Pathophysiology of Inflammation Flashcards
What is the purpose of inflammation?
- Mobilize and attract immune components to the site
- Neutralize invasion of microbes and limit their spread
- Remove debris and prepare for repair
- Finally, RESOLVE when the job is done
What are the two types of inflammation?
Acute and Chronic
Describe acute inflammation
- Short in duration (<2 weeks)
- Involves discrete set of events
- Localized to the area of injury or infection
- Critical for human health
Describe chronic inflammation
- More diffuse area
- Extends over longer period
- Usually maladaptive/harmful
- May result in scar tissue formation, tissue destruction, deformity
- May be the cause of illness and disability
Inflammation Path Summary (Based on the diagram)
Injury
Neutrophils + macrophages // Vasoactive chemicals // Chemokines
Vasodilation + Vascular permeability
Emigration of neutrophils and macrophages into tissue
Phagocytosis
Acute Inflammation - Sequence of Events
- Precipitating Event: tissue damage or microbial invasion
- Activation of local inflammatory cells (macrophages, dendritic and mast cells, neutrophils)
- Generation of local mediators: leukotrienes, prostaglandins, bradykinin, histamine, complement cascade, neutrophil proteases, ROS. Causes VASODILATION, VASCULAR PERMEABILITY
- Recruitment and emigration of more neutrophils, macrophages, plasma proteins, including clotting proteins (if needed)
- Bacteria, debris, dead cells phagocytosed
- If wound present, platelets seal the area –> clotting
- Resolution of inflammation: healing, fibrosis, scar
How does inflammation lead to edema?
Increased vascular permeability of blood vessels
The gaps between endothelial cells are widened, allowing plasma proteins and leukocytes to enter the site of tissue damage
Fluid leakage through those vessels results in EDEMA
What are the cardinal signs of inflammation?
- Pain
- Heat
- Redness
- Swelling
(loss of function could be a fifth!)
Signs and Symptoms of Inflammation
- Fever
- Neutrophilia (release of neutrophils)
- Lethargy, feeling tired
- Muscle catabolism (increase AA pool for antibody production)
- Liver releases acute phase proteins in response to IL-1, IL-6, TNF-alpha (pro-inflammatory cytokines released primarily by macrophages, can be measured in patient’s blood)
What are acute-phase proteins?
A protein whose plasma concentrations increase during inflammation
Innate Immunity
Does not require previous exposure to antigen
Rapid action, quick resolution
Kill invading organisms via phagocytic cells, NK, protein cascade
Acquired Immunity
Adaptive Immunity
Previous exposure required
Slower initial activation, can last a lifetime (but response can be rapid on second exposure)
Immune cells (T cells, B cells)
Cell-mediated immunity (cytotoxic killer T cells)
Humoral immunity (B cells, antibodies)
What are the two pathways for leukocyte (WBC) development?
Lymphoid
Myeloid
What does the lymphoid pathway give rise to?
Lymphocytes
NK cells
What does the myeloid pathway give rise to?
Granulocytes, monocytes, macrophages, dendritic cells, megakaryocytes, erythrocytes
What do Helper T cells do?
- Activate other T cells and macrophages
- Stimulate B cell proliferation and antibody production
- Secrete pro-inflammatory cytokines
What do cytotoxic, or “killer” T cells do?
Kill infected cells (NOT the pathogen, the pathogen-infected cells)
What do B lymphocytes do?
Created and developed in bone marrow
Produce antibodies
Long-lived
Have memory cells that produce daughter cells programmed to produced the same antibodies
Differentiate into plasma cells, “antibody factories” that can synthesize large quantities of antibodies when they are needed
What is the relationship between T helper cells and B cells?
T helper cells help activate b cells
Antibodies are produced by _____
B lymphocytes
Are soluble form of BCRs, circulate in blood, ly,ph, found in mucus
Describe an antibody’s structure
Four polypeptide chains
two long heavy chains
two short light chains held together by disulfide bonds
What are some antibody functions?
- Function as antitoxins, bind and neutralize bacterial toxins
- Are OPSONINS: Coat antigens and make it more recognizable to phagocytes
- Can activate complement cascade (when bound to antigens on cell membranes)
- Form antibody-antigen complexes that precipitate out of body fluids, problematic in certain autoimmune disorders
Neutrophils, eosinophils, mast cells, and basophils are examples of _____
Granulocytes - Myeloid lineage
Where are mast cells found?
Found in tissues, especially tissues that interface the external environment
Where are basophils found?
Found in the circulation
Which cells are a part of the myeloid lineage?
Granulocytes (neutrophils, eosinophils, mast cells, basophils)
Antigen-presenting cells (monocytes, macrophages, dendritic cells)
RBCs, megakaryocytes
What are granulocytes?
White blood cells that have cytoplasmic granules containing enzymes needed to kill bacteria and other invaders
How do granulocytes work (intracellularly and extracellularly)?
