What is the goal of inflammation?
a protective response to dilute, isolate, and/or get rid of injurious stimulus, and the consequences of the injury
what can be a major consequence of inflammation?
it can be inappropriately triggered or poorly controlled leading to tissue injury
What is acute inflammation?
- rapid onset
- short duration (hrs to a few days)
- characterized by edema and emigration of White blood cells
What is chronic infammation?
- back-up plan
- long duration
- characterized by lymphocytes, macrophages, proliferation of vessels, fibrosis, and tissue destruction
What are the 4 events of acute inflammation?
- stimuli for acute inflammation
- vascular changes
- cellular reaction: white blood cells extravasation and phagocytosis
- termination of acute inflammatory response
What are the 5 cardinal signs of inflammation?
- calor, rubor, tumor, dolor, and lasesa
what is calor?
heat caused by vasodilation
What is rubor?
redness caused by increased blood flow
What is tumor?
swelling due to increased blood flow and vascular permeability
what is Dolor?
pain due to stimulation of nerolan pathways by bradykinin, prostaglandins, histamine and serotonin
what is lasea?
loss of function
What are the 3 major components of acute inflammation?
- increased blood flow
- leakage of plasma proteins= edema
- white blood cell emigration
What are the stimuli for acute inflammation?
- foreign bodies or environmental elements
- tissue necrosis
- immune reactions
What types of infections stimulate inflammation?
bacterial, viral, fungal, parasitic, and microbial toxins
What are some examples of foreign bodies and environmental elements?
UV light, radiation, trauma, thermal injury, chemicals
How does tissue necrosis cause inflammation?
necrotic cells release uric acid, ATP, DNA which induce inflammation
How does hypoxia induce inflammation?
via hypoxia-induced factor- 1a
What is hypoxia-induced factor-1a?
released by cells deprived of O2 activating the transcription of many mediators involved in inflammation
What is the function of VEGF?
known to increase vascular permeability
How is inflammation induced by immune reactions?
- hypersensitivity reactions
- cytokines for t cells
What is stimulated with inflammation?
innate immune system
What is the innate immune system?
non-specific defense for environmental stimuli
What are the 4 components of the innate immune system?
- physical barriers and microenvironments
- molecular products from mucosal epithelia
- preformed and synthesized chemical mediators from tissue effector cells
- effector molecules in the blood like plasma proteases and in certain nerve fibers
What are the physical barriers and microenvironments that make up the innate immune system?
skin, mucosa, pH, mucociliary escalator, salivia, mucous secretions, peristalsis
What are some molecular products for mucosal epithelia that make up the innate immune system?
lactoferrin, antimicrobial peptides, surfactant protiens
What are the chemical mediators of mast cells?
histamine and TNF-alpha
What are the chemical mediators of white blood cells?
cytokines, degradative enzymes
What are the chemical mediators of macrophages?
What are the effector molecules in blood and nerve fibers that make up the innate immune system?
blood: complement, kinin, clotting fibers
nerves: sensory fibers, C-reactive fibers that release substance-P
What do the severity and clinical signs of acute inflammatory response depend on?
- the route of exposure
- the physical and biological characteristics of the stimulus
What is a TLR?
What are PAMPs?
pathogen associated molecular patterns
What does the TLR do?
recognizes the PAMPs
Once the TLR recognizes the PAMPs, what happens?
triggers release of chemokines and cytokines to activate cells
what are some examples of PAMPS?
LPS, lipotheicoic acids, and peptidoglycan
What are the chemical mediators of acute inflammation?
vasoactive amines, plasma proteases, lipid mediators, PAF, cytokines, chemokines and NO
In acute inflammation, how is vascular flow and caliber changed?
vasodilation, increased permeability of the microvasculature, loss of fluid, and leukocyte accumulation along the vascular endothelium
What is vasodilation?
- early manifestation
- constriction of arterioles for a few seconds, then opening of new capillary beds in the area to increase blood flow
What does vasodilation result in?
heat and redness
What mediates vasodilation?
hisamine and NO
What occurs with you increase the permeability of the microvasculature?
there is an outpouring of protein-rich fluid into extravascular tissues (edema)
What is a consequence of the loss of fluid to the extravasculature space?
inc. conc of RBCs in small vessels, increased viscosity of blood, dilation of vessels, and slow blood flow
What is the hallmark of acute inflammation?
increased vascular permeability leading to edema
What are some ways the vascular permeability is increased?
