The usefulness of the more time consuming process of evaluating eosinophils in induced sputum is also questionable, with no evidence of its utility in children 81 , 82 and no impact on symptoms or lung function in adults, although a trend toward reduced exacerbations has been reported. The reason NICE failed to learn from the successful Finnish national asthma programme, in which objective confirmation of diagnosis using lung function testing was the key component, is unclear.
It is a curiosity that in most specialties, the fundamental tests supporting their practice are readily available. It is easy to obtain a full blood count, blood glucose, CXR, or ECG, yet health care systems are yet to embrace the need for widely available, high quality lung function testing LFT.
The fact that this is not the case and the majority of children with asthma in primary care are neither diagnoses or monitored using spirometry 3 , 84 is another example of the failure of the respiratory world to advocate for their patients and should be source of embarrassment. A very recent study from the U. Many countries in South America report a high prevalence of asthma despite few of these individuals manifesting atopic markers such as skin prick test positivity. Several studies have shown that despite increasing atopy within populations accompanied by increases in eczema and allergic rhinitis, over recent years the prevalence of asthma has fallen or remained static.
The explicit recognition of atopic and non-atopic asthma 97 reinforces the concept, that while atopy may be an exacerbating co-morbidity, it is not central to the manifestation of asthma. Association does not imply causality. As a result, the prevalence of asthma is probably greatly over-estimated 24 making assessment of trends over time almost meaningless. Indeed the majority of those with an allergic rhinitis or eczema do not manifest asthma.
It appears very likely that many individuals with a seasonal rhinitis due to grass pollen or perennial rhinitis due to an allergen such as house dust mite will have airways inflammation due to an allergic bronchitis. In the absence of significant bronchoconstriction these individuals may experience cough and some increase in airways secretions. These subjects with an allergic bronchitis will respond to ICSs if their cough is troublesome 99 — Despite corticosteroid responsiveness and some asthma like symptoms they do not have asthma in that they do not exhibit significant bronchoconstriction due to ASM activity.
It is also increasingly recognized that eosinophilic bronchitis is absent in many asthmatics — arguing against the eosinophil having an essential role in the development of asthma thought they may well-contribute to symptoms.
Conversely, in those who out-grow their asthma there is evidence that the inflammatory profile persists in most subjects studied suggesting that the AHR has altered and homeostasis has been restored despite persistence of ongoing inflammation — A study in asymptomatic subjects previously diagnosed with asthma found evidence that FeNO fell after introduction of inhaled steroids but, importantly, there was no change in clinical status , again questioning the link between FeNO and asthma per se.
While several studies suggested this ongoing inflammation may predispose to relapse, there is no evidence to support or refute this suggestion.
However, the discrepancy between re-established airways homeostasis and ongoing inflammation suggests the inflammation per se is not the critical factor. The central role of the eosinophil has also been questioned through observations that early studies with anti-IL-5 agents in asthmatic subjects significantly reduced eosinophilia but had little or no clinical impact , Even in this minority of asthmatic patients there is debate as to whether driving therapeutic decisions on the basis of eosinophil numbers is any better than making changes on the basis of symptoms.
Importantly there is no data to suggest that atopic status significantly impacts on the response to inhaled corticosteroids. Moreover, should they prove to have a role, it is unclear why some individuals should develop ASM hyper-responsiveness as a consequence of the activity of this type of cells when they are present in all individuals. Pre-term individuals are an interesting group, in whom there is a significantly higher rate of asthma as defined by demonstrable bronchodilator responsiveness than the general population and in whom atopy appears not to be a significant risk factor — There is evidence of on-going neutrophilic but not eosinophilic inflammation in the majority of these patients , — well into childhood, but the relevance of this, if any, to the development of asthma in a minority, is unclear.
Older patients often report no significant benefit when started on ICSs which may imply that in many the BHR may not improve with steroid or that years of adaptation to low lung function has resulted in physiological adaptation as with severe poorly controlled asthmatic or may reflect the impact of the CLD structural changes as a co-morbidity.
