Kapitel 1 - Inflammatory respons Flashcards
Vad är negavtiva effekter vid förlängad och okontrollerad inflammation?
Q
Vad är negavtiva effekter vid förlängad och ukontrollerad inflammation?
A
1) Smärta
2) Immunosuppression
3) Organ dysfunktion
4) Död
Akronym: DOSI
Vad är faserna av det akuta vaskulära respons i inflammation?
1) Vasodilation (Snabb vasoconstriction initiellt)
2) (Ökad) Permeabilitet
3) Stasis
4) Leukocyt extravation
Vad är de klassiska makroskopiska symtom på inflammation?
1) Rubor (Rödma)
2) Dolor (Smärta)
3) Calor (Värma)
4) Tumor (Svullnad)
5) Functio Laesa (Förlust av funktion)
Vad är faserna av det akuta vaskulära respons i inflammation?
1) Vasodilation (Snabb vasoconstriction initiellt)
2) (Ökad) Permeabilitet
3) Stasis
4) Leukocyt extravation
Vilka vasoaktiva substanser stimulerar den snabba vasokonstriktion som kommer innan vasodilationen i akut inflammation?
Hur/var ifrån frigörs de?
Kringliggande vävnad: catecholaminer, serotonin, bradykinin, och prostaglandins
Sympatiska nervsystem: Norepinephrine
Vilka substanser stimulerar vasodilation i akut inflammation?
Nitric oxide, histamine, leukotriener, prostaglandiner och komplement faktorer som
Vilka substanser/faktorer ökar den vaskulära permeabiliteten?
- Direkt trauma till vävnad
- Histamin och serotonin (ökar antalet intracellulära kanalförbildelser)
- hypoxia, endothelial injury, cytokines, or other inflammatory mediators (ökar premabiliten genom formation av interendothelial gaps.
Vad orsakar ödem under inflammation och har den en funktion?
Ökad premabilitet –> förlust av serum proteiner –> minskat intravaskulärt osmotiskt tryck –> interstitiellt vätskeutträde
Funktion: Leverera viktiga substanser (antikroppar och akutfasproteiner) till inflammationsområdet
MEN ödem orsakar smärta och till viss del minskad funktion
Vad är de 4 faser som leukocyterna går igenom som ledar till extravation (efter hemostasen)?
1) Rolling
2) Integrin aktivation
3) Stabil adhesion
4) Extravasion
Acronym: RISE
Vad är Selectin?
Glykoproteinreceptorer på endotelcellerna som interagerar med rullande leukocyter
Vilka är det vanligaste selectin och vad står dom för?
E, P and L- selectin
Endothelial selectin
Platelet selectin
Leukocyte selectin
Genom vilket protein binder leukocyterna till kärlväggen och vilka är speciellt aktiva under inflammation?
Integrins (på leukocyterna yta)
Integrins med subunits α (CD11a, CD11b, CD11c) and β (CD18) subunits
Vad kallar man processen där leukocyten går ut från kärlet?
Var händer det?
Diapedes.
Genom interendotheiala junctions i postkapillära venuler
Vad är den första leukocyt som ingår i inflammationen typiskt?
Efter hur lång tid har de peak population?
Neutrofiler
24-48 h
Vad kallas den största (primaty) granulen i en neutrofil och vad innehållet den?
Azurophil (primary) granule
Innehåller: microbicidal polypeptides such as myeloperoxidase, defensins, lysosome hydrolases, and neutral proteases
Vad innehåller neutrofilernas secondary and tertiary granules?
Secondary granules: Metalloproteases
Smaller, specific (secondary) granules contain metalloproteases.
Gelatinase (tertiary) granules and secretory vesicles contain preformed receptors for enhanced cellular communication
Nämn två typer av macrofager
- Tissue-resident macrophages
- Monocyte-derived macrophages
Vad är funktionen av tissue-resident macrophager?
Tidigt detektion av inflammatoriska stimuli och är en stor tidig producents av proinflammatoriska cytokiner.
Vad triggar monocyter till att extravasera iut i vävnaden?
