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Host Defence In The Lung Flashcards

1
Q

Acute inflammation

A

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

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2
Q

Community acquired pneumonia

A

• Affects 250,000 adults per annum in UK
• 33% of these admitted to hospital
•Mortality of those admitted is ~10%

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3
Q

Inflammation- mediated tissue damage in the lung

A

Chronic obstructive pulmonary disease
Acute respiratory distress syndrome
Bronchiectasis
Interstitial lung disease
Asthma

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4
Q

ARDS

A

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…

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5
Q

Pathophysiology of ARDS

A

Endothelial leak – leading to extravasation of protein and fluid
Lungs – reduced compliance, increased shunting
Heart – pulmonary hypertension, reduced cardiac output
Hypoxia

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6
Q

What is acute inflammation initiated by

A

Initiated in the tissues, by epithelial production of hydrogen peroxide and release of cellular contents

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7
Q

What is acute inflammation amplified by

A

specialist macrophages including:
Kupffer cells (liver)
alveolar macrophages (lung)
histiocytes (skin, bone)
dendritic cells

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8
Q

How does acute inflammation respond to pathogens or tissue injury

A

by recognising:
PAMPs (pathogen-associated molecular patterns)
DAMPs (damage-associated molecular patterns)

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9
Q

How do we recognise pathogens we have never seen before

A

Pattern recognition receptors (PRRs)

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10
Q

Signalling PRRs

A

Toll-like receptors (TLRs)
Nod-like receptors (NLRs)

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11
Q

Endocytic PRRs

A

Mannose receptors
Glucagon receptors
Scavenger receptors

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12
Q

Toll-like receptors

A

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

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13
Q

What does TLR4 recognise

A

Lipopolysaccharides (LPS)

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14
Q

What does TLR2 recognise

A

Lipotechoic acid (LTA)

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15
Q

Alveolar macrophages

A

AM comprise 93% of pulmonary macrophages.
Functionally, cytochemically and morphologically similar to mature tissue macrophages.
Long-lived and arise from monocytes.

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16
Q

Neutrophil

A

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

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17
Q

Primary neutrophil granules

A

Myeloperoxidase
Elastase
Cathepsins
Defensins

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18
Q

Secondary neutrophil granules

A

Receptors
Lysozymes
Collagenase

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19
Q

Neutrophil functions

A
  1. Identify threat- receptors
  2. Activation
  3. Adhesion
  4. Migration/chemotaxis
  5. Phagocytosis
  6. Bacterial killing
  7. Apoptosis- programmed cell death
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20
Q

What do Neutrophil receptors recognise

A

Bacterial structures – cell walls, lipids, peptides

Host mediators – cytokines, complement, lipids

Host opsonins – FcR (immunoglobulin)
CR3 (complement)

Host adhesion molecules

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21
Q

Neutrophil receptors

A

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

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22
Q

Neutrophil activation

A

“Stimulus-response coupling”
Identify threat through pathogen recognition receptors
Signal transduction pathways involving calcium, protein kinases, phospohlipases, G proteins

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23
Q

Neutrophil adhesion

A

Loosely tethered to endothelium by selecting for rolling
Integrins enable stable adhesion- extravasortion
Margination – Selectins
Adhesion – Integrins

Require changes in endothelium and in neutrophil

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24
Q

CD18 (beta-2 integrin) deficiency

A

NO transendothelial migration
Delayed separation of umbilical cord
Recurrent severe cutaneous and deep infections

