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
Chemical epithelial barriers produced by epithelial cells
antiproteinases
anti-fungal peptides
anti-microbial peptides
Antiviral proteins
Opsins
Mucus structure
Airway mucus is a viscoelastic gel containing water, carbohydrates, proteins and lipids
Secretory product of the mucous cells (the goblet cells of the airway surface epithelium and the submucosal glands)
Mucus function
Mucus protects the epithelium from foreign material and fluid loss
Mucus is transported from the lower respiratory tract into the pharynx by air flow and mucociliary clearance
How does mucus clearance occur
Via the mucociliary escalator
Cilia beat in directional waves to move the mucus up the airways
What is a cough
An expulsive reflex that protects the lungs and respiratory passages from foreign bodies
Voluntary or reflex
Causes of cough
Irritants- smokes, fumes, dusts, etc
Diseased conditions like COPD, tumours etc
Infections (influenza)
Afferent limb of a cough
Includes receptors within the sensory distribution of the trigeminal, glossopharyngeal, superior laryngeal and vagus nerves
Efferent pathway of a cough
Includes the recurrent laryngeal nerve and spinal nerves
What is a sneeze
Defined as the involuntary expulsion of air containing irritants from nose
Photic sneeze reflex
Sneezing when looking at a bright light affects up to one third of the population.
This phenomenon is known asphotic sneeze reflexor solar sneeze reflex.
Causes of sneeze
Irritation of nasal mucosa
Excess fluid in airway
Complete repair of airway epithelium
As exhibits a level of functional plasticity
Injury
Spreading and dedifferentiation
Cell migration
Cell proliferation
Redifferentiation
Regeneration
Metaplasia
reversible replacement of one differentiated cell type with another mature differentiated cell type.
Mucus plugs/inflammation
Associated with severe disease
Mucus and inflammatory cells block the airways
Which cells secrete mucous
Goblet cells of the airway surface epithelium and the submucosal glands
Afferent
Sensory
Efferent
Motor
What can cause injury to the airway epithelium
Trauma
Toxic compounds
Infection
Inflammation
What can basal cells differentiate into
Club cells (which become goblet cells or ciliated cells)
Ciliated cells
Smoking is known to adversely affect the clearance of mucus from the airways.
Which of the following provides cilia for the mucociliary escalator?
Columnar Epithelial Cells
Mechanism of a cough
- Epiglottis closes laryngeal inlet
- Abdominal muscles contract and diaphragm pushes upwards
- Increase in intrathoracic pressure
- Vocal chords open and epiglottis lifts away
- Pressure gradient causes high flow rate air expulsion
Airway epithelium repair
Can occur completely due to high functional plasticity : multi potent basal cell population can differentiate into respiratory epithelial cells
Metaplasia
Reversible replacement of non-squamous goblet cells with stratified squamous in heavy smoker
Mucus composition
Visoelastic gel containing carbohydrates fats and proteins
Mucus function
Protects epithelium from foreign material and fluid loss
Secretion and movement of mucus
Secreted by goblet cells and submucosal glands
Transported from lower to upper respiratory tract by mucociliary clearance
Neutrophil - apoptosis
Neutrophil phagocytosed by alveolar macrophages
Pathogen recognition receptors
TLRs
NLRs
Mannose
Glucan
Scavenger
TLR4 recognises
LPS
TLR2 recognises
LTA
Role of alveolar macrophages
Phagocytosis
Antigen presentation
Apoptosis
B and T lymphocytes are activated by
Antigens on pathogen surface
Free antigens in plasma
Peptides presented via MHC glycoproteins (on macrophages, B cells, dendritic cells)
Cell mediated immunity
T cells - made in bone marrow , mature in thymus
Treg cells
Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress immune response
Remove host cells capable of binding self antigens :immune tolerance
Failure: prone to opportunistic infections
Cytotoxic T cell receptor
CD8
Cytotoxic T cell MHC class
1
Cytotoxic T cell role
Mediate killing of tumours and virus-infected cells
- perforin creates holes in cell membranes
Perforin
Released by Cytotoxic T cell
Create holes in cell membrane
T helper cell receptor
CD4
T helper cell MHC class
2
T helper cell role
Release cytokines - stimulate B cell colonial expansion
Humoral immunity
B cells- produced and mature in bone marrow
Activated in lymph nodes—> differentiate into plasma cells- secrete antibodies
Primary lymphoid organ
Bone marrow
Secondary lymphoid organ
Lymph nodes
Affinity maturation
Throughout immune response, B cells produce antibodies with increased affinity for antigens due to somatic hypermutation
IgG monomer
Secondary immune response
Can cross placenta- fetal immunity
IgA diner
Mucosal secretions
Eg breast milk- protects baby’s gut- on mucosal surface
IgM pentamer
Primary immune response
CAN’T cross placenta
IgE monomer
Allergy and parasitic infections
Fc receptors on mast cells, basophils and eosinophils
IgD monomer
Naïve B cells
Activation /.maturation
Pneumonic
ACID + EGGT
Allergic, cytotoxic, immune-complex, delayed
IgE. IgG. IgG. T cell
Which kind of hypersensitivity reaction is IgE mediated, and what does it respond to?
Type 1, in response to things like anaphylaxis and hayfever
