Airway included bronchial hyper-responsiveness as an important
Airway epithelial cells and tissue remodeling in asthma: roleof the interaction between epithelial cells and allergensIntroduction:Bronchialasthma is one of the most important diseases to be studied worldwide.
The chronicnature of the disease carries huge economic burdens especially in westerncountries. An estimated 300million people worldwide suffer from asthma, with 250,000 annual deaths attributed to the disease. The main themeof bronchial asthma was self-limited inflammation that is chronic and leads to airway remodeling in the long-term cases ofasthma. The formerly stated pathology was proved to be not the bestunderstanding of asthma pathology. With the advancement of modern technology and the inventions of newdiagnostic tools; fiberoptic bronchoscope, helpeda lot in the understanding of the pathology of bronchialasthma and explaining the importance of the airway microenvironment (theepithelial mesenchymal trophic unit) in the disease development. Historical HintIn 1895, Henry Salter was thefirst to describe asthma as a disease of reversible airway obstruction. In1960, the definition of asthma included bronchial hyper-responsivenessas an important part of the pathology of asthma. By 1997, the National Heart,Lung, and Blood Institute defined asthma as: “achronic inflammatory disorder of the airways in which many cells play a role,in particular mast cells, eosinophils, and T lymphocytes.
In susceptibleindividuals, this inflammation causes recurrent episodes of wheezing,breathlessness, chest tightness, and cough particularly at night and/or in theearly morning. These symptoms are usually associated with widespread but variable airflowlimitation that is at least partially reversible, either spontaneously or withtreatment. The inflammation also causes an associated increase in airwayresponsiveness to a variety of stimuli.” In contrast to what had beenstated before that airway remodeling in asthma was a result of chronicinflammation, recent researches show, through airway biopsy studies in youngchildren, that restructuring of the airways can start upto 4 four yearsprior to the start of asthma symptoms.Airways remodeling becomesthe corner stone for asthma development as well as the development of new drugs.Airways are subjected to interact with different environmental allergens.
Thoseallergens include a variety of factors as dust, pollens, pet dander and scentsas well as other types of asthma that are due to exertion. All these factorstrigger changes in the body environment through release and control ofdifferent types of cytokines, chemokines, growth factors as well as geneticmodulation of the bronchial airways in asthmatic patients.Pathophysiology of asthma:There are differentmechanisms that work synergistically to give the complete picture of asthma. Inthe following lines, I am going to touch on those mechanisms rapidly:Goblet and mucous glands hyperplasia:In normal subjects, mucousglands play an important role in the protection of airways against allergensand foreign bodies. In case of asthma, mucous glands as well as goblet cells undergohyperplasia which is manifested by: increased mucous secretion, whichcannot be cleared via normal physiological body responses e.g. coughing. Moreover, there is airway narrowing inaddition to increased airway thickness.
Smooth Muscle:Smooth muscle is one of thepivot rules of maintaining the homeostatic environment of normal airways. Inasthma, smooth muscles increase in mass as they get stimulated in response toallergens as well as inflammatory mediators. The end picture of smooth muscleswill be inflammation, fibrosis with severe narrowing of the airways. Hyper- responsivenessof the airways.Angiogenesis:Is one ofthe main features that airways of asthmatic patients exhibit. Angiogenesis induces airway edema as well asthe delivery of inflammatory mediators.Sub-epithelial fibrosis:Is one of the main indicatorsof severe asthma.
Sub-epithelial fibrosis is claimed to be a result ofcontinuous airway hyper responsiveness of airways in asthmatic patients.Epithelial Alteration:Is one of the main causes ofdecreasing protective barrier. Nowadays, it is the cornerstone of understandingthe development of asthma. In this review, I am going tohighlight some of the body’s reaction in response to allergens and their effect on thebronchial airways in asthmatic patients. In the following lines, I amgoing to talk about the effect of some of the cytokines (IL-1B, TNF Alpha,GM-CSF (Granulocyte – macrophage colony stimulating factor), IL-11, IL-17,IL-16 & IL-4), Transforming growth factor – Beta 2 as well as endothelin-1on the bronchial airway remodeling in asthma.Cytokinesand airway remodeling:Cytokines are a broad and loose category of small proteins(5 – 20kDa) that are important in cell signaling.
