Why are the lungs a potential site of immunological vulnerabilty?
the two main condtions making lungs vunerable?
Inhale 8000L of air a day therfore is a major site of contact between the internal surfaces of the body and the environment/atmosphere
• Fast movement of air in and out of the lungs - this places limits on the level of filtering/barrier structures possible (e.g. the solution the GI tract uses – stomach acid – is not possible).
• Efficient gas exchange - requires a large surface area, a thin membrane at the gas-blood interface (delicate structures vulnerable to damage and infection), innervation by blood vessels, and a warm, moist environment to allow diffusion of respiratory gases (but in which microorganisms also thrive).
Given these conditions, the respiratory system is therefore a major site of immunological vulnerability
whar harmful organisms and particles are in the air?
4 different categories?
Microorganisms – bacteria, viruses, fungi, helminths
Allergens – dust, pollen
Organic particles – occupational exposures, pollution
Toxic gases – carbon monoxide, sulphur dioxide, nitrogen dioxide
Foreign body aspiration (e.g. food, liquid, choke hazards)
fine particulate material
Pollution (<2.5 - 1000 μm, depending on the specific particle/source. Nanoparticles from diesel exhausts appear to be particularly damaging to the respiratory system as they are able to reach lower parts of the respiratory tree due to their small size)
Dust (0.1-1000 μm)
Pollen (10 - 100 μm)
Fungal spores (2 - 10 μm)
Bacteria (0.5 - 5 μm)
Viruses (< 1 μm)
vulnerable to infection from inhaled micro-organisms
how can microorganisms be transmitted via resp system?
effect if upper resp tract effected?
resp surface effected?
Numerous microorganisms infect and are transmitted by the respiratory system (e.g. by breathing, droplet transmission, coughing/sneezing, etc.)
The pathology/symptoms depend on the particular microorganism and respiratory structures affected (e.g. upper respiratory tree = bronchitis/cough, respiratory surfaces = pneumonia)
vulnerable to damage from inhaled particles
what inhaled particles?
what does allergen trigger and what does this result in?
what can long term inhalation to particular organic particles result in?
damage by inhaled (inanimate) particles such as pollution, organic particles/workplace exposures (e.g. mining dust, asbestos, beryllium) and various allergens (e.g. pollen, dust mite proteins, pet fur/dander).
Allergens trigger an inappropriate and exaggerated (i.e. relative to the degree of threat posed to the body) immune system response that results in local inflammation and tissue pathology/dysfunction (e.g. airway obstruction within the airways).
Inhalation exposure to particular organic particles over the long term can result in chronic restrictive lung diseases (e.g. fibrosis, interstitial lung disease as seen in occupational lung diseases such as coalminer’s pneumoconiosis) due to the damaging effect of particle deposition within respiratory structures and the subsequent immune response triggered. Exposure to certain particles also increases the risk of lung carcinoma (cancer).
features and mechanisms that improve immunological defence
physical obstructions large scale? small scale?
immunological defence system?
o Physical obstructions:
Large scale = nasal hairs, nasal turbinates, branching airway structure.
Micro scale = cilia, mucus
Protective reflexes: coughing, sneezing, expiratory reflex
Immunological defence system:
Lung resident immune cells (e.g. alveolar macrophages)
Structural cells (epithelial cells)/innate immunity
Biological symbiosis? (commensals/microbiota)
nasal hair and turbinates
functions of above?
effect of nasal hair?
effect of turbinate?
effect of decreased nasal hair density and excessive mouth breathing?
help filter air and prevent particles from reaching the airways (+blood stream and lower resp surfaces)
. Nasal hairs within the first 1cm of the nasal passage filter out larger particles (>10μm) present in the air. The nasal turbinates/conchae are mucous membrane-lined, ridged structures within the nasal cavity that help to warm and humidify air before it reaches the airways/lungs, as well as help to filter out particles larger than ≈ 2μm.