There are a number of on-going studies addressing therapeutic approaches which may provide valuable information. As will be argued in more detail below, the fundamental defect leading to asthma appears to be a loss of the normal post-natal homeostatic control.
Antenatally, ASM contracts vigorously and frequently with regular peristaltic waves moving distally from even in the earliest stages of lung development. This is vital for lung development but toward term these peristaltic waves cease.
In contrast to it its marked physical contractions prenatally, post-natal ASM maintains a relatively constant length with relatively minor and non-coordinated oscillations around an optimal length, probably controlled by classic negative feedback loops. To date no clear role for ASM in a healthy individual after birth has been identified. The most likely role, if any, is likely to be helping to maintain an optimal luminal diameter in the conducting airways in order to minimize resistance to airflow while at the same time minimizing the dead space within the conducting airways.
Airways smooth muscle cells are generally considered to be as highly specialized cell whose function is essentially confined to shortening or lengthening with little or no other contribution to the function of the lungs. Moreover, bronchoconstriction and the resultant stress on cells such as epithelial cells and fibroblasts may also result in release of inflammatory cytokines secondary to the constriction.
It is also possible, but not proven, that this pattern of inflammation can, in some individuals, contribute to the development of loss of homeostatic control of ASM. Asthma does not appear to be analogous to type-1 diabetes, in which a key component of normal homeostasis is permanently lost.
Rather it seems more similar to the development of type-2 diabetes, which may or may not be evident in individuals of the same BMI. The same relative obesity does not lead to the manifestation of a condition in all individuals with a number of factors influencing whether homeostasis is maintained.
In subject of the same sex age and BMI some will have no identifiable problem with glucose homeostasis, others only when stressed and some will have very poor glycaemic control. Similarly removal of stimuli can result in greatly improved homeostasis improved diet or allergen avoidance, respectively , while control can be fully restored by life style changes in case of type-2 diabetes and by taking ICSs or growing out of asthma through mechanisms unknown.
As already noted, ASM has been shown to respond directly to corticosteroids with reduced cytokine production and changes in bronchial responsiveness, raising the possibility that a major effect of ICSs is on ASM — This is potentially most evident during exacerbation when they can positively influence ASM responses to bronchodilators when the ASM is exposed to viral RNA in the absence of any other cell type.
Some have argued that ASM is simply a vestigial tissue with no significant function in highly evolved mammals , This argument was one of a number used to promote the concept of thermoplasty and muscle destruction as a potentially safe approach to the treatment of asthma — Smooth muscle is distributed extensively in the primitive lungs of lung-fish and amphibians as well as the swim bladders of fish.
In the earliest air-breathing fish and amphibians, the primitive lung's airways smooth muscle contributed significantly to emptying the lung sacs. Air is actively forced into the primitive lungs by muscles in the upper airways while emptying is also an active process driven by largely the smooth muscle of the lower airway — Of note, much of the control mechanisms via the vagus nerve appears to have been established at the very earliest stages in the evolution of the lung and air breathing, while surfactants also date back to the earliest lungs and swim bladders — The evolution of the diaphragm, present only in mammals, and a separate relatively rigid thoracic cavity, together with robust elastic recoil provided for a much more efficient means of filling and emptying the lungs dinosaurs, birds, and reptiles developed completely different mechanisms for filling and emptying their lungs.
Consequently, the need for active contraction of muscle intimately associated with the lung in order to exhale air was negated. In diving mammals, ASM appears to act with cartilage to stabilize the airways while air is forced out of alveoli into more central and upper airways structures due to the increase external pressure at depth.
Emptying alveoli helps to both protect these fragile structures from barotrauma and prevent nitrogen narcosis. Surfactants appear to help unstick the closed alveoli, a role they probably served in the earliest rudimentary lungs , This led some to suggest that persistence of ASM may represent an evolutionary curiosity with no contemporary function but retaining the potential to cause harm analogous to the appendix , However, antenatal ASM plays a critical role in lung development grounded in millennia of evolution — and post-natally it probably plays a central role in the highly efficient process of inhalation and exhalation through maintaining an optimal configuration of the airways.
