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Inflammation and Disease

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Viola Geraldo

on 31 March 2017

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Transcript of Inflammation and Disease

Inflammation and Disease
Inflammation and Disease
Describe the inflammatory response and the mechanisms and classes of molecules involved.
Understand the importance of resolution of inflammation and discuss the role of inflammation in disease processes.
Describe current anti-inflammatory therapies and their use in disease.

Inflammation
Physical response to injury or infection resulting in:- fever, redness, swelling pain, tissue/organ dysfunction
Response to cellular insult by:
infectious agents - bacteria, fungi, viruses, parasites
toxins - chemical, radiation, UV, biological
physical stresses - mechanical, burns, trauma
Protective response: ultimate goal to remove initial cause of injury consequences of injury - the necrotic cells & tissues
Pro-inflammatory mediators
Resolution
Anti-inflammatory mediators
: anti-inflammatory cytokines (IL-10), soluble adhesion molecules - act as decoy, TIMPs - inhibit MMPs, plasmin activation system - clot recedes, opioid peptides - counteract pain, resolvins/protectins - anti-inflammatory lipid mediators
Inflammation
:
Acute
- necessary part of immune response, excessive leads to organ failure & death.
Chronic
- inappropriate with tissue destruction, leads to disease - autoimmune/neurodegenerative/chronic age-related disorders
Current & Novel anti-inflammatory therapies
: NSAIDs, steroids, immunosuppressive agents, novel - anti-cytokine (TNF antibodies)/anti-adhesion molecules (Abs to integrins, ICAM-1 etc)/MMP inhibitors/other small molecules
Inflammatory response
Part of innate immune system - cellular & plasma derived components: complement, acute phase proteins, interferons, cytokines (mediators released), chemokines (attract immune cells), kinins (bradykinin - pain)
Epithelial & endothelial cells release mediators
Neutrophils arrive first then monocytes which differentiate into macrophages (major cells in inflammation)
Phase I - pro-inflammatory phase, Phase II - resolution
Sequence
Insult by trauma/pathogen causes acute phase reaction
Platelet adhesion, transient vasoconstriction of efferent vessels
Cytokine-induced vasodilation of afferent vessels (increased heat & blood flow to area)
Activation of complement, coagulation, fibrinolytic & kinin system
Leukocyte adhesion
Increase vascular permeability & extravasation of serum proteins & leukocytes (swelling)
Phagocytosis of foreign material with pus formation
Cytokines
Synergistically working to carry out functions, many cell types respond &/ secrete these cytokines
Activate immune & other cells in local environment
Recruit immune cells to attack pathogen
Growth factors (M-CSF) stimulate immune & non-immune cell growth
Act as endogenous pyrogens
Induce acute phase proteins (APPs) in the liver
IL-1 - vasculature, liver, hypothalamus
TNF-alpha - vasculature, liver, induce cell death, neutrophil activation, cachexia
IL-12 - NK cells, promotes TH1
IL-6 - liver, influences adaptive immune system (B cells)
IFN-alpha&beta - induces antiviral state, activates NK cells
APPs
Fluctuate in response to tissue injury & infections
Usually made by hepatocytes
Synthesised in response to pro-inflammatory cytokines:
C reactive protein - opsonin
Fibrinogen - coagulation factors
Serum Amyloid A - cell recruitment & MMP inducer
Complement factors - opsonin, lysis, clumping, chemotaxis
Heptaglobin & ferritin - bind Hb/Fe
Chemokines
>50 small mw that are chemotactic
4 sub-families - CC, CXC, C, CXXXC which bind GPCRs
Act on different immune cell types
IL-8 (CXCL8) attracts neutrophils
Monocyte chemotactic protein 1 (MCP1/CCL2) attracts monocytes
Eotaxin (CCL11) attracts eosinophils --> allergic reaction
Redundancy & overlapping functions
Adhesion molecules
Not expressed, respond to activation
Transmembrane receptors that bind either to other cells or to ECM
4 main classes:
Ig superfamily
(eg. VCAM-1, ICAM-1) - sits on endothelial cells
Cadherins
Selectins
(E, P, L) - recognise carbohydrates
Integrins
ECM proteins:
Collagen type I, II & II - fibrillar found in bone, skin, cartialage
Collagen type IV - basement membrane
Laminin, Elastin, Proteoglycans, Aggrecan, Fibronectin, Matrillin, Nidogen
Metalloproteinases
Proteases who catalytic function requires metal, usually zinc
3 main families:
MMPs (matrix metalloproteinases) - degrade & remodel ECM, create chemokine gradients
ADAMS - cleave cytokine & adhesion molecule receptors from cell surface
ADAMTS - degrade proteoglycans
Redundancy in the families - many have similar functions
NF-kappaB
Family of transcription factors that regulate hundreds of pro-inflammatory mediators including:
cytokines - TNF, IL-1, IL-6
chemokines & their receptors - several - IL-8, MCP-1
adhesion molecules - VCAM-1, ICAM-1
MMPs - MMP-3, MMP-9
growth factors - GM-CSF, M-CSF
acute phase proteins - SAA
Full transcript