Decreased nasal hair density and excessive mouth breathing (e.g. due to upper respiratory occlusion) have both been linked to increased asthma risk/morbidity.
cilia and mucus function to trap and remove microorganisms and particles
what lines upper resp tract? produced by? what does this poduct consist of?
where does it lie on top of? importance of sufficient perciliary layer depth? what does the coordinated beating of cilia do?
how is the cilia beating produced? when does the cilia contact the mucus gel layer? effect of this?
what should healthy mucus be like?
mucus colourayion meaning? green/yellow could mean?
how can airway pathology result in changes to mucus viscosity?
how can the level of mucus produced and secreted into the airways be modulated? 2 things
why is large amounts of excessive viscous mucus be an issue?
what happens if mucociliary clearance is impaired?
The upper respiratory system (airways and nasal cavity) are lined by a layer of mucus produced by submucosal glands (90%) and goblet cells (10%), which traps inhaled particles. Mucus consists of a gel with elastic and viscous properties, which consists of 97% water and 3% solids (mucin, other proteins, salts, lipids), and also contains lysozyme and various antimicrobial proteins to destroy trapped microorganisms.
The mucus gel layer lies on top of a periciliary layer (≈ 7μm deep) which provides a media of low viscosity in which cilia can beat. Maintaining sufficient periciliary layer depth is critical to effective mucociliary clearance for this reason. As the respiratory tract is lined by ciliated epithelium (from the trachea down to terminal bronchioles (see diagram below), the coordinated beating of cilia produces a wave of movement that propels the mucus gel layer (and any trapped particles) towards the pharynx, where it is then swallowed or expelled.
Cilia beating and mucociliary clearance is produced by rhythmic movement of individual cilia – whilst each individual cilia moves backward and forwards, the cilia only contacts the mucus gel layer during the forward stroke, as the cilia bends during the reverse stroke so that its tip passes beneath the mucus layer. Thus, the gel layer is propelled in one direction.
Healthy mucus should be clear/slightly cloudy and easily cleared. Mucus colouration can indicate pathology, for example mucus may turn yellow or green following respiratory infection due the presence and breakdown of granulocytes. Airway pathology can also result in changes to mucus viscosity, either due to breakdown/shedding of surrounding epithelium (and the presence of ‘sticky’ negatively-charged DNA and cell debris) or mucus dehydration/poor clearance (e.g. cystic fibrosis).
The level of mucus produced and secreted into the airways can also be modulated by parasympathetic nervous system stimulation (via cholinergic activation of submucosal glands) as well as local inflammation (e.g. respiratory infection or during an asthma attack). However large quantities of excessively viscous mucus can obstruct the airways, limiting airflow (e.g. asthma, chronic bronchitis).
The important function of mucus and cilia in respiratory defence can be observed in patients where this mucociliary clearance is impaired. For example, in both cystic fibrosis and chronic bronchitis, mucus clearance is impaired leading to recurrent respiratory infections and resulting inflammation/tissue damage.
Protective reflexes remove irritant or harmful particles from the airways
how does neural reflex protect airways?
what are the 3 most disctinct identifiable reflexes?
describe the basic mechanism common to each reflex? where does the afferent fibre go?
how is sneezing initiated? 3 phases?
how is a cough similar? how is it different to a sneeze?
what is the laryngeal reflex? what is the role of this reflex?
neural reflexes protect the airways from particle exposure by triggering rapid expulsion of air (and therefore deposited particles).
The three most distinct identifiable reflexes (sneezing, coughing, and the laryngeal expiratory reflex) result from activation of nociceptors (by physical of chemical stimuli) within different parts of the upper respiratory tract.
The basic mechanism common to each reflex involves activation of afferent sensory neurons, which transmit the impulse to breathing centres within the brain (i.e. the medulla, located within the brainstem). Efferent signals are then transmitted to specific respiratory muscles (e.g. the diaphragm, intercostal and abdominal muscles), the glottis (i.e. to close/open the windpipe) and airways to initiate a coordinated respiratory effort which rapidly expels air from the nasal cavity/airways/lungs.
Sneezing is initiated by stimulation of sensory receptors within the nasal cavity and involves a deep inspiration phase (“ah….”), a compression phase (during which the glottis is closed, leading to pressure build-up), and a final expiration phase in which air is expelled (“….choo!”).