Chemotaxiner
(including cytokines, fibronectin, elastin, complement factors (C3a, C5a), thrombin, and growth factors (e.g., platelet-derived growth factor [PDGF], transforming growth factor-beta [TGF-β]))
Vad är Macrophage polarization?
makrofagers förmåga att anta två distinkta funktionella fenotyper: M1 och M2. M1
Vad aktiveras M1 makrofager av och vad är deras funktion?
Activated by:
- Infectious agents
- Proinflammatory cytokines
Function:
- Debridement by phagocytosis of foreign material, pathogens, and damaged cells.
- Production of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and prostaglandins, enhancing the inflammatory response
- Secretion enzymes like collagenases and elastases
What is M2 macrophages classically activated by and what are their function?
Activated by:
- Anti-inflammatory cytokines
Function:
- Aid in wound repair and healing
- Secretion of growth factors like PDGF or TGF-β, which stimulate fibroblasts to produce collagen, further dampening the inflammatory response
- Secretion enzymes like collagenases and elastases to dissolve the extracellular matrix, facilitating phagocytosis and remodeling,
- (antigen presenting cells that interact with lymphocytes.) (Adaptive immunesystem)
What are the life-spans of Tissue derived Macrophages and circulating Monocytes - respectively?
Tissue-resident Macrophages:
- Months to years
Circulating Monocyte:
- Day(s)
What are the cellular components of acute inflammation?
- Neutrophils
- Macrophages and monocytes
- Lymphocytes
- Mast Cells
- Endothelial cells
- (Antigen presenting cells like dendritic cells to cells of mesenchymal origin like fibroblasts and myocytes, the impact of these other cell types must be considered.)
Which are the main components of cell mediated immunity?
The helper (CD4+) T-cells and the Cytotoxic (CD8+) T-cells
CD4+ cells further differentiate into T-helper-1 (Th-1) and T-helper-2 (Th-2) cells
Where do we find Mast Cells
Mast cells are ubiquitously distributed in all organs
What do Mast cells degranulate in response to?
- Physical trauma
- Complement factors
- Microbial products
- Neuropeptides
What do Mast cells release?
And what are their overall function?
- Histamine (Primary soruce in acute inflammation)
- Pro-inflammatory mediators like:
- serotonin
- leukotrienes
- prostaglandin metabolites
- heparin
- cytokines
Overall function:
- Enhancing local inflammatory response
What are PAMS and give som examples?
Highly conserved microbial molecules, recognized as foreign to the host
- lipopolysaccharide
- lipoteichoic acid
- peptidoglycan
- microbial oligonucleotides.
What is the difference between DAMPS and PAMPS (Where are they produced - what do they signal?
PAMPS:
- Microbial molecules
- Recoqnized as “foreign” to the host
DAMPS:
- Endogenous molecule released with cellular damage (ex. fibrinogen, high-mobility group B1, Heat Shock Proteins, etc.)
- Alert the body to cellular damage initiated by infectious or noninfectious agents
What are heat shock proteins?
Heat shock proteins are intracellular chaperones that normally regulate proper protein folding.
Heat shock proteins are known to be produced in response to other stimuli than thermal injury and are found in the circulation after trauma and surgery
What are toll-like receptors, scavenger receptors, mannose receptors, C-type lectin-like domain–containing receptors, peptidoglycan recognition receptors, and nucleotide-binding site–leucine-rich repeat receptors examples?
What are their function?
Pattern Recognition Receptors
- Bind DAMPs and PAMPs -> Inflammation
Where do we find Pattern Recognition Receptors?
- Expressed on the cell surface
- Within the intracellular compartment
- Soluble forms may be found in bodily fluids
Where is histamin produced?
- In mast cells (mainly)
- basophils
- platelets
- or other cell types located in the same tissue or within the bloodstream
What are the main effects of histamine during inflammation?
- Arteriolar vasodilation
- Increased venule permeability
- Constriction of large arteries.
- Histamine also enhances vasodilation indirectly through prostaglandin synthesis
What are cytokines?
Give some examples
A very diverse group of small, soluble proteins that act as intercellular messengers.
