5. Inflammation Flashcards
What is the main function of inflammation?
To remove infected or damaged tissue to restore homeostasis
- crucial to maintaining the health and integrity of an organism
- soluble mediators (humoral) and cellular components work together in a systematic fashion
- tightly regulated response
- traditionally divided into acute and chronic responses
What is acute inflammation?
The rapid, short-lived (minutes to days), relatively uniform response to acute injury, characterized by accumulation of fluid, plasma proteins, and leukocytes (WBC)
What is paramount in acute inflammation? What happens if one does not occur?
Both the effective induction and resolution of inflammation are paramount
- timing, location , absolute levels and duration are important
- sustained induction or improper control contributes to chronic inflammation
What are the 4 main features of the physiologic changes accompanying acute inflammation?
- Vasodilation
- Vascular permeability
- Recruitment
- Fever
What are 4 cardinal clinical signs of inflammation?
- Rubor (redness)
- Dolor (pain)
- Calor (heat)
- Tumor (swelling)
Vasodilation
One of the earliest physical responses to acute tissue injury
- arterioles are the first to be involved, followed by the capillary beds, resulting in a net increase in blood flow
- increase blood flow = characteristic heat and redness (calor and rubor) associated with foci of acute inflammation
- increased transport of: O2, nutrients, glucose, leukocytes
- decreased blood pressure
- removal of cellular waste products
Vascular permeability
- Under normal conditions, the vascular endothelial cells fxn as a semipermeable membrane, restricting the plasma proteins to the intravascular space
- In response to inflammatory stimuli, endothelial cells lining the venules contract, widening the intercellular jxns to produce gaps, permitting passage of plasma proteins (tumor) and facilitating leukocyte extravasation. More severe injury is associated with endothelial cell necrosis.
- Leukocyte recruitment
Process recruits leukocytes from bloodstream and ultimately involves the bone marrow to focus on inflammatory activity
- these leukocytes migrate through the enlarged endothelial cell jxns and the basement membrane
- leukocytes released due to signals from soluble mediators (hormones, cytokines)
Fever
Agents producing fever (pyrogens) are released from leukocytes in response to specific stimuli, such as bacterial endotoxin
- a number of soluble pro-inflammatory mediators have been implicated in this process (IL-1, TNF-a, IL-6) and prostaglandins
- contributions from immune and neuronal systems
- fever remains the most poorly understood of the acute inflammatory responses
Initiation of inflammation - Recognition
- Innate immune recognition triggers an inflammatory response that focuses the immune system on the site of infection; recognition by mast cell or macrophage releases cytokines (pyrogens), chemokines, and lipid mediators
- Inflammation requires the coordinated response from resident cells, blood vessels, circulating leukocytes and hematopoietic compartment
3 Self and non-self triggers of inflammation
- Pathogens
- activation of the plasma protease systems by interaction with degradation products of the bacterial cell walls
- secretion of toxins - Injured cells
- release degradation products that initiate one or more of the plasma protease cascades
- upregulate expression of soluble molecules (ex. pro-inflammatory cytokines) - Foreign bodies from exogenous (ex. asbestos) or endogenous (ex. immune complexes) sources, physical injury (ex. burns), chemical agents (ex. caustic)
The toll-like receptors (TLRs) initiate many pro-inflammatory responses:
- First line of defense against incoming pathogens
- “Danger” hypothesis
- This family of receptors detects pathogens including bacteria, viruses, and fungi - Well conserved across evolution
- Conserved bc of its importance to early pathogen recognition - Remember that they work together with several other types of recognition receptors (ex resident macrophages, epithelial cells)
TLR signaling pathways
- TLRs
- MyD88 dependent or independent pathways
- Transcription factors
- Gene expression
- Functional protein
- Cellular response
3 inflammatory mediators
- Cytokines
- polypeptide signaling molecule that participates in immune responses
- often act locally (in an autocrine or paracrine manner) but can act systemically
- most are secreted molecules but membrane-bound versions often occur - Chemokines
- family of closely related small basic cytokines
- main fxn is as chemoattractants
- name in a contraction of a chemotactic cytokine - Hormones
- biomolecules synthesized in small amounts by ductless (endocrine) glands: polypeptide, amide, or steroid
- travel from site of synthesis to distant target tissues
- mediate regulatory effects by binding to specific cell surface receptors- intracellular receptors in case of steroid hormones
4 main actions of inflammatory regulators
- Induce vascular permeability to allow the influx of soluble immune components from the blood
- Change the adhesive properties of the endothelium to attract more phagocytes to the site of infection
- Activate the incoming leukocytes to promote their microbicidal action
- Induce production of complementary cytokines
- early: positive feedback to amplify pro-inflammatory repsonse
- later: negative feedback to induce anti-inflammatory responses
5 soluble mediators of inflammation
- Proinflammatory cytokines
- Lipid mediators
- Vasoactive amines
- Complement-derived mediators
- Anti-inflammatory cytokines
Diapedesis
The process of moving through 2 endothelial cells
Chemotaxis
movement of a cell up a gradient of chemotactic factors
- ex. through bloodstream or within a tissue to locate infecting pathogen
What does macrophage or mast cell recognition of a bacterial infection induce?
