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
Q

Neutrophil migration/chemotaxis

A

Protrude through gaps in endothelium (diapedesis)
Ability to detect a concentration gradient and move along it
By moving receptors to the leading edge

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26
Q

Neutrophil phagocytosis

A

Pseudopodia engulf pathogen to form phagolysosome
Membrane invagination and pinching PHAGOSOME
Fusion with granules -> PHAGOLYSOSOME

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27
Q

Neutrophil bacterial killing

A

Myeloperoxidase generates ROS by NADPH oxidase
Lysosomal enzymes – cathepsins, elastase
Reactive oxygen species – ROS

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28
Q

ROS (reactive oxygen species)

A

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

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29
Q

Why is lung especially at risk of inflammation/pathogens

A

Because of a huge area potentially in contact with the external environment

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30
Q

Non-respiratory functions of lungs

A

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.

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31
Q

Intrinsic lung host defences

A

Always present
Physical and chemical
Apoptosis, autophagy, RNA silencing, antiviral proteins

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32
Q

Innate lung defences

A

Induced by infection (interferon, cytokines, macrophages, NK cells)

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33
Q

Adaptive lung immunity

A

Tailored to a pathogen (T cell, B cell)
Antibodies produced
Longer-term response

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34
Q

How does the respiratory epithelium acts as a barrier to potential pathogens

A

Action of muco-ciliary escalator

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35
Q

Chemical epithelial barriers produced by epithelial cells

A

antiproteinases
anti-fungal peptides
anti-microbial peptides
Antiviral proteins
Opsins

36
Q

Mucus structure

A

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
Q

Mucus function

A

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
Q

How does mucus clearance occur

A

Via the mucociliary escalator
Cilia beat in directional waves to move the mucus up the airways

39
Q

What is a cough

A

An expulsive reflex that protects the lungs and respiratory passages from foreign bodies
Voluntary or reflex

40
Q

Causes of cough

A

Irritants- smokes, fumes, dusts, etc
Diseased conditions like COPD, tumours etc
Infections (influenza)

41
Q

Afferent limb of a cough

A

Includes receptors within the sensory distribution of the trigeminal, glossopharyngeal, superior laryngeal and vagus nerves

42
Q

Efferent pathway of a cough

A

Includes the recurrent laryngeal nerve and spinal nerves

43
Q

What is a sneeze

A

Defined as the involuntary expulsion of air containing irritants from nose

44
Q

Photic sneeze reflex

A

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.

45
Q

Causes of sneeze

A

Irritation of nasal mucosa
Excess fluid in airway

46
Q

Complete repair of airway epithelium

A

As exhibits a level of functional plasticity
Injury
Spreading and dedifferentiation
Cell migration
Cell proliferation
Redifferentiation
Regeneration

47
Q

Metaplasia

A

reversible replacement of one differentiated cell type with another mature differentiated cell type.

48
Q

Mucus plugs/inflammation

A

Associated with severe disease
Mucus and inflammatory cells block the airways

49
Q

Which cells secrete mucous

A

Goblet cells of the airway surface epithelium and the submucosal glands

50
Q

Afferent

A

Sensory

51
Q

Efferent

A

Motor

52
Q

What can cause injury to the airway epithelium

A

Trauma
Toxic compounds
Infection
Inflammation

53
Q

What can basal cells differentiate into

A

Club cells (which become goblet cells or ciliated cells)
Ciliated cells

54
Q

Smoking is known to adversely affect the clearance of mucus from the airways.

Which of the following provides cilia for the mucociliary escalator?

A

Columnar Epithelial Cells

55
Q

Mechanism of a cough

A
  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
Q

Airway epithelium repair

A

Can occur completely due to high functional plasticity : multi potent basal cell population can differentiate into respiratory epithelial cells

57
Q

Metaplasia

A

Reversible replacement of non-squamous goblet cells with stratified squamous in heavy smoker

58
Q

Mucus composition

A

Visoelastic gel containing carbohydrates fats and proteins

59
Q

Mucus function

A

Protects epithelium from foreign material and fluid loss

60
Q

Secretion and movement of mucus

A

Secreted by goblet cells and submucosal glands
Transported from lower to upper respiratory tract by mucociliary clearance

61
Q

Neutrophil - apoptosis

A

Neutrophil phagocytosed by alveolar macrophages

62
Q

Pathogen recognition receptors

A

TLRs
NLRs
Mannose
Glucan
Scavenger

63
Q

TLR4 recognises

A

LPS

64
Q

TLR2 recognises

A

LTA

65
Q

Role of alveolar macrophages

A

Phagocytosis
Antigen presentation
Apoptosis

66
Q

B and T lymphocytes are activated by

A

Antigens on pathogen surface
Free antigens in plasma
Peptides presented via MHC glycoproteins (on macrophages, B cells, dendritic cells)

67
Q

Cell mediated immunity

A

T cells - made in bone marrow , mature in thymus

68
Q

Treg cells

A

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
Q

Cytotoxic T cell receptor

A

CD8

70
Q

Cytotoxic T cell MHC class

A

1

71
Q

Cytotoxic T cell role

A

Mediate killing of tumours and virus-infected cells
- perforin creates holes in cell membranes

72
Q

Perforin

A

Released by Cytotoxic T cell
Create holes in cell membrane

73
Q

T helper cell receptor

A

CD4

74
Q

T helper cell MHC class

A

2

75
Q

T helper cell role

A

Release cytokines - stimulate B cell colonial expansion

76
Q

Humoral immunity

A

B cells- produced and mature in bone marrow
Activated in lymph nodes—> differentiate into plasma cells- secrete antibodies

77
Q

Primary lymphoid organ

A

Bone marrow

78
Q

Secondary lymphoid organ

A

Lymph nodes

79
Q

Affinity maturation

A

Throughout immune response, B cells produce antibodies with increased affinity for antigens due to somatic hypermutation

80
Q

IgG monomer

A

Secondary immune response
Can cross placenta- fetal immunity

81
Q

IgA diner

A

Mucosal secretions
Eg breast milk- protects baby’s gut- on mucosal surface

82
Q

IgM pentamer

A

Primary immune response
CAN’T cross placenta

83
Q

IgE monomer

A

Allergy and parasitic infections
Fc receptors on mast cells, basophils and eosinophils

84
Q

IgD monomer

A

Naïve B cells
Activation /.maturation

85
Q

Pneumonic
ACID + EGGT

A

Allergic, cytotoxic, immune-complex, delayed
IgE. IgG. IgG. T cell

86
Q

Which kind of hypersensitivity reaction is IgE mediated, and what does it respond to?

A

Type 1, in response to things like anaphylaxis and hayfever