Host Defence In The Lung Flashcards
Acute inflammation
Vasodilation leads to exudation of plasma, including antibodies
Activation of biochemical cascades, eg complement and coagulation cascades
Migration of blood leukocytes into the tissue, mainly neutrophils but also some monocytes
Community acquired pneumonia
• Affects 250,000 adults per annum in UK
• 33% of these admitted to hospital
•Mortality of those admitted is ~10%
Inflammation- mediated tissue damage in the lung
Chronic obstructive pulmonary disease
Acute respiratory distress syndrome
Bronchiectasis
Interstitial lung disease
Asthma
ARDS
Respiratory failure
Water and neutrophils fill the alveoli
Multi-system failure
Any condition causing inadequate tissue oxygenation may precipitate ARDS
- commonly trauma, lung infection, sepsis, surgery…
Pathophysiology of ARDS
Endothelial leak – leading to extravasation of protein and fluid
Lungs – reduced compliance, increased shunting
Heart – pulmonary hypertension, reduced cardiac output
Hypoxia
What is acute inflammation initiated by
Initiated in the tissues, by epithelial production of hydrogen peroxide and release of cellular contents
What is acute inflammation amplified by
specialist macrophages including:
Kupffer cells (liver)
alveolar macrophages (lung)
histiocytes (skin, bone)
dendritic cells
How does acute inflammation respond to pathogens or tissue injury
by recognising:
PAMPs (pathogen-associated molecular patterns)
DAMPs (damage-associated molecular patterns)
How do we recognise pathogens we have never seen before
Pattern recognition receptors (PRRs)
Signalling PRRs
Toll-like receptors (TLRs)
Nod-like receptors (NLRs)
Endocytic PRRs
Mannose receptors
Glucagon receptors
Scavenger receptors
Toll-like receptors
Funny flies, vulnerable to fungal infections
Mice resistant to endotoxic shock
Recognise conserved molecular patterns in pathogens
TLR4 recognises lipopolysaccharide (LPS)
TLR2 recognises lipotechoic acid (LTA)
Also recognise endogenous mediators of inflammation
What does TLR4 recognise
Lipopolysaccharides (LPS)
What does TLR2 recognise
Lipotechoic acid (LTA)
Alveolar macrophages
AM comprise 93% of pulmonary macrophages.
Functionally, cytochemically and morphologically similar to mature tissue macrophages.
Long-lived and arise from monocytes.
Neutrophil
70% of all white blood cells
80 million are made each minute, more in sepsis
Turnover 100 million a day
Myeloid cells, related to monocytes and macrophages
Primary neutrophil granules
Myeloperoxidase
Elastase
Cathepsins
Defensins
Secondary neutrophil granules
Receptors
Lysozymes
Collagenase
Neutrophil functions
- Identify threat- receptors
- Activation
- Adhesion
- Migration/chemotaxis
- Phagocytosis
- Bacterial killing
- Apoptosis- programmed cell death
What do Neutrophil receptors recognise
Bacterial structures – cell walls, lipids, peptides
Host mediators – cytokines, complement, lipids
Host opsonins – FcR (immunoglobulin)
CR3 (complement)
Host adhesion molecules
Neutrophil receptors
GPCRs – FPRs, BLT1,2, PAFR, C5aR, CXCR1,2, CCR1,2
FC-receptors – 6 gamma, 2 epsilon
Selectin and integrin receptors – 5
Cytokine receptors – Type I, Type II, TNF (20)
Innate immune receptors TLRs(8)
C-type Lecins (5)
NOD-like*
RIG-like* receptors
*intracellular
Neutrophil activation
“Stimulus-response coupling”
Identify threat through pathogen recognition receptors
Signal transduction pathways involving calcium, protein kinases, phospohlipases, G proteins
Neutrophil adhesion
Loosely tethered to endothelium by selecting for rolling
Integrins enable stable adhesion- extravasortion
Margination – Selectins
Adhesion – Integrins
Require changes in endothelium and in neutrophil
CD18 (beta-2 integrin) deficiency
NO transendothelial migration
Delayed separation of umbilical cord
Recurrent severe cutaneous and deep infections
Neutrophil migration/chemotaxis
Protrude through gaps in endothelium (diapedesis)
Ability to detect a concentration gradient and move along it
By moving receptors to the leading edge
Neutrophil phagocytosis
Pseudopodia engulf pathogen to form phagolysosome
Membrane invagination and pinching PHAGOSOME
Fusion with granules -> PHAGOLYSOSOME
Neutrophil bacterial killing
Myeloperoxidase generates ROS by NADPH oxidase
Lysosomal enzymes – cathepsins, elastase
Reactive oxygen species – ROS
ROS (reactive oxygen species)
generated by a membrane enzyme complex – the NADPH oxidase
Cytochrome B 91kD (X-linked)
P47 cytosolic factor (Aut Rec)
Severe recurrent infection Staph and fungi
Interferon restores P47 activity
Usually dead in their 20s
Why is lung especially at risk of inflammation/pathogens
Because of a huge area potentially in contact with the external environment
Non-respiratory functions of lungs
Synthesis, activation and inactivation of vasoactive substances, hormones, neuropeptides
Lung defence: complement activation, leucocyte recruitment, host defence proteins, cytokines and growth factors
Speech, vomiting, defecation.
Intrinsic lung host defences
Always present
Physical and chemical
Apoptosis, autophagy, RNA silencing, antiviral proteins
Innate lung defences
Induced by infection (interferon, cytokines, macrophages, NK cells)
Adaptive lung immunity
Tailored to a pathogen (T cell, B cell)
Antibodies produced
Longer-term response
How does the respiratory epithelium acts as a barrier to potential pathogens
Action of muco-ciliary escalator