Production of TNF and IL-1 which act on neighboring cells to produce more of these cytokines until the response is propagated to the endothelial cells
- Endothelial cells rapidly traslocate P-selectin from intracellular storage and vesicles to the plasma membrane and begin to synthesize E-selectin and integrin ligands such as ICAM-1 and VCAM
- Chemokine synthesis also occurs which bind to cell-surface proteoglycans that extend into the vessel (luminal side). Also diffuse through circulation
Leukocytes flow through the blood until they contract endothelial cells expressing what? What is key to the shifts in leukocyte recruitment?
Selectins
- slows down leukocyte movement with the fluid flow to a rolling motion = allows the recognition of chemokines
- chemokine and cytokine kinetics are key to shifts in leukocyte recruitment, transitions btw induction and resolution
- only after this process can infiltrating leukocytes engage pathogens or tissue repair at the tissue challeng site
Inflammation triggered by bacterial infection is initially dominated by:
Neutrophils (innate killing response) -> monocytes (killing/repair) -> lymphocytes (adaptive response)
Why?
- neutrophils are very destructive
- monocytes participate in immune defenses but also wound healing (and less destructive)
- lymphocytes critical to subsequent adaptive responses
Inflammation at the microscopic scale
- dilated post-capillary venules
- leukocytes marginating on epithelia
- mild expansion of superficial dermis
- edema
CYTOKINES as central regulators of adaptive cell-mediated (TH1) or humoral (TH2) responses
- shift balance to “hone-in” on the best response
- relevance to normal physiological changes (eg. TH2 pregnancy and susceptibility)
- pathogens can also take advantage of this to evade host defenses
Chronic inflammation
- Of longer duration than acute and includes influx of lymphocytes and macrophages
- Occurs when incomplete clearance of causative agent or due to multiple acute events at the same location
- Growth of fibroblasts and vascular tissue associated with scarring
- Tissue granulomas: collection of inflammatory cells (macrophages, lymphocytes) surrounded by a fibrotic wall. Typical of intracellular bacteria infections as tuberculosis.
Tissue granulomas
collection of inflammatory cells (macrophages, lymphocytes) surrounded by a fibrotic wall. Typical of intracellular bacteria infections as tuberculosis.
Regulation of pro-inflammatory cytokine activity
Occurs through a series of feedback inhibitory mechanisms
TNF induces the shedding of TNF receptors
- proteolytic release of extracellular domain of TNFR
- decreases the sensitivity of the cell to TNF
- act as competitive inhibitors for TNF binding of surrounding cells
TNF also induces production of tristetraprolin
- an intracellular inhibitor of TNF production
Delayed production of macrophages of soluble IL-1R
- act as competitive inhibitors for IL-1 binding of surrounding cells (can’t signal)
Macrophages produce IL-10 and TGF-B
- both promote wound healing at the expense of microbe- killing fxns
Phagocytosis of apoptotic cells vs pathogens
Phagocyte + pathogen = pro-inflammatory
Phagocyte + apoptotic body = anti-inflammatory
Despite conservation of innate responses across evolution we find significant differences in how different animal hosts induce and resolve inflammation (Eg. efficiency, duration, absolute levels). What does this impact?
Impacts capacity to defend against pathogens and susceptibility to inflammatory diseases