- retraction of the endothelial cells
- direct endothelial cell injury
- delayed prolonged leakage
- leukocyte-mediated endothelial injury
- increased transcytosis
- leakage from new blood vessels
What is the most common mechanism of increasing vascular permeability?
retraction of the endothelial cells
What triggers the contraction of endothelial cells?
histamine, bradykinin, NO, leukotrienes, and neuropeptide substance-P
What does direct endothelial injury result in?
endothelial cell necrosis or platelet adhesion and thrombosis
What is delayed prolong leakage of the endothelium caused by?
mild to moderate injury:
- thermal, UV, radiaton, or certain bacterial toxins
Where does leukocyte-mediated endothelial injury normally occur?
venules, pulmonary capillaries, and glomerular capillaries
How does leukocyte-mediated endothelial injury normally occur?
by WBCs adhering to the endothelium for prolonged periods of time
What is a visiculovacular organelle?
channel in the cytoplasm of endothelial cells that is made up of vesicles and vacuoles in which transcytosis takes place
What is VEGF?
- vascular endothelial grwoth factor
- inc. vascular leakage by increasing the size of vesiculovacuolar channels
What is extravasation?
sequenced events of white blood cells from the vessel lumen to the interstitial tissue
What are the effector cells of the acute inflammatory response?
- vascular endothelial cells
- mast cells
- macrophages/ monocytes
What is the function of vascular endothelial cells?
- regulate hemostasis/coagulation, vascular pressure, angiogenesis during wound healing, carcinogenesis, leukocyte homing, and inflammation
Where are mast cells normally found?
in the interstitium:
- skin, mucous membranes
What do mast cells respond to?
foreign proteins and microbes
what antibody do mast cells have a high affinity for?
What is mast cell degranulation triggered by?
What is the first type of white blood cell in inflammatory exudate?
what are the main functions of neutrophils?
- kill or limit the growth of microbes
- to kill tumor cells
- to eliminate foreign materials via phagocytosis
What is the life span of a neutrophil?
what do neutrophil granules contain?
myeloperoxidase, defensins, cathelicidins, lactoferrin, elastases, and gelatinase
What is the function of myeloperoxidase when it is released by neutrophils?
What is the function of defensin and cathelicidin when released by neutrophils?
degrade by forming pores in microbial membranes
what is the function of lactoferrin?
inhibits growth of phagocytosed bacteria be sequestering iron
what is the function of elastase?
hydrolyzes bacterial cell wall proteins and tissue elastin
What is the function of gelatinase and myeloperoxidase when they are release by neutrophils together?
kill extracellular microbes and degrades the ECM
What do eosinophil granules contain?
What types of pathological processes are eosinophils normally seen?
- helminthic infections and allergic diseases
How are monocytes recruited for circulation to sites of inflammation?
What do macrophages trigger?
trigger the adaptive immune response by presenting antigens to T cells
what is the function of macrophages?
phagocytosis and cytokine release
What does leukocyte activation result in?
increased Ca and activation of enzymes
What are the steps of extravasation?
- margination (cell accumulation)
What are the mediators of margination?
selectins an cytokines/chemokines
What are the mediators of rolling?
selectins and integrins
what are the mediators of activation and adhesion?
integrins and chemokines
What are the mediators of transmigration?
What is another word for transmigration?
Whate mediators stimulate the distribution of P-selectin on endothelial cells?
histamine, thrombin, and PAF
What is the predominant cell type in the first 6-24 hours of acute inflammation?
In viral infections, what cell type is the first to arive?
How long do neutrophils predominate in pseudomonas infections?
In hypersensitivity reactions, what is the main type of cell?
What molecules are important in white blood cells to get rid of bacterial infections?
What is leukocyte adhesion deficiency?
- mutation in B2 integrins
- results in neutrophilia with impared transmigration bc they cannot adhere to the endothelium
- severe gingivitis, tooth loss, ulcers, abscesses lacking pus, pneumonia
Is there a treatment for leukocyte adhesion deficiency?
What is phagocytosis?
release of enzymes by neutrophils and macrophages to eliminate injurious agents
What are the steps in phagocytosis?
- recognition and attachment to antigen
- engulfment in vacuole
- killing or degradation of ingested material
What is phagocytosis dependent on?
polymerization of actin filaments and requires similar signals as in chemotaxis