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25
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
26
Neutrophil phagocytosis
Pseudopodia engulf pathogen to form phagolysosome Membrane invagination and pinching PHAGOSOME Fusion with granules -> PHAGOLYSOSOME
27
Neutrophil bacterial killing
Myeloperoxidase generates ROS by NADPH oxidase Lysosomal enzymes – cathepsins, elastase Reactive oxygen species – ROS
28
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
29
Why is lung especially at risk of inflammation/pathogens
Because of a huge area potentially in contact with the external environment
30
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.
31
Intrinsic lung host defences
Always present Physical and chemical Apoptosis, autophagy, RNA silencing, antiviral proteins
32
Innate lung defences
Induced by infection (interferon, cytokines, macrophages, NK cells)
33
Adaptive lung immunity
Tailored to a pathogen (T cell, B cell) Antibodies produced Longer-term response
34
How does the respiratory epithelium acts as a barrier to potential pathogens
Action of muco-ciliary escalator
35
Chemical epithelial barriers produced by epithelial cells
antiproteinases anti-fungal peptides anti-microbial peptides Antiviral proteins Opsins
36
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)
37
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
38
How does mucus clearance occur
Via the mucociliary escalator Cilia beat in directional waves to move the mucus up the airways
39
What is a cough
An expulsive reflex that protects the lungs and respiratory passages from foreign bodies Voluntary or reflex
40
Causes of cough
Irritants- smokes, fumes, dusts, etc Diseased conditions like COPD, tumours etc Infections (influenza)
41
Afferent limb of a cough
Includes receptors within the sensory distribution of the trigeminal, glossopharyngeal, superior laryngeal and vagus nerves
42
Efferent pathway of a cough
Includes the recurrent laryngeal nerve and spinal nerves
43
What is a sneeze
Defined as the involuntary expulsion of air containing irritants from nose
44
Photic sneeze reflex
Sneezing when looking at a bright light affects up to one third of the population. This phenomenon is known as photic sneeze reflex or solar sneeze reflex.
45
Causes of sneeze
Irritation of nasal mucosa Excess fluid in airway
46
Complete repair of airway epithelium
As exhibits a level of functional plasticity Injury Spreading and dedifferentiation Cell migration Cell proliferation Redifferentiation Regeneration
47
Metaplasia
reversible replacement of one differentiated cell type with another mature differentiated cell type.
48
Mucus plugs/inflammation
Associated with severe disease Mucus and inflammatory cells block the airways
49
Which cells secrete mucous
Goblet cells of the airway surface epithelium and the submucosal glands
50
Afferent
Sensory
51
Efferent
Motor
52
What can cause injury to the airway epithelium
Trauma Toxic compounds Infection Inflammation
53
What can basal cells differentiate into
Club cells (which become goblet cells or ciliated cells) Ciliated cells
54
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
55
Mechanism of a cough
1. Epiglottis closes laryngeal inlet 2. Abdominal muscles contract and diaphragm pushes upwards 3. Increase in intrathoracic pressure 4. Vocal chords open and epiglottis lifts away 5. Pressure gradient causes high flow rate air expulsion
56
Airway epithelium repair
Can occur completely due to high functional plasticity : multi potent basal cell population can differentiate into respiratory epithelial cells
57
Metaplasia
Reversible replacement of non-squamous goblet cells with stratified squamous in heavy smoker
58
Mucus composition
Visoelastic gel containing carbohydrates fats and proteins
59
Mucus function
Protects epithelium from foreign material and fluid loss
60
Secretion and movement of mucus
Secreted by goblet cells and submucosal glands Transported from lower to upper respiratory tract by mucociliary clearance
61
Neutrophil - apoptosis
Neutrophil phagocytosed by alveolar macrophages
62
Pathogen recognition receptors
TLRs NLRs Mannose Glucan Scavenger
63
TLR4 recognises
LPS
64
TLR2 recognises
LTA
65
Role of alveolar macrophages
Phagocytosis Antigen presentation Apoptosis
66
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)
67
Cell mediated immunity
T cells - made in bone marrow , mature in thymus
68
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
69
Cytotoxic T cell receptor
CD8
70
Cytotoxic T cell MHC class
1
71
Cytotoxic T cell role
Mediate killing of tumours and virus-infected cells - perforin creates holes in cell membranes
72
Perforin
Released by Cytotoxic T cell Create holes in cell membrane
73
T helper cell receptor
CD4
74
T helper cell MHC class
2
75
T helper cell role
Release cytokines - stimulate B cell colonial expansion
76
Humoral immunity
B cells- produced and mature in bone marrow Activated in lymph nodes—> differentiate into plasma cells- secrete antibodies
77
Primary lymphoid organ
Bone marrow
78
Secondary lymphoid organ
Lymph nodes
79
Affinity maturation
Throughout immune response, B cells produce antibodies with increased affinity for antigens due to somatic hypermutation
80
IgG monomer
Secondary immune response Can cross placenta- fetal immunity
81
IgA diner
Mucosal secretions Eg breast milk- protects baby’s gut- on mucosal surface
82
IgM pentamer
Primary immune response CAN’T cross placenta
83
IgE monomer
Allergy and parasitic infections Fc receptors on mast cells, basophils and eosinophils
84
IgD monomer
Naïve B cells Activation /.maturation
85
Pneumonic ACID + EGGT
Allergic, cytotoxic, immune-complex, delayed IgE. IgG. IgG. T cell
86
Which kind of hypersensitivity reaction is IgE mediated, and what does it respond to?
Type 1, in response to things like anaphylaxis and hayfever

CVR (22 decks)

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