inflammation is a process carried out in response to either physical or immunological tissue insult....
TRANSCRIPT
Inflammation is a process carried out in response to either physical or immunological tissue insult.
It consists of a destructive process to remove the inflammatory trigger and damaged tissue, followed by repair and replacement.
The main actors in the destructive phase are neutrophils and macrophages.
Inflammation is signaled by heat, pain, redness, and swelling (calor, dolor, rubor, tumor).
Inflammatory conditions are named with the suffix itis.
Chapter 10 Inflammation
Macrophages are highly complex cells engaged in normal tissue maintenance and turnover.
Among their varied functions, they are sentinels against infection, both through the use of receptors for common molecules carried by pathogens, and through opsonization.
Macrophages exist in various levels of activation, wherein they become more aggressive at destroying macromolecules, and sending distress signals to recruit other components of the inflammatory response.
The most aggressively activated macrophages are derived from blood monocytes in response to inflammatory signals. These are called “infiltrating macrophages”.
Names of Macrophages According to Tissue Locations
Location
Connective tissue
Serous cavity
Liver
Bone tissue
Lung
Nervous system
Spleen
Skin
Inflamed tissue
Name
Histiocyte
Peritoneal macrophage
Kupffer cell
Osteoclast
Alveolar macrophage (dust cell)
Microglial cell
Sinusoidal lining cell
Langerhans cell
Infiltrating macrophage
Macrophage activation:
Toll-like receptors (TLR1-10) & C-type lectin receptors:
Moieties found in cell walls of Gram positive and Gram negative bacteria, Mycobacteria, Trypanosomes, Treponema, Neisseria; bacterial flagellin; viral glycoproteins; dsRNA; virus single stranded RNA; unmethylated CpG DNA; malarial pigment haemozoin; Toxoplasma gondi profilin-like protein; HIVgp120; fungus -glucans; zymosan.
Opsonization:
Immune complexes with IgG, IgA, activated complement on bacterial cell wall.
T lymphocyte signaling
Interferon
Homing
lymphocyte selectin binds endothelial addressin
cellular integrins bind endothelial ICAM/VCAM
Cells involved in inflammatory response
Neutrophils
Monocytes -> Infiltrating Macrophages
T lymphocytes
Resolution phase:
Epithelial cells
Fibroblasts
Leukocytes and % of Each Type in Blood
Granular
Neutrophils
Eosinophils
Basophils
%
59.0
2.7
0.3
Nongranular
Monocytes
Lymphocytes
%
4.0
34.0
Some cytokines involved in inflammatory responses
IL1 Macrophage distress signal; recruits and activates CD4 and CD8 T cells; systematically causes fever.
INF, IL2 Drives TH1 response.
IL4,5 Drives TH2 response; suppresses TH1 response.
TGF Deactivate macrophages; stimulate resolution; promote matrix synthesis; switch B cells from IgG to IgA.
IL3 Stimulates production of more blood cells.
IL8 Chemotactic factor for neutrophils.
INF, Shuts down translation; initiates virus-resistant state.
Mediators of inflammatory responses
Histamine
Kinins
Serotonin
Kinins are produced from kininogens during the coagulation cascade.
Serotonin is released from platelets during platelet activation.
Neutrophil/ macrophage interaction
Activated neutrophils secrete oxygen radicals, antimicrobial peptides, lysosomal granule contents, and signals to attract monocytes.
Monocytes differentiate to macrophages which will remove dead neutrophils and their secreted products.
Kinin (bradykinin) receptors
Acute inflammation Chronic inflammation
B2 receptor B1 receptor
Constitutively expressed Induced by chronic stimulation
Rapidly desensitized Not desensitized
When phagocytes fail to remove the inflammatory trigger:
Purulent exudate (pus) formation in an abscess – typically means that a bacterial pathogen is resisting killing by macrophages.
Fibrosis – formation of abnormal scar tissue because repair cells can not properly access the still-inflamed area.
Chronic inflammation – a long term state of inflammation in which there will be loss of tissue.
Steps and inhibitors of hemostasis
1. Vascular spasm
2. Platelet plugging
aspirin (acetylsalicylic acid), plavix (colpidogrel)
3. Coagulation
coumadin (warfarin), dicoumerol (active form of coumarin)
Vascular Spasm
Contraction of smooth muscle cells surrounding the injured vessel. Upstream constriction reduces blood loss. Can last 30 minutes.
