Chronic Inflammation Flashcards
What is chronic inflammation?
Long lasting inflammatory response (weeks, months)
may be after acute inflammation
slow insidious onset (not preceded by acute)
attempts to repair damaged tissue via scarring and fibrosis
Aetiology of chronic inflammation
Fails to eliminate agent causing inflammation eg Mycobacterium tuberculosis
Exposure to low level irritants or foreign materials that cant be decimated by enzymatic breakdown or phagocytosis
An autoimmune disorder in which the immune system recognizes the normal component of the body as a foreign antigen, (Rheumatoid Arthritis, Systemic Lupus Erythematosus)
A defect in the cells responsible for mediating inflammation leading to persistent or recurrent inflammation (Auto-inflammatory disorders)
Recurrent episodes of acute inflammation. However, in some cases, chronic inflammation is an independent response and not a sequel to acute inflammation
Biochemical inducers of oxidative stress and mitochondrial dysfunction - increased production of free radical molecules, advanced glycation end products (AGEs), uric acid (urate)crystals, oxidized lipoproteins, homocysteine etc.
Chronic inflammation underlies many disorders: cancer cancer, atherosclerosis, Alzheimer, type 2 diabetes
Outcomes of chronic inflammation
Injury -> acute inflammatory response -> vascular changes, neutrophil receuitment and cytokine production -> should resolve issue
- could lead to fibrosis after healing
- or if acute inflammation is progressive leads to chronic
- or injury that triggers chronic inflammation
Causes of chronic inflammation
Failure to close acute inflammatory reactions
(persistent infections eg bacteria, viruses, fungi, parasites)
Misdirected inflammatory reaction
=> harmless environmental substances (allergies)
=> self antigens (autoimmune diseases)
Chronic inflammation underying many disorders eg cancer, atherosclerosis, Alzheimer’s type 2 diabetes
-> directed against endogenous substances: crystals => cholesterol (atherosclerosis), urate (gout
Chronic vs acute inflammation
Longer duration
More immune cells - adaptive immune responses
- macrophages, lymphocytes, T cells and B cells
Altered tissue structure/function- eg
- destruction and scarring (necrosis, fibrosis, scarring- deposition of collagen)
- Angiogenesis
Cells in chronic inflammation
Macrophages- act as sentinels
=> derive from monocytes (circulation); inflammation
=> tissue resident macrophages: Kupffer cells (liver), microglia (brain), alveolar macrophages (lungs); different origin – foetal liver, yolk sac
Lymphocytes in chronic inflammation
Bidirectional signalling in chronic inflammation
T cell differentiates by receiving signals from APC via MHC and TCR + cytokines = Th1 cell
Signals come from APC and activated macrophage
Th1 then activates B cells and cytotoxic T cells to propagate inflammation
BIDIRECTIONAL bc signals from Th1 -> releases IFN-y to activate macrophage (+ CD40 and CD4 provide signals)
Macrophage can receive INF-y signalling from Th1 and NK cells
Where are mast cells found?
Connective tissue close to vessels
Where is MBP found?
Major basic protein in eosinophils- destroys parasites/tissues
in IgE mediated allergic reactions
Neutrophils in chronic inflammation
some types of chronic inflammation: suppurative inflammation (abscess, osteomyelitis); lung disease smoking/irritants
recruited by chemokines (IL-8) from macrophages/T cells
neutrophil-rich infiltrate called ‘acute on chronic inflammation’
Interferon gamma (IFN-y)
Produced by T cells, NK cells
Activates macrophages (increased MURDER activity)
Soluble mediators in chronic inflammation
Cytokines IFN-y TNF- alpha IL-17 IL-12
Types of chronic inflammation
Non-specific chronic inflammation
Often develops when acute inflammation fails to eradicate causative agent
Tissue destruction: e.g. gastric / duodenal peptic ulcers
Ulcer / ulceration:
=> local defect/excavation of the surface of an organ or tissue
=> caused by sloughing/shedding of inflamed necrotic tissue
=> oral mucosa, stomach, intestines, genitourinary tract
- peptic ulcer stomach/duodenum: acute and chronic inflammation coexist
=> skin and subcutaneous tissue of lower limbs (old people with circulation problems => ischemic necrosis)
Helicobacter pylori-associated gastritis
Peptic ulcer (gastric/duodenal)
Bc of H. pylori or NSAIDs
Acute inflammation phase: neutrophil infiltration in ulcer margins & base
Chronic inflammation phase:
=> granulation tissue formation in ulcer margins & base followed by
=> fibrous scarring, infiltration with lymphocytes, macrophages, plasma cells
Chronic inflammation in autoimmune disease
Rheumatoid arthritis
Progressive damage to cartilage in joints
=> joint synovium expanded by inflammatory cell infiltrate and fibrin deposition (pannus)
=> ~70% patients have antibodies anti-rheumatoid factor (IgM antibodies anti-Fc portion of IgG)
Chronic suppurative inflammation
Abscess
Fibrosis walls off a focus of acute inflammation => localised collection of purulent inflammation
Often pyogenic bacteria
Central area of necrotic leucocytes & tissue cells; zone with neutrophils; fibroblast proliferation and fibrotic area
Often may have to be laid open to heal (incision & drainage)
Chronic granulomatous inflammation
Granuloma causes
Chronic granulomatous inflammation
Mo- macrophages
Granuloma - microscopic appearance
Multinucleated giant cell
Macrophage fusion = multinucleate giant cells (many nuclei)
- adjacent macrophage try to phagocytose the same particle
0hard to destroy particles -> silica, mycobacterium, Schistosoma ova
called LANGERHANS GIANT CELLS
horseshoe arrangement of nuclei
Granuloma
What kind of granuloma has a necrotic centre
Caseating granuloma
What are the 2 outcomes of granulomatous inflammation in TB?
