8. Acute Inflammation IV Flashcards
REVIEW: LAD
LAD1 - genetic mutation in which expression of one subunit of ___ is reduced, cannot adhere to EC, and the neutrophils cannot transmigrate > display susceptibility to infection; severe LAD1: expression of integrin by ___ > not survive past few months, delayed umbilical cord separation and infection will spreads; moderate LAD1: recurrent infection, manifests as gingivitis/periodont
LAD2 - defect in earlier molecule > if ligand for ___ is absent > neutrophil will not roll > cannot firmly adhere > similar manifestation
LAD3 - integrins expressed normally, but they must be activated by chemokines and then aggregate on surface and bind ICAM1 (surface of endo); cannot ___ them, cannot bind ___ > same phenotypes as LAD-I, but they also have ___ > mutation in gene is also present in ___ of bleeding
b-integrin
98%
selectin
activate
ICAM-1
bleeding disorders
homeostasis
Direct migration of leukocytes in response to a gradient of chemoattractants
Bc of tissue injury, the first cell activated is the ___ > release of histamine > firstly, causes ___ and increase in ___ (redness, heat, swelling are a result of this)
Initiates neutrophil recruitment/rolling: histamine also acts on vascular endothelial cells > ___ on endo cells > upon histamine binding: presynthesized selectin gets translocated from cytosol into membrane quickly
Macrophages produce ___ and ___ > major target: endo cells > increase ___ gene expression, and the expression of ___
Macrophages also produce ___ > activate integrin on surface of leukocytes, also induce chemotaxis
And then ___ is also an important chemoattractant
Concentration of cytokines is highest closest to the ___ > this gradient is important, no gradient = no ___
mast cells
vasodilation
vascular permeability
P-selectin
TNFalpha
IL1
E-selectin
ICAM1
chemokines
complement (C5a)
microbe
migration
Chemotaxis: Directed Cell Movement
Exogenous:
- ___ products;
- ___ peptide
Endogenous:
- complement pathway: ___ and ___
- lipid-derived mediators: ___
- cytokines, particularly those of the chemokine family (e.g., ___)
Exogenous:
Can be produced from microbes and host; from microbes (mostly) is exogenous (N-formyl-methionyl peptide), receptors for this is on surface of ___ > migration
Endogenous:
Activation of complement > C3a: more important for ___ activation thereby inducing ___
in early phase; and C5a: more important on ___ activation
Lipid derived mediator (LTB4) > important ___ chemoattractant; produced from ___ and ___
Cytokines (IL-8) is important for inducing ___
Defects in chemotaxis > increased risk of aggressive infection, and in oral cavity > ___
bacterial
n-formyl-methionyl
C3a
C5a
leukotriene B4
IL-8
neutrophil
mast cell
degranulation
neutrophi
neutrophil
macrophages
mast cells
chemotaxis
gingivitis/periodontitis
Recognition of microbes > receptors for chemoattractants (___ domain, GPCR) > upon activation > ___ changes and signal transduction > increased avidity > ___ of neutrophils on endothelium; followed by chemotaxis
TLR > amplify ___ signals
Release of ___ and ___ > result of phagocytic receptors (can also phagocytose microbe into phagosome), cytokine receptors and TLR
7 TM
cytoskeletal
adhesion
inflammatory
lysosomal enzyme
ROS
Why is this cell called neutrophil/PMN?