They affect the surroundingcells in different ways; autocrine, paracrine and endocrine signaling asimmunomodulating agents. They include;interferons, interleukines, Tumor necrotizing factors and generally nothormones or growth factors. Cytokines affect many immune cells especially eosinophils,macrophages, T lymphocytes and mast cells,mainly in asthma. Wasserman et al.
were meticulous in studying the effect ofdifferent cytokines on bronchial epithelium in symptomatic vs. asymptomaticasthmatic patients. They studied different cytokines (TNF, GM-CSF, IL-1B, IL-2and IL-6) from Bronchio-alveolar lavage (BAL) of symptomatic and asymptomatic patients. Theyfound that TNF and GM – CSF were able to increase the eosinophil effectorfunction in vitro. TNF increased the production of superoxide as well as thecytotoxicity of eosinophils to bronchial endothelium. They also found that TNFand IL-1B are the main inducers of endothelial – leukocyte adhesion molecule 1as well as intracellular adhesion molecule 1.
They pointed out that theproduction of TNF, IL-1B and GM – CSF will increase the adhesion of circulatingleukocytes to the active pulmonary endothelial cells as well as theinflammatory cells to the antigen stimulated airways. IL-4 and asthma:IL-4 is one of the pro-inflammatory cytokines. IL-4 issecreted via the activation and the differentiation of Th2 cells. IL- 4 is responsible for the induction of IgE isotypeswitch, increased expression of vascular adhesion molecule 1 and stimulates theeosinophilic transmigration through the endothelium as well as stimulation ofmucous production.
That is why IL-4 is critical in the development of asthma.Knowing that IL-4 is one of the main cytokines claimed in the development ofasthma opened up a spacious venuefor clinical trials to control the development of asthma via opposing the roleof IL-4.Agosti et al. designed an experiment through which theytried to block IL-4 receptor (IL-4R) and investigate this on the FEV1 inasthmatic patients. They found that administration of anti IL-4 improves theFEV1 in asthmatic patients vs. those on placebo.IL-17 in asthma:Il-17 is one of the pro-inflammatory cytokines. They aresecreted by Th2 cells.
Experiments showed that there is higher expression ofIL-17 in BAL of asthmatic patients than those of healthy subjects. This wasalso supported by the higher ratio of Th2 cells in the lavage from asthmaticpatients in contrast to those from healthy patients.The previously stated effects of different cytokines lead tomodification of the bronchial endothelial cells and keep them in a state ofinflammation as well as cease their ability to go into complete resolution. Instead, they keep the bronchialendothelial cells in a continuous state recruiting inflammatory cells as wellas potentiating endothelial overgrowth.The effectof IL-11, IL-6 on airway remodeling:Generally, Interleukin 11 (IL-11) is a protein that inhumans is encoded by IL11 gene. IL-11 is a multifunctional cytokine firstisolated in 1990. It is a key regulator of multiple events in hematopoiesis.Concerning asthma, IL-11 is a pleiotropic cytokine produced by a variety ofstromal cells.
Targeted overexpression of IL11 in mice results in markedremodeling of both airway hyper responsiveness and obstruction.Hamid et al. were interested in studying the effect of IL-11on airway remodeling. They investigated the expression of IL-11 messenger RNA(mRNA) within the airways of mild to severe asthmatic patients compared tonon-asthmatic healthy controls. They obtained bronchial biopsies from mild,severe asthmatic patients as well as healthy controls by using fiberopticbronchoscopy. They noticed that there was overexpression of IL-11 mRNA and wassignificantly higher in the epithelial and sub-epithelial cells in severeasthmatic patients compared to cells isolated from mild, moderate asthmaticpatients and healthy controls.
To confirm this finding, Hamid et al. didsequential immunostaining for IL-11 in airway tissues and found strong evidenceof positive results within tissues from severe asthmatic patients compared toother groups. They concluded that IL-11 is involved in chronic airwayremodeling seen in asthmatic patients and that the severity of the disease isdirectly correlated to the expression of IL-11. They also noted that there is a high production of IL-6 fromeosinophils and that IL-6 also has a pivotal role in the development of asthma.They highlighted that IL-11 was a new venue through which many treatment modalities could target asthma from theaspect of controlling airway remodeling. Bronchialairway remodeling and TGF Beta2:Transforming growth factor beta 2 (TGF-B2) is a veryimportant key role in the airway remodeling in severe asthmatic cases. TGF-Beta 2 they are secreted by the fibroblasts and carried via exosomes tobronchial epithelial cells. They have many important roles: inhibit cellproliferation as well as stimulate the apoptosis of the bronchial epithelialcells (BEC).
