Airway epithelial cells and tissue remodeling inasthma: role of interaction between epithelial cells and allergens. Introduction:Bronchialasthma is one of the most critical global diseases. The chronic nature of thedisease carries enormous economic burdens especially in western countries.According to the statistics done by American Academy of Allergy Asthma andImmunology, only 50 million asthmatic patients can survive annually out of 300million asthmatic patients all over the world 1. Bronchialasthma was thought to be a chronic self-limited inflammation that leads toairway remodeling in long-term patients.
The previously stated pathology wasproven not to be the best understanding of asthma pathology. The advancement ofmodern technology and the inventions of new diagnostic tools, such asfibreoptic bronchoscope, enhanced our understanding of the pathology ofbronchial asthma and the importance of epithelial-mesenchymal trophic units inthe disease development 1. Theinvention of Nanotechnology helped tracing the complicated intracellularinteractions between adjacent cells. Scientists were able to identify theeffect of different cytokines by labelling them using specific conjugated antibodiesand tracking their immunofluorescence by various means, e.g., Flow cytometer.
HistoricalHint:The conceptof reversible airway obstruction in the pathology of asthma was established in1985 by Henry Salter. In 1960, the Heart and Lung institution added bronchialhyper responsiveness as an important part of the pathology of asthma 2.Then by1997, the National Heart, Lung and Blood Institute defined the role of manyimmune cells such as mast cells, eosinophils and T lymphocytes in airway inflammation3 whichcauses recurrent episodes of wheezing, breathlessness, chest tightness andcough particularly at night and in the early morning. These symptoms areusually associated with widespread and variable airflow limitation that isreversible either spontaneously or with treatment. This inflammation alsocauses an increase in the airway responsiveness to a variety of stimuli 4.Researchesshow, through airway biopsy studies in young children, that restructuring ofthe airway can start up to four years before the start of asthma symptoms 5.
Incontrast to what has been stated before that airway remodeling in asthma was aresult of chronic inflammation. Pathophysiologyof asthma: Differentmechanisms synergistically interact to give the whole picture of asthma. In thefollowing lines, I am going to briefly uncover some of these mechanisms.
Airwayremodeling in asthma means the change in the structure of small airways. Thesechanges include: hyperplasia of goblet cells and mucous glands, smooth muscleshyperplasia, angiogenesis, sub-epithelial fibrosis and epithelial-mesenchymal trophicunit dysfunction 6.Goblet and mucous glands hyperplasia: Inhealthy subjects, mucous glands play an essential role in the protection of theairways against allergens and foreign bodies.
In case of asthma, hyperplasia ofboth goblet cells and mucous glands lead to airway narrowing on top ofincreased airway thickness 7. Increased smooth muscles mass: Inhealthy individuals, smooth muscles have a pivot role in maintaining thehomeostatic environment of normal airways. However, in asthmatic patients,smooth muscles increase in mass as they get stimulated in response to allergensvia inflammatory mediators. Stimulated smooth muscles will become inflamed,fibrosed with severe narrowing of airways 8.Angiogenesis: Neovascularformation is directly related to the development of asthma. Angiogenesisinduces airway edema as well as the delivery of inflammatory mediators whichlead to more airway narrowing and consequently to asthma progression 9, 10. Sub-epithelial fibrosis: Isone of the leading indicators of severe asthma. Sub-epithelial fibrosis isclaimed to be a result of continuous airway hyperresponsivenss in asthmaticpatients 11, 12.
Epithelial-mesenchymal trophic unit dysfunction: Theepithelial-mesenchymal unit dysfunction will directly lead to decreasingairways protective barrier which might be because of the effect of immunemodulators on the tight junctions between airways building units13.Allergensand epithelial-mesenchymal units in asthmatic patients: Inthe next lines, I am going to highlight some of the airway epithelial reactionsin response to allergens and how they produce a state of imbalance between thepro-inflammatory and anti-inflammatory cytokines which in turn results inchanges in the epithelium of the bronchial airways. Iwill state the effect of some of the cytokines (IL-1B, TNF alpha, GM-CSF,IL-11, IL-17, IL-16 and IL-4) , Transforming growth factor beta as well asendothelin-1 on the bronchial airway epithelial cells. Also I will show thelink between all of the above mentioned factors to the airway remodeling inasthmatic patients.