• Primary granules – Azurophilic – \_\_\_, BPO, LL-37, Elastase, Cathapsin • Secondary granules – \_\_\_ • Tertiary granules – \_\_\_ • All granules contain \_\_\_
- Small ___ apparatus
- Sparse ___ and ribosomes
- No ___
- ___ for energy production
- Phagocytosis/Respiratory burst /degranulation
Produced in ___, short-lived, only function is to phagocytosis
Do not require oxygen for ATP production, consumption occurs when activated > ___ (creation of free radicals)
the primary granules are the most important, can view them as lysosomes that digest ___ materials
MPO
lectoferrin
gelatinase
lysoszymes
golgi
mitochondria
rough ER
glycolysis
BM
respiratory burst
phagocytosed
Phagocytosis: 3 steps
___
___
___
Firstly, neutrophil must recognize the microbe, and then neutrophil must engulf (phagosome formation), and then contents of lysosome released into phagosome > phagolysosome, and then all mediators are released into the PL > degradation of microbe
recognition
engulfment
killing/degradation
Opsonization and Phagosome Formation • Phagocytosis – Opsonins; • IgG (\_\_\_) • C3b (Complement receptors 1 and 3 (\_\_\_) – Phagosome: • A cellular compartment in which a pathogenic microorganisms can be killed and digested. – Killing and degradation:
IgG and C3b > bind ___, and prepare them to be phagocytosed; there is a ___ receptor on neutrophil, and ___ for C3b thereby promoting binding and recognition
FcgammaR
CR1/CR3
microbes
FcgammaR
CR1/CR3
Killing and Degradation of Microbes
[LOOK AT SLIDE FOR DIAGRAM]
Respiratory burst:
NADPH oxidase > present on surface of ___ (membrane) > consists of 6 subunits > normally ___
Upon formation of phagolysosome it becomes ___ > transfers electron from ___ > conversion of oxygen into oxygen radicals > ___ dismutation > ___ (by itself this is not efficient) (oxygen ___)
Phagolysosome > primary granules > ___ > combine with H2O2 to produce ___ (___ acid, constitutive of bleach) > digests microbes (oxygen ___)
There are other important proteins: ___ released from granules (produced from neutrophils); ___ is an anti-micro peptide that punches hole in membrane (produced from neutrophils, ___ 37 ___ peptide); and ___ that degrades bacterial coat
phagosome inactive active NADPH spontaneous H2O2 dependent
MPO
HOCl
hypochlorous
independent
BPI LL37 leucine-leucine AA lysozyme
Chronic Granulomatous Disease
- Etiology/Pathogenesis:
- Mutations: Functional inactivation of ___ (phox) gene
- Inability to generate ___
- Clinical manifestation:
- Recurrent ___ infection
- Most susceptible to ___ bacteria.
- ___ skin infections
- Abscesses
- ___
- Gingivitis
Mutation in one of six subunits that prevents the aggregation of all ___ for proper function
Chronic granulomatous disease > more susceptible to catalase-positive bacteria > breaks down H2O2 into H2O; if the individual cannot produce H2O2 and the bacteria is reducing further, then the patient is more ___
Similar to symptoms of ___ and ___
phagocyte NADPH oxidase
ROS
bacterial
catalase-positive
superficial
cellulitis
subunits
susceptible
LAD
neutropenia
Chronic Granulomatous Disease (CGD)
[CASE REPORT]
Unresponsive to antibiotic
___ > catalase-positive organism
High WBC
High PMN % (50-70%)
Normal sialyl lewis X on surface of leukocytes > not ___
Normal CD11b/CD18 > not ___, but can potentially have LAD3 (expression is normal, but activation is defective)
Normal chemotaxis > no problem with leukocyte rolling and diapedesis
Abnormal respiratory burst > ___
___ infiltrate > do not see presence of neutrophils (recruitment of monocytes); however, there are neutrophils located in the abscess
Take neutrophil from normal individual, and test to kill microbes > 100% death; but take from CGD > bacteria ___ (killing is diminished, but there is some killing observed)
Diagnose: test ___, or genetically test for the ___ of the gene
Treatment: antibiotics, but also the presence of ___ > antifungals, ___ > cytokine, produced by T cells and activates macrophages, ___ therapy
This mutation only occurs in leukocytes, side effects of gene therapy [???]
burkholderia
LAD2
LAD1
CGD
mononuclear
persists
respiratory burst
subunit
fungus
INFgamma
HCT/gene
Chediak-Higashi Syndrome
- Etiology/Pathogenesis:
- Mutation in ___.