Airways smooth muscle appears very early in fetal development and exhibits spontaneous rhythmic contraction and relaxation as well as having functional cholinergic innervation — Of note, in utero , the peristalsis is proximal larynx to distal, as is the case in the gastrointestinal GI tract from which the lungs develop.
The pressure generated at the tip of the lung buds by this peristalsis acting on intraluminal fluid appears critical to lung growth and its absence results in hypoplastic architecture. Indeed complete inhibition of ASM prenatally is not compatible with life due to severe lung hypoplasia. The branching structure of the conducting airways is complete before term with post-natal growth being largely in relation to the size of conducting airways and number and size of alveoli and associated respiratory structures In utero , a proximal pacemaker appears to be operating, co-ordinating peristalsis in a distal direction , There also appears to be differential control of new and relatively newly formed ASM and that in more established central airways.
As the fetus approaches term the phasic activity progressively declines starting in the more central airways and essentially disappearing even in the most distal airway by term.
In primitive amphibians, SM played a role in both developing the primitive lung and emptying the lung. In mammals, the evolution of the thoracic cage with a powerful diaphragm to drive inhalation and use of elastic recoil of the chest to exhale fundamentally changed the means of inflating and deflating the lungs.
Consequently, in contrast to the gut smooth muscle, ASM normally ceases to constrict in a coordinated manner shortly before term. This suggest that a fundamental change in control has occurred in which homeokinetic control is established in order to maintain a stable airway that minimizes the work of breathing air through minimizing resistance to airflow, while minimizing the anatomical dead-space of the conducting airways.
An example of the post-natal resistance to significant narrowing presumably through negative feedback mechanisms is the very small change in airways resistance noted in most normal individuals even when inhaling very high doses of agonists such as methacholine.
One would predict that establishing stability of mammalian airways in post-natal life would be the norm, as there would not appear to be any evolutionary advantage in having the airways contract sufficiently to impair potentially life-saving activities such as running away from a predator! Birth brings about major changes with the fetus transitioning from a submerged life to an air breathing terrestrial existence.
The surges in catecholamines associated with birth are one of factors driving the physiological and functional changes. Fluid is rapidly removed from the airways, oxygen is obtained from the lungs and there are major changes in vascular resistance and circulation. The epithelium of the conducting airways undergoes significant changes from the relatively primitive squamous epithelium to a complex post-natal epithelium and it is very likely that their functional activity changes—changes probably paralleled when taking submerged bronchial epithelial cell cultures and exposing them to an air-liquid interface.
Post-natally, airways caliber is tightly controlled. There is evidence of relatively slow phasic contractions , — , presumably due to ASM length oscillating around an optimal mean. These oscillations appear to be relatively small with little or no impact on total airflow resistance. In order to maintain an optimal airways caliber the ASM is presumably under some form of classic negative feedback control. There is little or no evidence that the acute lower respiratory illnesses so common in the first year of life evoke significant bronchoconstriction further strengthening the suggestion that asthma is an acquired dysfunction of ASM.
Indeed infants, soon after birth, may have relatively greater ASM in their airways than older subjects based on comparative animal studies It is unclear whether there is co-ordinated contraction and relaxation of ASM around or whether units operate independently.
One possibility is that stability is achieved by ASM cells contracting randomly and independently with the lack of coordinated constriction producing stability of the airways Of note, selective vagotomy abolishes both the baseline tone and the oscillation, indicating that centrally derived cholinergic innervation plays an important role in one arm of the homeostatic control of airways caliber.
While the lungs have evolved over millennia to operate as efficiently as possible it is argued that this optimal design places the airways at risk of significant functional limitation if the normal geometry is perturbed The conducting airways take up as little space as possible and the configuration represents the least space consistent with minimizing resistance.
However, relatively small decreases in caliber can have significant impact due to the resistance being related to the fourth power of the radius.
This vulnerability will vary from individual to individual based on their airway morphology. This potentially contributes to differences in the impact of similar degrees of airways shortening on lung function in different individuals.