Signaled by:
Thromboxane A2
Thrombin
Platelet activation
Receptors:
Glycoprotein Ib/V/IX --> von Willebrand Factor
Glycoprotein Ia --> collagen
Glycoprotein VI --> collagen
Glycoprotein IIb/IIIa --> fibronectin, other platelets
Signals:
Thromboxane A2 (COX pathway) [inhibited by aspirin]
ADP [inhibited by plavix]
(Other N.S.A.I.D.s inhibit COX, but are reversible inhibitors).
True or False?
http://biochem.uthscsa.edu/hardies-bin/survey.pl
The glycoproteins of this kind are generically called “adhesion proteins”
Three of the proteins are of a class called “integrins”. Integrins exhibit “inside out” signaling. That means:
a) When activated, the cell turns inside out.
b) When it binds its ligand, a signal is passed into the cell.
c) When the cell is activated, it shifts the integrin from an inactive to an active binding conformation.
d) They cause platelets to become “sticky”.
NSAIDs (non steroidal anti inflammatory drugs) include:
True or False?
http://biochem.uthscsa.edu/hardies-bin/survey.pl
a) aspirin
b) ibuprofin
c) tylenol
d) naproxin
e) prednisone
COO- Vitamin K /Protein-CH2-CH2-COO- + HCO3- ---------> Protein-CH2-CH \ COO-
Glutamic acid Carboxylase -carboxy glutamic acid
-carboxy glutamic acid modification in liver
coumadin (warfarin)
vitamin K vitamin K epoxide
vitamin K epoxide reductase
dicoumerol
carboxylaseinactive factor gamma carboxylated factor
O
Coagulation Complexes
neg. surface
XII HMW kininogen
preKallikrein Kallikrein
kinin
XIIa
platelet surfaceVIIIa
IXa X
Ca+2
Ca+2
Xa
tissue cellTF
X
Ca+2
VIIa
platelet surfaceVa
Xa II
Ca+2IIa
Ca+2 Ca+2
Coagulation Pathways
vWF+
PTT+
PT/INR+
Coumadin
Coumadin
Coumadin
Coumadin
platelets
aspirinplavix
hemophilia A
hemophilia B
kininogenkinin Inflammation
Tissue cell
collagen fibers
+
++
+
(platelet count; platelet function assay)
ristocetin +vWFaggregation
True or False?
http://biochem.uthscsa.edu/hardies-bin/survey.pl
a) The lab test for coagulation integrity in a patient taking coumadin is PTT.
b) von Willebrand Disease can look like a mild factor VIII deficiency.
c) A lab test for adequate compensation for classic hemophilia is INR.
d) A specific test for von Willebrand Disease is the ristocetin agglutination assay.
Regulation of coagulation
heparin: chopped up glycosaminoglycan released from mast cells, or administered clinically. Stimulates antithrombin III, which inhibits factors IIa, IXa, Xa, XIa, and XIIa. Reversed by protamine sulfate.
heparan sulfate: on surface of endothelial cells acts like heparin.
thrombomodulin: on surface of endothelial cells; activates Protein C & S; Protein C cleaves and inactivates factors VIIIa and Va.
prostaglandin I2 (PGI2): secreted by endothelial cells inhibits platelet activation.
Causes of abnormal bleeding
Genetic
hemophilia. A (F-VIII),
B (F-IX). X-linked
von Willebrand Diseaseup to 1%, men or women
Drugs
coumadin, plavix, aspirin,
Vascular fragilityvitamin C deficiency, connective tissue disorders
Diseases affecting platelets
leukemia, AIDS
Diseases affecting the liver
cirrhosis
chemotherapy, alcohol,
broad spectrum antibiotics
Laboratory Tests
Platelet count
Prothrombin time (PT/INR)
plasma from patient plus thromboplastin (contains triggers of extrinsic pathway)
Measures 3 Vit K dependent factors. VII has shortest half life of vitamin K-dependent factors.
Time to clot normalized by normal controls and adjusted for the potency of the thromboplastin is called INR (0.8 – 1.2 is normal).
Partial thromboplastin time (PTT)
plasma from patient plus thromboplastin (without TF) plus trigger of intrinsic pathway.