- tumor necrosis factors (TNF)
- interleukins
- transforming growth factor
- interferons
Give examples of some Proinflammatory cytokines and their function
- TNF-α
- IL-1β
- IL-6
increase the innate immune response
Give examples of some Antiinflammatory cytokines and their function
- IL-10,
- L-1 receptor antagonist [IL-1ra])
Attenuate the inflammatory responses
Name some beneficial and deleterious effects of TNF-a
Beneficial: is necessary for protection from mycobacterial infection. Blocking its activity have shown increase mortality in septic human patients.
Negative effects: hypotension, metabolic acidosis and endotoxic shock
Which cytokine has been used to predict postoperative infection, sepsis-associated mortality, and the recurrence of abdominal adhesions?
Interleukin 6 (IL-6)
considered to be not only a mediator but also a diagnostic and prognostic biomarker of inflammation.
How are prostaglandins produced?
In the cyclooxygenase pathway, where arachidonic acid metabolism is catalyzed by the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
How are COX-1 och COX-2 expressed?
COX-1: present in the majority of mature cells and involved in hemostasis.
COX-2: expression is induced by trauma, growth factors, proinflammatory cytokines, and other mediators.
Name some prostaglandins and some of their functions
Give examples of reactive oxygen species and names some of their effects
- hydroxyl radical
- superoxide anion (O2−)
- hydrogen peroxide (H2O2)
Effects: antibacterial defense, wound debridement, intracellular signaling, and pathologic tissue damage
What is frustrated phagocytosis?
When a phagocyte fail to engulf its target and release damaging agents into the extracellular inflammatory environment.
In surgery, what adverse effects can elevated ROS have?
- abdominal adhesions
- delayed wound healing
- excessive scarring.
What is redox signaling?
It is the process in which Reactive oxygen species function as important cellular messengers. For example, cells can produce H2O2 in the wound bed to promote keratinocyte migration and proliferation.
Give examples of gases inflammatory mediators
- Nitrogen oxide
- Carbonmonoxide
- Hydrogen sulfide
What are the three forms of nitric oxide and when are they produced?
- Endothelial-derived nitric oxide synthase: continuously produced
- Neuronal-derived nitric oxide synthase: continuously produced - Inducible nitric oxide synthase: produced in response to cytokines and other inflammatory mediators
What is the primary physiological function of nitric oxide?
Regulation of vascular tone; it produces vasodilation by diffusing into smooth muscle cells leading to smooth muscle relaxation.
+ antagonizes the vasoconstrictive effects of angiotensin II, endothelins, and reactive oxygen species, therefore it is a major contributor to early-stage vasodilation
In what conditions can we see sustained nitric oxide release?
chronic inflammatory joint disorders (rheumatoid arthritis and osteoarthritis) and chronic inflammatory gastrointestinal disorders
What are the hallmarks for acute phase reaction?
- Fever
- Leukocytosis
- changes in serum concentrations of acute phase proteins
What are Negative acute phase proteins? Give some examples
Proteins active in regulating homeostasis that decrease in concentration by at least 25% during an inflammatory response
Albumin (main one), transferrin, apolipoprotein A, retinol-binding protein, cortisol-binding protein, and transthyretin
What are positive acute phase proteins? Give some examples
Proteins that show an increase in plasma concentration by at least 25% during an inflammatory response
eg. CRP, SAA
What are the three different complement pathways?
- Classical pathway; activated by immune complexes
- Lectin pathway; activated via interaction with lectin proteins (e.g., mannose-binding lectin) with surface carbohydrates on pathogens.
- Alternative pathway; initiated by contact with foreign microbes
Where does the complete pathways merge?
At at the cleavage of C3 to form C3b
How is the intrinsic and the extrinsic coagulation pathways activated?
Intrinsic: when factor XII (Hageman factor) contacts a negatively charged surface
Extrinsic: initiated by activation of factor VII by tissue factor.
What is the function of bradykinin? And which enzyme inactivates it?
Similar to histamine, bradykinin stimulates venous dilation through local nitric oxide release, increases vascular permeability, and produces the associated pain response.
Inactivating enzyme: Kininase
What is tachykinins?
Neuropeptides released from peripheral neurons after stimulation or direct trauma of sensory nerves
What is cross-tolerance?
A type of “down regulation” of immune response in which exposure to another stimulus, such as lipoteichoic acid from Gram-positive bacteria, leaves the cell unresponsive to endotoxin