One mechanism that may be important in limiting the potential harm that can arise from excessive constriction lies in the partial helical orientation of ASM which results in shortening as well as narrowing of the bronchi which appears to limit transverse narrowing This may be mediated centrally with anticholinergic therapy being reported to abolish the increase in BHR observed in asthmatics following breath holding.
The transition from the submerged environment in utero to air breathing independent existence parallels, in many aspects, the evolutionary transition from a wholly aquatic existence to land dwelling creatures. Understanding how this profound developmental change is established, perhaps through comparing pre-natal and post-natal function; epigenetics or gene expression, may finally give us the answer to what is the fundamental defect underlying the development of asthma in post-natal life.
This would suggest that cure might be possible if we genuinely understood the homeostatic mechanisms in healthy airways. In some of these individuals, asthmatic symptoms will reoccur at a later date. As has been recognized for centuries there is a hereditary predisposition to the disease, but environmental factors are clearly essential for initiating and perpetuating the condition. The onset of occupational asthma in previously well-adult individuals 3 further emphasizes the potential for loss of homeostasis at any age.
Below this figure the treatment effects are often completely lost. Studies indicate that lung function variability improves more quickly than BHR [ 40 — 42 ; Figure 2 ].
The greatest impact on lung function is on the daily trough Figure 3. The large falls from one's best being eliminated in those with good control. In many the maximum flows also increase after introduction of ICS, this effect being seen in most in those with the more troublesome asthma.
Much, but not all, of the benefit from commencing ICS, in terms of reduced BHR, is achieved within the first 4—8 weeks. Evidence suggests that BHR may continue to improve over a year and if ICS are stopped at this point lung function and BHR may return to previous values though this may be a little slower than after a shorter course , In contrast to the relatively slow onset of action, the effect of ICS in restoring homeostasis and preventing the day to day variation in caliber attributable to ASM activity is, intriguingly lost within days of discontinuing them after short term treatment.
Bronchial sensitivity appears to have two components; inherent baseline sensitivity and a more labile variable component. As with all physical and physiological traits there is likely to be a normal innate distribution of inherent sensitivity to constrictor stimuli. Conversely allergen avoidance such as moving to high altitude for house dust mite sensitive individuals appears to be associated with a reduction in sensitivity This was accompanied by a 0.
In a similar study a significant improvement in PC20 was observed at h when compared with placebo By days the PC20 had increased by mean of 3. Within a week of discontinuing therapy, the PC20 had returned to placebo values Indeed, in long term studies the improvement in BHR is most marked during the first 4—8 weeks but it continues to improve, albeit much more slowly, over many months. For those who have been prescribed ICS for a number of years the rate of reversion to the mean appears to be slower but still occurs.
The increased BHR [sensitivity] and asthmatic symptoms can persist even if the specific IgE and bronchial response to challenge with a particular agent resolves. This observation does not however determine whether there has been a permanent change in ASM sensitivity per se or whether the effect is mediated through other changes in the host, such as ongoing inflammation in the absence of the initial driver.
In comparison with B Sen far less work has been undertaken regarding the nature of reactivity and how it is influenced by factors such as inhaled corticosteroids and allergen exposure. Importantly we do not know whether changes in B Sen are paralleled in changes in B Rea.
Any reduction in lung function is generally minimal. Very high doses of histamine, for example, can induce systemic side effects such as flushing and marked tachycardia in the absence of further constriction suggesting the driver to constriction is substantial but the normally homeostatic mechanism are very effective at resisting bronchoconstriction.
Amongst asthmatic subjects there appears to be a spectrum of responsiveness with many exhibiting a plateau in their maximal constriction such that while symptomatic further doses do not lead to death Figure 2. The concept that an individual's BRea in large part determines the severity rather than frequency of symptoms would be consistent with the observation that the best guide to future significant exacerbations is previous exacerbations—those who have had severe episodes before are likely to have them again.
In support of this, Brown et al. It should be noted the closure was limited to the area of application. In support of this suggestion is the observation that a significant number of asthmatic deaths and near death episodes appear to be acute asphyxiating episodes often following exposure to a particular allergen.
