimminity, allergic diseases
Prolonges exposure to toxic agents
Cancer
Cells in chronic inflammation
Activated macrophages help activate T cells
TNF and IL-17, and chemokines lead to reccruitment of neutrophils and macrophages. Inflammation.
Activation of macrophages can again activate T cells through antigen presentation to T cells
Graulomas
morphological manifestation of chronic inflammation
Aggregation of T cells and macrophages to contain an offending agent that is difficult to eradicate
Atherosclerosis
Endothelial damage
Fatty streak formation- contains lipid filled macrophages (foam cells) and activated T cells
Fibrous cap- advanced stage to wall off lesion
Plaque rupture- material inside plaque released, thrombus occurs
Treated by statins- decreased leukoccyte adhesion and NO, inhibits cholesterol synthesis
Inflammatory bowel disease
Ulcerative colitis and crohns disease
persistant immine response to normal fluora
activated macrophages and CD4+ T cells sectere cytokines, prostaglandins, leukotrienes, NO
Characterized by diarrhea, rectal bleeding, and weight loss
Increased risk for colorectal cancer
Overview of inflammation
Inflammatory cytokines promote cancer
Acute vs Chronic Inflammation
Causative agent
Major cells involved
Primary mediators
Onset
Duration
Outcomes