The Role of IL-1B, TNF alpha, GM-CSF, IL-2 and IL-6 inasthma: Wassermanet al. were meticulous in studying the effect of different cytokines onbronchial epithelium in symptomatic vs. asymptomatic asthmatic patients 14. Theyexamined various cytokines (TNF alpha, GM-CSF, IL-1B, IL-2 and IL-6) derivedvia bronchio-alveolar lavage (BAL) of symptomatic and asymptomatic patients.They found that TNF alpha and GM-CSF were able to increase the eosinophileffector function in vitro 14. Moreover,TNF alpha increased the production of superoxide as well as the cytotoxicity ofeosinophils to bronchial endothelium.
In addition, they also found that TNFalpha and IL-1B are the primary inducers of endothelial-leukocyte adhesionmolecules as well as intracellular adhesion molecule 1 14-16. Theproduction of TNF alpha, IL-1B and GM-CSF increased the adhesion of circulatingleukocytes to the active pulmonary endothelial cells as well as theinflammatory cells to the antigen-stimulated airways 17. Thus,specific cytokines affect the adhesion molecules of the epithelial cells in theairway of asthmatic patients in response to allergens.The role of IL-4 in asthma: IL-4is responsible for the induction of IgE isotype switch increasing theexpression of vascular adhesion molecule 1 and stimulates the eosinophilictransmigration through the endothelium as well as stimulation of mucousproduction 18.
That iswhy IL-4 is one of the critical player in the development of asthma. Knowingthat IL-4 is one of the primary cytokines claimed in the event of asthma,opened an important venue for clinical trials to control the growth of asthmaby opposing the role of IL-4 19-21. Agostiet al.
designed an experiment through which they tried to block IL-4 receptor(IL-4R) and investigate this on the FEV1 in asthmatic patients. They found thatadministration of anti-IL-4 improved the FEV1 in asthmatic patients versusthose on placebo 22. The Role of IL-17 in asthma: Il-17is one of the pro-inflammatory cytokines secreted by Th17 cells. Experimentsshowed that there was a higher expression of IL-17 in BAL of asthmatic patientscompared to those of healthy subjects.
This was supported by the higher ratioof Th17 cells in the lavage from asthmatic patients in contrast to those fromhealthy individuals 23. Thepreviously stated effects of different cytokines lead to not only modifying thebronchial epithelial cells but also, keeping the state of inflammation. Thus,bronchial epithelial cells are not restoring the normal state.The Role of IL-11 and IL-6 in asthma: IL-11is a pleiotropic cytokine produced by many stromal cells 24. Targetedoverexpression of IL-11 in mice results in marked remodeling of both airwayhyperresponsivenss and obstruction 25.
Hamidet al. investigated the expression of IL-11 messenger RNN (mRNA) within theairways of mild to severe asthmatic patients compared to non-asthmatic healthycontrols 24. Theyobtained bronchial biopsies from mild and severe asthmatic patients as well ashealthy controls by using fiberoptic bronchoscopy. They noticed that there wasan increase in the production of IL-11 mRNA. The increase in IL-11 mRNAproduction was noticeably higher in the epithelial and sub-epithelial cells insevere asthmatic patients in contrast to the cells isolated from healthyindividuals. Toconfirm that finding, Hamid et al.
did sequential immunostaining for IL-11 inairway tissues and found an evidence of positive results within tissues fromsevere asthmatic patients compared to other groups. Theyconcluded that IL-11 is involved in chronic airway remodeling seen in asthmatic patientsand that the severity of the disease was linked to the expression of IL-11 24. They alsonoted that there is a high production of IL-6 from eosinophils and that IL-6also has a central role in the development of asthma 24. Theyhighlighted that IL-11 was an important area of research through which manytreatment modalities could target asthma from the aspect of controllingepithelial airway remodeling.The role of TGF beta in airway remodeling: Transforminggrowth factor beta 2 (TGF-B2) has a significant participation in the airwayremodeling in severe asthmatic cases.