Tissue repair vs healing
Repair => used for parenchymal and connective tissue
Healing => used for surface epithelia
Types of tissue repair
REGENERATION
=> proliferation of residual healthy cells (e.g. epithelial cells)
=> proliferation and maturation of tissue resident stem cells
REPLACEMENT
Replacement with connective tissue => scar formation
Tissue repair
Macrophages and resolution of inflammation
Complex process where apoptosis of neutrophils and their subsequent clearance drive potent anti-inflammatory, tissue-restoring mechanisms.
Critical role of alternatively activated macrophages, which secrete anti-inflammatory and reparative mediators, and orchestrate these reparative processes
Healing of tissue
Infectious agent or tissue damage causes acute inflammation
Damaged tissue, dead inflammatory cells and dead organisms are phagocytosed and cleared
Healing starts with organisation (ingrowth of capillaries and fibroblasts => form granulation tissue)
Healing ends with resolution (complete restitution to normal) or more commonly repair (scarring)
Healing of skin wounds
Regeneration of epithelial cells and
Formation of connective tissue scar
Depending on size and nature the wound heals by 1) primary intention or 2) secondary intention
Primary intention
=> injury limited to epithelial layer
=> repair by regeneration
e.g. clean, uninfected surgical incision closed by surgical sutures
Secondary intention
=> more extensive tissue loss
=> repair by regeneration & scarring
e.g. large wounds, abscesses, ulcerations, ischaemic necrosis
Skin wound healing primary vs secondary intention
Healing by primary intention: steps
Injury/wound => activation of coagulation => clot formation
=> clot fills wound; external surface of clot dehydrates => wound scab
~24h: neutrophils infiltrate wound margins
=> release of proteolytic enzymes => clear debris/microbes
24-48h: migration & proliferation of epithelial cells at wound edges
=> deposit ECM (extracellular matrix) components
=> meet in the midline, beneath wound scab, thin layer to close wound
Day 3: macrophages replace neutrophils
- granulation tissue starts to invade wound space
=> Mϕ clear debris, fibrin; promote angiogenesis, ECM deposition
Day 5: granulation tissue fills wound; neovessels + edema
=> fibroblast proliferation => produce collagen => deposits in wound
2nd week
fibroblast proliferation & collagen deposition continue
vessel regression
reduction of inflammatory infiltrate -> scar ‘blanching’
1 month
scar made of connective tissue, without/very few inflammatory cells
normal epidermis
dermal appendages destroyed by incision lost permanently
wound strength increases in time
=> fresh wound well sutured => 70% strength of normal skin
=> sutures removed (1 week) => 10% strength
=> wound strength (3 months) => 70-80% strength
=> no further improvement in strength
Healing by secondary intention
Larger wounds (big tissue loss)
- bigger clot, more exudate, inflammation more intense
- higher risk for inflammation-mediated tissue injury
Granulation tissue is more extensive -> bigger scar
- Pale avascular scar (fibroblasts, dense collagen, no inflammatory cells)
- Dermal appendages destroyed by incision lost permanently
- Epidermal layer recovers full thickness and structure
Wound contraction - esp for large surface wounds
- helps close wound and reduces wound surface
- myofibroblasts- modified fibroblasts with smooth muscle cell features
- 6 weeks: reduction of ski defects to 5-10% of original wound size
Which one is primary vs secondary
Left- primary
Right- secondary
Abnormal tissue repair
Keloid
Scar grows beyond margins of original would, predisposing in Afro-Caribbean