Intracellularly - break down pathogens that are engulfed and endocytosed
Extracellularly - they release into the nearby environment by the granulocyte, can cause tissue damage
Which cell is the primary cell type of acute inflammation?
Neutrophils
They arrive quickly to the site
Function of neutrophils
Move from blood into tissue
Phagocytose and kill invading organisms, then undergo apoptosis
How do neutrophils arrive to the area of injury?
Chemotaxis // chemotactic factors
includes complement fragments and cytokines
When phagocytosis occurs, what neutrophil killing mechanisms are activated?
Generation of ROS –> “oxidative burst”
Breakdown of bacterial proteins by lysosomal proteases
ROS and lysosomal proteases released onto nearby tissues can cause secondary tissue damage including reperfusion injury)
How do endothelial cells that line the blood vessels help move WBCs from the blood to tissues?
Upregulate protein adhesion molecules that capture WBCs, including neutrophils, monocytes
Physically alter position to aid movement of WBC into tissue (diapedesis)
Have anti-clotting and anti-inflammatory activity
Promoting leukocyte/WBC recruitment and platelet adhesion
Chemokines –> promote movement into the tissue
What do selectins promote?
Neutrophil rolling
What do integrins promote?
Neutrophil adhesion
What does “shift to the left” refer to?
An increase in the percentage of immature neutrophils released from bone marrow (usually during bacterial infection)
AKA, more immature neutrophils pushed out by bone marrow to fight invaders –> push to the left causing a band neutrophil to form
During what phase of allergic responses are eosinophils important in?
The late phase of allergic responses
What do eosinophils do?
Contain potent killing agents (mainly proteases) that are meant to be exocytosed onto larger targets (such as parasites) too big for phagocytosis
Can injure healthy tissue –> its usual targets are large, so they can cause damage to healthy human tissue
What do basophils contain/do?
Contain histamine and other mediators
Circulate in blood in healthy people, but can be recruited to inflamed tissue
What do basophils do?
They are the major cell of allergic responses
“cousins” of basophils
Contain histamine, other mediators –> vascular permeability, vasodilation
Bind IgE with Fc receptors –> allows antibodies to then bind with antigen
Describe how antibodies allow mast cells to bind with antigens
The antibody (IgE) binds with mast cells first
This then allows it to bind to an antigen (via mast cell’s Fc receptors)
In other words, mast cells must be “primed” with IgE before they will respond to a particular antigen
How does inflammation increase the lifespan of monocytes?
Inhibits their apoptosis
Usual lifespan: 1-3 days
When a monocyte’s lifespan increases due to inflammation, what can it then do?
Differentiate into macrophages
Becomes phagocytic, ingests bacteria and cell debris/cleaning up after tissue injury
Inflammatory, cytokine secretion
Immunological, present antigen to helper T cells
Chronic inflammation, “bad actors”
How are macrophages the “bad actors” in chronic inflammation?
Remain in the inflammatory focus/state
Secrete stimulatory cytokines
Provide ongoing stimulation of inflammatory processes
Can live for months to years, inhibit their own apoptosis
What do dendritic cells do?
Capture and present antigens to T cells
Produce chemical messengers (ex. type 1 interferon for viruses suppresses viral replication machinery in nearby cells
What are examples of arachidonic acid metabolites?
Prostaglandins
Leukotrienes
Thromboxane A2
What are the two pathways that result in inflammation (from arachidonic acids)?
Cyclooxygenase (COX)
5-Lipoxygenase
Describe the COX pathway that results in inflammation
Arachidonic acid
COX (1 and 2)
Prostaglandins
Prostacyclin // // Thromboxane A2
Vasodilation, inhibit platelet aggregation // // vasoconstirction, platelet aggregation
PGD2 or PGE2
Vasodilation & increased vascular permeability (just like histamine)
What are cytokines?
Signaling molecules
Alter the activity of WBCs
Associate with macrophages and lymphocytes (T cells)
examples: TNF-alpha, IL-1, IL-6
What 3 pathways activate complement?
Classical, lectin, and alternative
What are the functions of complement?
Enhances inflammation
Induces production of TNF-alpha, IL-1, etc.
Induce mast cell degranulation
Opsonization, greatly enhances phagocytosis
Increase vascular permeability
Direct cytotoxic effect on target cells (Membrane Attack Complex / MAC) –> eventually the cell will lyse
What are kinins and what do they cause?
Small polypeptides
Vasodilation, inflammation, increased vascular permeability, smooth muscle contractions, pain, helps intimate clotting
How does acute inflammation resolve?
Neutrophil apoptosis
Macrophage phagocytosis of debris
Stimulation of new tissue growth and angiogenesis
Monocytes and macrophages return to normal lifespan
Fluid and proteins removed via lymphatic drainage
Fibroblasts repair the wound, and create a scar
What is fibroblasts’ role in wound healing?
They proliferate (due to growth factors released by macrophages)
Synthesized connective tissue (including collagen)
Able to migrate to site
Scar formation
What is fibrosis?