TGF-B2 is secreted and carried viaexosomes to bronchial epithelial cells 26. They havemany vital roles: inhibit cell proliferation and stimulate the apoptosis of thebronchial epithelial cells (BEC) 26. Salemet al. studied the effect of TGF-B2 on the epithelial cell remodeling in severeasthmatic patients. They hypothesized that in asthmatic patientsfibroblasts-derived exosomes enhance the proliferation of epithelial cellsthrough carrying lower levels of TGF-B2 compared to healthy subjects 26. Theyshowed that TGF-B2 expression is drastically lower than that excluded from BECsof healthy subjects. Inaddition to using different in vitrocultures to emphasize their objectives, they identified that TGF-B2 secretionknock-down enhanced the proliferation of bronchial epithelial cells. Moreover,they noted that the induction of TGF-B2 secretion inhibited the proliferationof bronchial epithelial cells even with BECs isolated from severe asthmaticpatients 26, 27.
Investigatingthe role of TGF-B2 in airway remodeling as one of the leading players indeveloping severe asthma opened a new research area as well as clinical trialsto study the possibility of inducing TGF-B2 secretion either extrinsically orintrinsically to down regulate the epithelial cells proliferation in severeasthmatic patients. This will help in treating the cause of asthma rather thanmere symptomatic treatment.Endothelin-1 and airway remodeling in asthma: Fasoliet al. demonstrated that human bronchial smooth muscle cells have specificbinding sites for endothelin-1 28, 29. Theyfound that the amount of endothelin-1 in bronchio-alveolar lavage fromasthmatic patients was markedly higher than those in the bronchio-alveolarlavage of healthy subjects in theabsence of any significant alteration in the level of circulating peptides 28. Theyconcluded that in case of asthmatic patients the secretion of endothelin-likematerial was released in higher amounts in comparison to those in healthycontrols. They suggested that one of the promising interventions would be thedevelopment of specific antagonists to endothelin-1 activity at the receptorlevel 28. Conclusion: Fromthe clinical perspective, bronchial asthma is one of the most critical researchtopics worldwide as representing an enormous economic burden as well as itshigh predominance among population.
With the advent of modern technology andthe invention of different diagnostic modalities, e.g., fiberopticbronchoscopy, the researchers could obtain various samples and specimens tohelp them examining the pathology and the mechanisms involved in thedevelopment of asthma. Fromthe basic science perspective, the advancement of imaging modalities, electronmicroscopy as well as different conjugated cytokines markers. Researchers wereable to identify the critical role of interaction between different cytokinesand micro building units of airways in asthma. Bronchial asthma turned to be avery complicated pathological process rather than a simple, straight forwardairway hyperresponsivenss and a self-limited, reversible disease. Airwayremodeling is the primary key in the pathogenesis of asthma. It happened inresponse to different allergens initiated by various factors: cytokines, growthfactors as well as voltage-gated channels.
Understanding the pathology behindasthma opens various avenues for developing new curative therapies that targetthe pathology rather than the symptoms. Some of these treatments, as mentionedabove, targeted IL-4 by competitively antagonizing IL-4 at the level of thereceptors. Those patients whom received anti-IL-4 showed marked improvement inFEV1 compared to those on placebo.
Recommendations: Thepathophysiology of bronchial asthma should be investigated more as it is a sortof interaction between many key players and the structural unit of the airways.Many of the previously done studies focused on one or two factors affecting theairway remodeling in asthmatic patients and none of them tried to assess thebalance between different factors at the same time. Moreover, different studygroups did not take into consideration the different cofounders that may beinvolved in asthma like: ethnicity of the studied groups, the geneticpredisposition in different patients. I think that investigating thosecofounders in future experiments will open up new aspects for understandingbronchial asthma.One of themost interesting findings in asthma pathogenesis was the role of Nuclear Factorkappa (NF) in the development of asthma. Researchers investigated the effect ofglycogen synthetase kinase 3 in asthma. They found that GSK3 Beta has aregulatory role on nuclear factor kappa 30.
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