- Abnormal ___ formation
- Melanocytes: large ___
- Neutrophils: giant ___ granules
- Clinical manifestation:
- Identified in ___
- Oculocutaneous Albinism
- ___
- Gray Hair color
- Recurrent ___ infection
- ___
- Oral Ulceration
- ___ diseases
• Diagnosis: ___ smear
Easy diagnosis: take a blood smear; normal > PMN and the neutral granular components; CHS > ___ is relatively normal, but the ___ become large
• Treatment: ___, ___ transplantation (HTC)
lysosomal trafficking modulator gene (CH51/LYST)
lysosome
granules
azurophilic
infancy/childhood photophobia bacterial gingivitis periodontal
blood
nucleus
granules
antibiotics
hematopoietic cell transplantation (HTC)
Papillon-Lefevre Syndrome • Mutation and loss of \_\_\_ gene (\_\_\_ protease) • \_\_\_ development and \_\_\_ function • \_\_\_ Keratoderma and Periodontitis • Antimicrobial peptide \_\_\_ in neutrophils • Treatment: – Skin lesions: \_\_\_ (acitretin) – Periodontisis -\_\_\_ + \_\_\_ and \_\_\_ control
LL37: synthesized as a precursor (pro-LL37) > in order to become activated, the serine protease must cleave it > LOF in this ___ > no production of LL37
Palmoplantar Keratoderma > palms/soles have abnormal ___ > can see at a very early age > main reason is because of lack of production of LL37
cathepsin C serine skin neutrophil palmoplantar LL37 retinoid antibiotics plaque calculus protease thickening
Beneficial Suicide (NETosis): Why neutrophils die to make NETs
All the above are intracellular mechanisms, there are also EC mechanisms
Red= nucleus, green = cytoplasm
Upon activation > NADPH > transfer of ___ > nucleus undergoes disintegration > ___ and ___ component mix together (nucleus = jelly-like, granular = ___, disorganized) > jelly-like component > as neutrophil dies it releases it EC > neutrophil extracellular trap
When neutrophil has performed function, it is dying, but it is releasing its ___ content thereby trapping other microbes
electrons nucleus granular phagolysosome IC
Bacterial Strategies to Avoid/Evade Neutrophils (Bacterial virulence Factors)
___
– (Aggregatibacter Actinomycetemcomitans, AA)
• Proteases that inactivate
___
– PG
• Factors that bind ___ of IgG
– Staph Aureus Protein A
• ___:
– Klebsiella pneumoniae
– Streptococcus pneumoniae
Bacterial virulence factors:
Leukotoxin released from AA, and is toxic to the ___ and can eliminate it
leukotoxin
antibodies/complement
Fc region
carbohydrate capsules
neutrophils
Acute Inflammation and Resolution
• PGD2, PGE2, PGI2, LTB4 (vasodilation, Permeability, PMN chemotaxis)
• Lipid mediator class switching from PGs and LTs to ___
—• ___ monocyte recruitment
—• Inhibition of ___ PMN influx
—• Anti-inflammatory ___
• PUFA (EPA; Resolvins) and (DHA: Protectins and Maresins)
- –• Increase ___ generation
- –• ___
• Resolution
—• Resolved exudate removed through ___ vessel
• Failed Resolution:
—• ___ Inflammation
lipoxins
non-phlogistic
LTB4-induced
cytokine
lipoxin
efferocytosis
lymphatic
chronic
Acute Inflammation and Resolution cont.
Formation of ___ > important for resolution of inflammation
Monocyte recruitment in response to lipoxins (normally they secrete cytokines) recruited to remove dead neutrophils but not to release ___ (do not want to increase inflammation) > promote ___ (NP die after 1-2 hours)
Lipoxins inhibit LTB4-induced PMN, thereby decreasing recruitment of ___; and they produce anti-inflam cytokines
Exudate that is formed following efferocytosis is removed into lymphatic vessel and is terminated
lipoxins
cytokines
efferocytosis
neutrophils
Acute Inflammation and Resolutioin
PMN in pus > pro-inflam mediators produced here, and once it wanes > pro-resolving mediators (reducing recruitment)
Non-phlogistic monocyte recruitment > anti-inflam ___
Neutrophils into EV > production of ___ and ___
When removed by macrophages > production of ___ of ___/___ > put a break on everything
cytokines
EPA
E-resolvins
DHA
D-resolvins
protectins
Caries, Pulp inflammation and beyond……..