Coughing similarly involves these three phases, but is triggered by stimulation of receptors within the larynx and large airways. In contrast to sneezing, coughing can also be initiated voluntarily, and involves bronchoconstriction to further increase expulsion pressure.
The laryngeal reflex is a short, forcible expiratory effort without a preceding inspiration (differentiating it from coughing), triggered by stimulation of sensory receptors within the vocal folds. The role of this reflex is to prevent foreign bodies entering the airways, and to expel phlegm and the upper respiratory tract. An initial inspiration before expiration (such as with coughing) is undesired in some circumstances as it could potentially lead to inspiration pneumonia.
The branching structure of the airways also helps to filter particles
how does airlfow change when branch site reached? effect of this?
The overall structural pattern of the airways acts to increase filtering of air and prevent particles from reaching lower respiratory structures. Human airways branch approximately 23 times between the trachea and alveoli.
When inhaled air reaches an airway branching site, airflow changes from laminar to semi-turbulent flow pattern, increasing particle deposition as more particles come into contact with the mucus-lined airway wall.
Resident immune cells provide the last line of defence
Whilst several adaptations exist to prevent particles and microorganisms reaching respiratory tissues, resident immune cells (macrophages, and structural cells (e.g. epithelial cells) are present within the tissue structure to provide further defence, coordinate immune responses, and remove deposited particles.
Alveolar macrophages contribute to immunological defence & remove particles
what are alveolar macropahges? how do they develop?
what do they do? how are products removed?
what can’t AM act on? effect of this?
how to show the importance of role of alveolar macrophages?
what must the immune system be balanced against? examples of diseases where there is no balance?
what can structural cells such as epthelial cells and fibroblasts do?
Alveolar macrophages (AM) are the resident phagocytes within the lung and develop from progenitors produced in the bone marrow that migrate to the lung. AM are found within the airspace (and can travel between alveoli) and phagocytose pathogens, foreign material and cell debris, digesting it into residual material that is subsequently removed by the lymphatic system. However certain particles (e.g. asbestos fibers, coal/silica dust) cannot be digested and cleared by macrophages, triggering inflammation and tissue damage/fibrosis. Macrophages constitute part of the innate immune system, and help to trigger further inflammation and an adaptive immune response by secreting cytokines and other inflammatory mediators in response to Toll-like receptor stimulation. Some macrophage populations can also act as antigen presenting cells (presenting antigens to T cells to stimulate cell-mediated immunity, B cell antibody production, etc.), however alveolar macrophages display very little capacity for this.
The important role of alveolar macrophages and the immune system in general in prevent respiratory infections can be observed in deficient experimental animals and relevant clinical conditions. Transgenic mice deficient in alveolar macrophages, show increased biomarkers of infection and reduced survival following infection with various pathogens, including influenza A virus (see Schneider et al. 2014). Similarly immunocompromised human patients (e.g. AIDS) are at great risk of developing opportunistic respiratory infections such as tuberculosis and bacterial pneumonia.
However whilst the immune system plays a critical role in protecting against pathogens, its activity needs to be balanced against the potential damage caused by excessive/recurrent inflammation (for example in asthma, anaphylaxis, COPD and fibrosis).
In addition to leukocytes, structural cells such as epithelial cells and fibroblasts also express pattern recognition receptors, secrete antimicrobial peptides and signal (via cytokine release) to initiate/coordinate immune responses.
The airway / lung microbiota also help to maintain immunological balance
role of airway and lung microbiota?
A final factor involved in protecting the lung against disease and pathogen infection, which has received much recent research effort, is the role that the airway and lung microbiota plays.
The mucosal surfaces of the respiratory system are not sterile (even in healthy individuals) – they are colonised by huge numbers of commensal bacteria . Our current understanding is that these organisms play important roles in resisting infection by other pathogens and the development/modulation of a healthy immune system. The populations of organisms colonising airways in health vs. disease appear to vary, however whether this change contributes to the pathology, or merely results from it, is still under debate. Perhaps cultivating a healthy respiratory microflora could one day constitute a future treatment aim ?