Salem el al. was interested in investigating the effect ofTG –Beta2 on epithelial remodeling in severe asthmatic patients. Theirhypothesis was that fibroblasts – derived exosomes stimulate the proliferationof epithelial cells in severe asthmatic patients through carrying lower levelsof TGF–Beta2 in comparison to those of healthy individuals. They used differenttechniques to validate their hypothesis. The western blot showed that TGF–Beta2expression is markedly lower than that excreted from the BECs of the healthyindividuals.
They also used different in vitro cultures to emphasize theirobjectives. They found out many important things; TGF–Beta2 secretion knockdown will enhance the proliferation of bronchial epithelial cells. They also notedthat the induction of TGF–Beta2 secretion will inhibit bronchial epithelialcell proliferation even with BECs isolated from severe asthmatic patients. The previously stated experiments highlighted the importanceof TGF–Beta2 in airway remodeling and as one of the main players in developingsevere asthma. This in turn opened a new research area as well as clinicaltrials to study the possibility of inducing TGF–B2 secretion eitherextrinsically or intrinsically to down regulate the epithelial cells proliferationin severe asthmatic patients. Consequently, this will help to treatthe cause of asthma rather than merely symptomatic treatment.
Endothelin-1 and airway remodeling in asthma:Endothelin-1 is one of the family of endotheliniso-peptides, is a potent constrictor of human bronchial smooth muscle andcarries its action via voltage-dependant calcium at low concentrations. Fasoliet al. demonstrated that human bronchial smooth muscle cells possess a singleclass of specific binding sites for endothelin-1. Fasoli et al. ran experimentson broncho-alveolar lavage (BAL) from asthmatic patients in comparison tohealthy controls. They found that the amount of endothelin-1 in BAL fromasthmatic patients is markedly high than those in BAL of healthy subjects inthe absence of any significant alteration in the level of circulating peptides.They concluded that, in the case of asthmatic patients the secretion ofendothelin- like material is released in higher amounts compared to those inhealthy controls.
They suggested that one of the promising interventions wouldbe the development of specific antagonists to the endothelin-1 activity at thereceptor level. The previously stated recommendation would support theimportance of endothelin-1 in the pathogenesis of asthma. Conclusion:Bronchial asthma is one of the most important research topicworldwide not only being a heavy economic burden but also because of the greatpredominance among population. With the grace of modern technology and theinvention of different diagnostic modalities e.
g. fiberoptic bronchoscopy,investigators could obtain various things to help them in examining thepathology and mechanisms involved in the development of asthma e.g.Broncho-alveolar Lavage (BAL), Bronchial biopsies. With the advance in imagingmodalities, electron microscopy and different biomarkers, researchers were ableto identify the key roles in the development of asthma.
Bronchial asthma turnedto be a very complicated pathological process rather than a simple straightforward airways hyper-responsiveness and a self-limited, reversible disease.Airway remodeling is the main key in the pathogenesis of asthma. Airwayremodeling in response to different allergens is initiated by differentfactors; cytokines, growth factors as well as voltage gated channels. Havingall that amount of knowledge about asthma is just a small scene of the wholepicture.
Understanding the pathology behind asthma opens up various venues fordeveloping treatments for the cause rather than the currently availabletreatments that mainly deal with relieving symptoms.Some of these treatments, as mentioned above, target IL-4 bycompetitively antagonizing IL-4 at the level of the receptors. The previoustreatment has shown a marked improvement in FEV1 is asthmatic patients comparedto those on placebo. Last but not least, pathophysiology had been studied for 50years now, yet we still do not know except a small part of this multi-facetedcomplex. What is next?Investigators should dig deeply into the mechanism ofasthma, taking into consideration that pathophysiology of asthma is a sort ofcomplicated interaction between different cytokines, airway remodeling andgrowth factors.
Glycogen metabolism should be considered as one of the comingimportant factors that affect asthma development. Correlational relationshipsbetween percent predicted FEV1 values and numbers of cells expressingIL-11 mRNA within (A) subepithelium and (B) epithelialcell layer. There were significant correlations between numbers of IL-11mRNA-positive cells in both airway epithelium and subepithelial regions andthis index of pulmonary function (P < .05). IL-11 expression is increased in severe asthma: Associationwith epithelial cellsand eosinophils .
Eleanor Minshall, PhD,a Jamila Chakir,PhD,b Michel Laviolette, MD,b Sophie Molet, PhD,a Zhou Zhu, MD,c RonOlivenstein, MD,d Jack A. Elias, MD,c and Qutayba Hamid, MD, PhDa Montrealand Sainte Foy, Quebec, Canada, and New Haven, Connecticut