An individual who is cyanosed and unconscious may be walking and free of significant respiratory distress a short time after an injection of adrenalin, suggesting the homeostatic mechanisms are overwhelmed but the ASM is not locked down, as occurs in those with viral exacerbations.
While ICS therapy does tend to increase the maximum PEF, it has a much greater impact on the minimum PEF, largely abolishing the significant diurnal variation characteristic of many with asthma Figure 3. When the ICS are discontinued the minimum morning PEF generally returns to approximately pre-treatment levels suggesting that there is no fundamental change in reactivity.
This suggests that once the tipping point required to destabilize the ASM is reached, it will constrict to a similar degree to that seen in periods of poor control. There are clearly confounders such as failure to perceive deterioration in poorly controlled subjects. Despite these, post-mortem studies suggest that there are differences, with short duration deaths being characterized by greater mast cell degranulation and neutrophils with fewer eosinophils and less mucus — As noted above, this suggests that many rapid deaths are predominantly due to acute constriction, which may or may not occur on top of signs of poor control.
This suggests that being aggressive before lung function starts to fall significantly with a viral exacerbation is effective in stabilizing the airways, through combining bronchodilation and increased steroid exposure. Assessment of ASM mass in post mortem specimens, resected lungs, and imaging suggests that asthmatics appear to have more smooth muscle than non-asthmatics 67 , — Rather relatively greater ASM mass may, with other factors such as airways size, influence the magnitude of narrowing if the homeostatic state is destabilized.
It may also explain in part the differences in severity of airflow obstruction noted across the spectrum of asthma severity. It is likely that, as with other biological variables, the amount of ASM is normally distributed amongst healthy individuals.
One prospective study suggested that ASM mass in early childhood is the best predictor of asthma later in childhood , suggesting that ASM mass maybe a risk factor for the manifestation of asthma, though this was not replicated in a second study The limited available data from adults suggests that the ASM bulk in asthmatics is related to severity and not duration of asthma If this is the case, it suggests that the more severe asthmatics have a pre-existing relative increase in ASM though it is also possible there may be an early increase in muscle mass but the ability to increase in size is limited and hence not progressive.
If there is an increase in ASM mass, is this due to hyperplasia rather than hypertrophy? Some studies have suggested that ASM cells increase in number, but to date there has not been any evidence of increased proliferation in situ For skeletal and cardiac muscle, the response to increased load appears to be hypertrophy rather than hyperplasia. These findings are similar to observations in a short-term human study , though it should be noted that even after the repeated stimuli, the values in those who had repeated constriction were similar to those of the controls.
Of note, they did not assess the effect on ASM. A subsequent study involving repeated bronchoconstriction in adult asthmatics was unable to identify any impact on lung function In studies reviewing the impact of thermoplasty , it is clear that ASM mass in larger airways is reduced post procedure, though it appears that the improvement in control does not correlate with the reduction of mass and hence maybe in part due to other effects including those on ASM innervation.
The greatest impact appears to be on the frequency of events associated with significant contraction reflecting reactivity such as reduced oral steroids use, ED presentation and hospitalization.
Pre and post bronchodilator lung function was largely unchanged ASM may be altered in other ways; resting tone and length may be re-set or its function may be altered with more rapid recycling of contractile units producing a greater effect for a given stimulus. Evidence suggests that ASM show a significant degree of plasticity and do not have a force-response curve typical of skeletal muscle.
Asthmatic ASM does not appear to generate greater forces for a given stimulus than that from non-asthmatics , Krishnan et al. It is well-established that in the GI tract there is parasympathetic innervation which exerts both excitatory and inhibitory control on the tone of the smooth muscle as well as sympathetic innervation that has a predominantly inhibitory effect during extra-uterine life However, in the case of the human respiratory tract, sympathetic innervation is sparse and predominantly supplies blood vessels and submucosal glands.