___ > Periapical Abscess > Porulis, cutaneous sinus cellulitis, ludwig’s angina, CST, leptomeningitis
___ > chronic inflammation
virulent (pyogenic)
non-virulent (non-pyogenic)
Anatomic features affecting pulp inflammation • Unyielding calcified walls – Limits \_\_\_ • Constricted blood source – Limits \_\_\_ – Subject to \_\_\_ • Tooth surrounded by bone – Bone infection very \_\_\_
Classification of inflammatory pulpal pathology • Classification of Pulpitis • \_\_\_ and \_\_\_ Pulpitis? • \_\_\_ or generalized? •\_\_\_ or sterile? • \_\_\_ and \_\_\_ • Pulp necrosis
Swelling constricts the BV, and the formation of edema strangulates the BV > pulp becomes necrotic > can spread into the underlying bone
swelling
blood supply
strangulation
common
acute chronic subtotal infected reversible irreversible
Periapical Abscess
• Collection of ___ exudate at apex of a non vital tooth
Etiology: infection, ___ pulp
Clinical: pain, swelling, elevation of tooth; sens to ___; fever, leukocytosis, ___…
Radiography: early: thickening of ___; late: diffuse ___ loss
Thermal, EPT: no ___
Histopath: dense infiltrates of ___, ___ nec.
Treatment: establish ___; ___ sensitivity; ___
necrotic percussion malaise PDL bone response PMNs liquefactive drainage culture antibiotics
Periapical Abscess:
Spread into ___ space and infect bone > ___
Spread into overlying soft tissue > ___
Can appear on ___ surface due to sinus tract [pain???], or can appear on ___ (called a purulis)
Sinus tract: a ___ pathway (elongated channel) that allows escape of fluid from a deep focus of infection to an opening on the surface
Parulis: A ___ on the gingiva at the site where a draining ___ tract reaches the surface
medullary
osteomyelitis
cellulitis
cutaneous
surface
drainage
sessile nodule
sinus
Abscess/Cellulitis: • \_\_\_ • \_\_\_ • \_\_\_ Depends on: • The length of the \_\_\_ • Root \_\_\_/Muscle \_\_\_ • Bone \_\_\_
buccal palatal lingual root apex attachment thickness
Apex above buccinator > ___
Apex below buccinator > ___
Apex is closer to palate > ___
buccal spread/cellulitis
intraoral spread
palatal spread
Ludwig’s Angina
- Initial infection: ___ space (apices of the 2nd and 3rd molar below the ___ ridge 65% of the time)
- ___ cortical plane thicker in the molar region
- ___ plate is usually perforated
Mylohyoid (goes from mandible to hyoid); if apex of mandibular tooth is above the spread will be ___
But if apex is below mylohyoid > ___ > initial infection in submaxillary space > bc apices of 2nd/3rd molar are below the mylohyoid muscle > will spread intraorally via the path of least resistance
Also depends on cortical plane (outer is thicker than inner), so the infection passes path of least resistance (along with being below mylohyoid)
Elevated ___, and swelling below the chin; initially ___, then becomes ___
If not treated: may die of asphyxiation
submaxillary
mylohyoid
outer
lingual
sublingual
ludwig’s angina
tongue
unilateral
bilateral
Neutrophils oral homeostasis and inflammatory diseases
– Neutropenia – LAD (I,II,III) syndromes – Chronic Granulomatous disease – Chediak Higashi syndrome – Papillon-Lafevre Syndrome – Gingivitis – Periodontitis – Pulpitis, Periapical abscess – Cellulitis, Ludwig’s angina – Gingivitis, Periodontitis
YAY
