Host Defence In The Lung: Innate Immunity Flashcards
Acute inflammation
Vasodilatation leads to exudation (fluid leaks out) of plasma, including antibodies
Activation of biochemical cascades to target bacteria, e.g. complement and coagulation cascades. They also trigger pain receptors. Pain then helps you cough
Cascade: a series of chemical reactions that occur within a biological cell when initiated by a stimulus
Migration of blood leukocytes into the tissues, mainly neutrophils but also some monocytes
Inflammation
Inflammation is our defence against infection and a hostile environment
BUT
Many of us will die of diseases caused by inflammatory processes as inflammation can cause tissue damage in the lung if. It is prolonged and repeated
What is inflammation?
Recognised from:
Hot
Red
Painful
Swollen
Loss of function
Inflammation must be finely balanced in the lungs to prevent disability of the lungs
COPD- Chronic Obstructive Pulmonary disease
Alveolar units are destroyed
The walls are broken down by repeated inflammation
The delivery of neutrophil proteases occurs- these break down proteins in the lung
Lungs are aligned with mucus and inflammatory cells
Takes up to 20 years of smoking to occur
Acute respiratory distress syndrome
Occurs very rapidly
Any condition causing inadequate tissue oxygenation may precipitate ARDS
- commonly trauma, lung infection, sepsis, surgery…
Leads to
Respiratory failure as instead of alveoli being very thin and delicate Water and neutrophils fill the alveoli
Multi-system failure
Pathophysiology of ARDS
Endothelial leak – leading to extravasation of protein and fluid
Lungs – reduced compliance, increased shunting
Heart – pulmonary hypertension, reduced cardiac output
Hypoxia- deficient supply of oxygen to tissues
Acute Inflammation
Initiated in the tissues, by epithelial production of hydrogen peroxide and release of cellular contents, providing a stimulus for other cells too that produce cytokines and chemo lines to then reduce inflammatory cells and cascade of inflammation
Amplified by specialist macrophages (deal with low level threats) including:
Kupffer cells (liver)
alveolar macrophages (lung)
histiocytes (skin, bone)
dendritic cells
Every tissue has a very specialised resident macrophage population. Even within these populations of macrophages the phenotype of the macrophage isn’t exactly the same and DEPENDING ON WHATS HAPPENING IN THE MACROPHAGE (ENVIRONMENT) the PHENOTYPE CAN CHANGE
Respond to pathogens or to tissue injury by recognising:
-PAMPs (pathogen-associated molecular patterns)
-DAMPs (damage-associated molecular patterns)
Innate immune system must recognise substances it’s never seen before whereas adaptive immune system recognises and has specific pathways for the different stimuli
So Innate immune system has Pattern Recognition receptors
Pattern recognition receptors can be signalling or endocytic receptors
Signalling Toll-like receptors (TLRs)
Nod-like receptors (NLRs) intracellular signalling
Tell the cell how to respond
Endocytic Mannose receptors
Glucan receptors
Scavenger receptors
These engage between the host cell and pathogen and allow the cell to efficiently phagocytosis them
Toll like receptors
Vulnerable to fungal infection
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 (things released from other cells can also stimulate these receptors)
The Alveolar Macrophage
AM comprise 93% of pulmonary macrophages
Functionally, cytochemically and morphologically similar to mature tissue macrophages.
Long-lived and arise from monocytes
Initially produced during foetal life and they colonise the lung
These cells are damaged by particulate matter we exposed to during our life’s
When they become exhausted they are removed from the lung
As they are removed new macrophages are recruited from the blood and populate the lung so that by the end of life people have a range of different alveolar macrophages in the lung
Macrophages role in inflammatory insult or infectious insult (MACROPHAGE PLASTICITY)
they can polarise towards this host defence phenotype where their main job is to produce substances that activate the immune system, activate cells around them to act, to take up and to kill the bacteria
When the threat is gone, the macrophages will switch their phenotype over to a tissue repair or other resolution phenotype which enables them to start healing the tissues around and allowing other cells to leave or to be removed
The 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
Contain GRANULES- beneficial to their harmful and beneficial function
PRIMARY granules– myeloperoxidase, elastase, cathepsins, defensins
SECONDARY granules– receptors, lysozyme, collagenase
Neutrophils Spend half of their life in circulation whilst other half they are marginated (adhered to the endothelium of lung)
Ensures the neutrophils can rapidly invade the lung if needed
If a circulating neutrophil encounters negative tissue damage…
The pattern recognition receptors on the surface of the macrophages recognise the PAMP/DAMP on the foreign substance. This activates the neutrophils in the blood vessel. This also increases permeability of the blood vessels and causes them to dilate.
Initially the neutrophils stick to the endothelium and start to roll and then it’ll firmly adhere and then start to trans migrate between the endothelial cells into tissues.
This is accompanied by the oedema
Classic signs of inflammation, these neutrophils in the tissues that are the predominant phagocytic cell take up the bacteria and digest them and kill them within them
But they can also release these granule contents that can damage tissues so at the end of the process, the neutrophils must be safely removed
A large part of this removal is by the death of the neutrophil by apoptosis, genetically programmed cell death where the key effector proteins are cut up by proteases within the cell, enabling this cell to be recognised as apoptotic and taken up by macrophages and removed from the area of inflammation (this switch in function of the macrophages is signalled by neutrophils)
So neutrophils have ensured that after a period of inflammation the tissues are restored to their normal state
Neutrophil functions
1) Identify the threat – receptors
2) Activation
3) Adhesion
4) Migration into tissues/chemotaxis
5) Phagocytosis
6) Bacterial killing
7)Apoptosis – programmed cell death
- Receptors recognise
Bacterial structures – cell walls, lipids, peptides
Host mediators – cytokines, complement, lipids
Host opsonins – FcR (immunoglobulin)
CR3 (complement)
Host adhesion molecules which allow neutrophils to stick to vessel walls and migrate tissue
- Stimulus response coupling
If you’ve only got a few bacteria you don’t need a very big response vice versa
Neutrophils need a way of sensing what’s going on around them- ie know the size of threats and to know what other neutrophils are there. This is done through the:
Signal transduction pathways involving calcium, protein kinases, phospohlipases, G proteins
- Adhesion
Margination – Selectins
Further capturing by Adhesion to Integrins
So intergrins mediate the firm adhesion and these are a couple of molecules on the neutrophil and on the endothelium that bind very firmly so initially they will just be captured and then there will be a firm interaction with integrins that sits the neutrophils down on the endothelium
Each of those will the flatten out and they’ll start to migrate directly, invade between the end to then migrate into tissue
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
- Migration/chemotaxis
Ability to detect a concentration gradient and move along it
By moving receptors to the leading edge
- Phagocytosis
Membrane invagination and pinching PHAGOSOME
Fusion with granules PHAGOLYSOSOME
- Bacterial killing
Lysosomal enzymes – cathepsins, elastase
Reactive oxygen species – ROS
ROS generated by a membrane enzyme complex – the NADPH oxidase which uses ATP to generate ROS
People who lack:
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
Phagocytic clearance of apoptotic cells
Even when neutrophils is dead it has a key function of switching the macrophage function from attach to defence and to restoration of normal tissue function
Summary
Acute inflammation often affects the lung
It may be beneficial in eradicating pathogens
Frequently, however, it is deleterious
The lung is especially at risk….
Because of a huge area potentially in contact with the external environment