Thickening of previously-healthy tissues
Can lead to loss of function due to non-elastic tissue (scar tissue)
Happens due to chronic inflammation
What are some results of chronic inflammation?
Angiogenesis (result in an increase of WBC entering)
Mononuclear cell infiltrate (remain activated)
Fibrosis (scar) –> loss of function due to non-elastic tissue
What marks chronic inflammation?
Presence of long-lived cell types (macrophages, lymphocytes, plasma cells, and fibroblasts)
Macrophages remain in an activated state –> continue to release cytokines that perpetuate the pro-inflammatory state, their lifespan also increases
Continued cytokine release
How do macrophages maintain chronic inflammation?
By causing tissue injury and fibrosis
Continue to release pro-inflammatory cytokines (IL-1, TNF-alpha)
What is SIRS?
Systemic Inflammatory Response Syndrome
massive, uncontrolled, systemic inflammatory response
Extremely serious, can be due to infectious or non-infectious causes (burns, pancreatitis, others)
Widespread tissue injury
Can be fatal
General S/Sx of SIRS
Increased body temp or low body temp
High heart rate
High RR, low arterial PaCO2
High WBC count, presence of band neutrophil (shift to the left)
T cells and B cells require a ______ to be activated
T cells and B cells require a COSTIMULATORY to be activated; not sufficient to simply recognize and bind to an antigen
What is miRNA’s role in the regulation of immune function?
Tamps down immune response by preventing translation of genes involved in inflammation
How does the immune system recognize “self” from “non-self”?
Major Histocompatibility Complex (MHC)
Key role in the activation of helper and cytotoxic T cells
Guide cytotoxic T lymphocytes toward target cells
Which class of MHC molecules are found on all nucleated cells?
Class I MHC molecules
Which class of MHC molecules are found on APCs: B cells, macrophages, and dendritic cells?
Class II MHC molecules
How do Class I MHC molecules help initiate an immune response?
Present self and non-self antigen to cytotoxic T cells
Cytotoxic T cells only react to abnormal antigens
Self antigens are ignored
How do Class II MHC molecules help initiate an immune response?
Present antigen to helper T cells
What is Rheumatoid Arthritis (RA)?
An autoimmune disease that is very painful and results in joint destruction
Explain how RA causes joint destruction
B cells form autoantibodies to multiple molecules/proteins
Rheumatoid factor (RF) is an autoantibody to a person’s own IgG
Anti-cyclic citrullinated peptide antibodies (ACPAs) more specific for RA –> cause inflammation
Often leads to immune complex deposition in the joints
Other autoantibodies can be found as well in the synovial fluid of patients with RA
What is the primary target of the autoimmune response in RA?
The synovial membrane (synovium)
What are the results of RA?
Synoviocytes undergo hyperplasia and hypertrophy
Angiogenesis –> provides more SA for leukocyte recruitment
Increased lymphocytes, macrophages, neutrophils, and inflammatory mediators
Synovial membrane transformed into thick, inflammatory tissue –> the pannus (which destroys cartilage)
Cartilage destroyed –> bones deteriorate, joint becomes stiff, immobile, and ankylosing
Which hypersensitivity types are mediated by antibodies?
Types I, II, III
Which hypersensitivity types are mediated by T cells?
Type IV
Type I Hypersensitivity
AKA immediate hypersensitivity
ALLERGY and ALLERGIC REACTION
IgE principle mediating antibody
Mast cells, basophils, histamine
Can become anaphylaxis and potential death if not treated immediately
First vs. second exposure: antigen binding to IgE
First exposure: T helper cells induce B cell class-switching to IgE antibodies, IgE binds to mast cells (now primed)
Second exposure: immediate release of mast cell granules
Anaphylaxis S/Sx
SOB, coughing, wheezing 2/2 bronchoconstriction
Hives, itching, flushing
Oropharyngeal or ocular swelling, feeling of tightness in throat
Increased HR, hypotension
Nausea, vomiting
MEDICAL EMERGENCY
Describe Type II Hypersensitivity
Tissue-specific, cytotoxic, or cytolytic hypersensitivity
Often immediate, but can be delayed
Antibodies attack antigens bound to the surface of specific target cells or tissues
Causes lysis or phagocytosis of target cells
Examples: blood transfusion reactions, thyroiditis, Myasthenia Gravis
Describe Type III Hypersensitivity
Immune complex reaction
Not tissue-specific
Response to an Ag-Ab complex (antigen-antibody complex)
The immune and phagocytic systems fail to remove these Ag-Ab complexes, they then move into tissues
Activate complement, neutrophils arrive, ROS released –> tissue damage
Examples: systemic lupus, erythematosus, immune complex glomerulonephritis
Describe Type IV Hypersensitivity
AKA delayed hypersensitivity
No primary antibody involvement
Sensitized T cells react with altered or foreign cells and initiate inflammation and cell destruction
Examples: poison ivy, contact dermatitis, Tuberculin-type hypersensitivity