In contrast to humans, spinal adrenergic sympathetic nerves supply ASM in some mammals such as guinea pigs, cats and dogs , , In humans it is the cranial parasympathetic nervous system that predominantly controls the ASM through extensive plexuses. The vagus nerve carries both cholinergic and non-adrenergic non-cholinergic NANC nerves, activation of the former leading to constriction and the later to relaxation.
Selective vagotomy results in loss of the normal rhythmic contraction of ASM and bronchodilation. Given the position of parasympathetic ganglia which are predominantly located along the trachea and large bronchi, it is possible the effect of thermoplasty may be on neuronal control of ASM. Nitric oxide [NO] and vasoactive intestinal peptide VIP act as the principle transmitters in the mammalian NANC parasympathetic bronchodilating system with the former predominating in humans though to date there is no direct evidence that NO gas is released during these responses.
It appears that parasympathetic mediated relaxations of ASM requires higher frequency of stimulation than those needed to evoke parasympathetic cholinergic contractions , , The lack of spinal adrenergic innervation capable of contributing to control of ASM tone may place humans at particular risk of loss of homeostatic control particular given the potent potential constricting effects of cholinergic innervation.
Impaired NANC negative feedback in the absence of adrenergic support would result in destabilization of the normal negative feedback homeostatic controls.
A further constrictor effect such as release of histamine and other constrictors would place the system under strain and lead to symptoms in those whose negative feedback homeostatic controls are relatively impaired. Certainly, bronchodilation is observed in the first few minutes of moderately intense exercise in both asthmatics and, to a lesser extent, healthy subjects with bronchoconstriction in asthmatics typically not occurring until around 6—8 min of continuous exercise This exercise related bronchodilation maybe related to the release of adrenaline or diminished vagal mediated parasympathetic tone If novel approach to preventing tachphylaxis were identified this may provide an effective alternative treatment.
It is beyond the scope of this review to review these issues though it is worth reflecting again that inflammation per se as in CF, COPD etc.
For many years, investigators have been seeking an epithelium-derived relaxing factor akin to the role played by nitric oxide in control of endothelial control but despite intense activity no such factor has been identified , Larger, more detailed studies were unable to demonstrate significant differences in epithelial integrity when biopsies of asthmatics were compared with those from healthy individuals, though there was goblet cell hyperplasia — Reviewed by: Okan Elidemir, MD.
Larger text size Large text size Regular text size. What Is Asthma? What Causes Asthma? Asthma isn't contagious. You can't catch it from someone who has it. How Asthma Affects Breathing With normal breathing, air flows in through the nose or mouth and then into the windpipe trachea.
What Are the Signs and Symptoms of Asthma? Asthma Flare-Ups An asthma flare-up or "attack" is when a person's symptoms get worse. During a flare-up, a person might have: trouble breathing a tight chest a whistling sound when breathing wheezing a cough Things that bring on a flare-up are called triggers. These can vary, but common triggers include: allergens , like pollen, mold, or other things that cause an allergic reaction in some people airborne irritants and pollutants , like smoke , strong scents, or high levels of air pollutants exercise weather , like cold, dry air or extreme heat or humidity respiratory tract infections , like colds and the flu Other things can trigger asthma flare-ups too: Some girls find their asthma gets worse just before their periods.
How Is Asthma Treated? Avoiding Triggers People with asthma need to avoid the things that might cause flare-ups. Taking Medicine Most asthma medicines are breathed directly into the lungs inhaled , but some are pills or liquids.
There two types of medicines are: Quick-relief medicines, which act fast. They can be used as needed during a flare-up. Quick-relief medicines act fast, but their effect doesn't last long. These kinds of medicines are also called "fast-acting" or "rescue" medicines. Long-term control medicines, which manage asthma and prevent symptoms from happening in the first place. Airway remodeling does not have to happen. Work with a healthcare professional to minimize asthma flare-ups and find a treatment plan that works for you.
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But when asking yourself what is homeostasis, just remember that it can be many things. It refers to the natural balance of your body when everything is running smoothly and your body is in harmony, and it can refer to the complicated mechanism that helps keep you thereby reacting to external stimuli.
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