Complex airway behavior and paradoxical responses to bronchoprovocation.

Heterogeneity of airway constriction and regional ventilation in asthma are commonly studied under the paradigm that each airway's response is independent from other airways. However, some paradoxical effects and contradictions in recent experimental and theoretical findings suggest that considering interactions among serial and parallel airways may be necessary. To examine airway behavior in a bronchial tree with 12 generations, we used an integrative model of bronchoconstriction, including for each airway the effects of pressure, tethering forces, and smooth muscle forces modulated by tidal stretching during breathing. We introduced a relative smooth muscle activation factor (T(r)) to simulate increasing and decreasing levels of activation. At low levels of T(r), the model exhibited uniform ventilation and homogeneous airway narrowing. But as T(r) reached a critical level, the airway behavior suddenly changed to a dual response with a combination of constriction and dilation. Ventilation decreased dramatically in a group of terminal units but increased in the rest. A local increase of T(r) in a single central airway resulted in full closure, while no central airway closed under global elevation of T(r). Lung volume affected the response to both local and global stimulation. Compared with imaging data for local and global stimuli, as well as for the time course of airway lumen caliber during bronchoconstriction recovery, the model predictions were similar. The results illustrate the relevance of dynamic interactions among serial and parallel pathways in airway interdependence, which may be critical for the understanding of pathological conditions in asthma.     

Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs.

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0-20 cmH(2)O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls (P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi (P < 0.01) and smooth muscle strips (P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.     

Airway smooth muscle: contraction and beyond

Airway smooth muscle (ASM), an important tissue involved in the regulation of bronchomotor tone, exists in the trachea and in the bronchial tree up to the terminal bronchioles. The physiological relevance of ASM in healthy airways remains unclear. Evidence, however, suggests that ASM undergoes marked phenotypic modulation in lung development and in disease states such as asthma, chronic bronchitis and emphysema. The shortening of ASM regulates airway luminal diameter and modulates airway resistance, which can be augmented by cytokines as well as extracellular matrix alterations. ASM may also serve immunomodulatory functions, which are mediated by the secretion of pro-inflammatory mediators such as cytokines and chemokines. In addition, ASM mass increases in chronic airway diseases and may represent either a pathologic or an injury-repair response due to chronic inflammation. This review will present evidence that ASM, a "passive" contractile tissue, may become an "active participant" in modulating inflammation in chronic lung diseases. Cell facts 1. Found in the trachea and along the bronchial tree. 2. Critically important in regulating bronchomotor tone of the airways. 3. Differentiation state is associated with the expression of various "contractile proteins." 4. Displays phenotypic modulation of mechanical, synthetic and proliferative responses. 5. Secretes cytokines, chemokines and extracellular matrix proteins. 6. May serve as a potential new target for the treatment of chronic lung diseases.     

Asthma: the importance of epithelial mesenchymal communication in pathogenesis. Inflammation and the airway epithelium in asthma

Asthma is a disorder of the airways in which Th-2-mediated inflammation is considered to provide the basis for altered structure and function that leads to bronchial hyper-responsiveness (BHR) and variable airflow obstruction. This linear progression underpinning asthma pathophysiology is questioned on the basis of observations on the pathology of the disease in early childhood, the independent genetic factors that influence atopy and BHR, incomplete responses to treatment with corticosteroids despite powerful anti-inflammatory effects and the recent disappointing results with targeted therapies that almost abolish eosinophilia in the blood and airways and yet produce little effect on the clinical outcomes of asthma. An alternative hypothesis is put forward in which atopy/airway inflammation and altered structure and function of the formed airway elements are parallel but interacting factors. For asthma to develop as a chronic disease, genetic and environmental factors that drive each of these components are required. Fundamental to this is the concept of aberrant signalling between the airway epithelium and underlying mesenchyme and persistent activation of the epithelial mesenchymal trophic unit.     

Correlation between airway responsiveness and proteoglycan production by bronchial fibroblasts from normal and asthmatic subjects

Asthma is characterized by an airway remodeling process involving altered extracellular matrix deposition such as collagen, fibronectin and proteoglycans. Proteoglycans determine tissue mechanical properties and are involved in many important biological aspects. Not surprisingly, it has been suggested that proteoglycan deposition may alter airway properties in asthma including airway hyperresponsiveness. In chronically inflamed airway tissues, fibroblasts likely represent an activated fibrotic phenotype that contributes to the excessive deposition of different extracellular matrix components. To investigate whether this was the case for proteoglycans, the production of hyaluronan, perlecan, versican, small heparan sulphate proteoglycans (HSPGs), decorin and biglycan was quantified in the culture medium of primary bronchial fibroblast cultures, established from four normal and six asthmatic subjects. Values were further correlated to the airway responsiveness (PC(20) methacholine) of donor subjects. Fibroblasts from subjects with the most hyperresponsive airways produced up to four times more total proteoglycans than cells from subjects with less hyperresponsive or normoresponsive airways. We observed a significant negative correlation between the PC(20) and perlecan, small HSPGs and biglycan, while such correlation was absent for decorin and close to significant for hyaluronan and versican. Altered proteoglycan metabolism by bronchial fibroblasts may contribute to the increased proteoglycan deposition in the bronchial mucosa and to airway hyperresponsiveness characterizing asthma.     

Distribution of airway narrowing responses across generations and at branching points,assessed in vitro by anatomical optical coherence tomography

Background

Previous histological and imaging studies have shown the presence of variability in the degree of bronchoconstriction of airways sampled at different locations in the lung (i.e., heterogeneity). Heterogeneity can occur at different airway generations and at branching points in the bronchial tree. Whilst heterogeneity has been detected by previous experimental approaches, its spatial relationship either within or between airways is unknown.

Methods

In this study, distribution of airway narrowing responses across a portion of the porcine bronchial tree was determined in vitro. The portion comprised contiguous airways spanning bronchial generations (#3-11), including the associated side branches. We used a recent optical imaging technique, anatomical optical coherence tomography, to image the bronchial tree in three dimensions. Bronchoconstriction was produced by carbachol administered to either the adventitial or luminal surface of the airway. Luminal cross sectional area was measured before and at different time points after constriction to carbachol and airway narrowing calculated from the percent decrease in luminal cross sectional area.

Results

When administered to the adventitial surface, the degree of airway narrowing was progressively increased from proximal to distal generations (r = 0.80 to 0.98, P < 0.05 to 0.001). This ''serial heterogeneity'' was also apparent when carbachol was administered via the lumen, though it was less pronounced. In contrast, airway narrowing was not different at side branches, and was uniform both in the parent and daughter airways.

Conclusions

Our findings demonstrate that the bronchial tree expresses intrinsic serial heterogeneity, such that narrowing increases from proximal to distal airways, a relationship that is influenced by the route of drug administration but not by structural variations accompanying branching sites.     

Pathophysiological mechanisms of asthma. Application of cell and molecular biology techniques

Asthma is a common increasing and relapsing disease that is associated with genetic and environmental factors such as respiratory viruses and allergens. It causes significant morbidity and mortality. The changes occurring in the airways consist of a chronic eosinophilic and lymphocytic inflammation, together with epithelial and structural remodeling and proliferation, and altered matrix proteins, which underlie airway wall narrowing and bronchial hyperresponsiveness (BHR). Several inflammatory mediators released from inflammatory cells such as histamine and cysteinyl-leukotrienes induce bronchoconstriction, mucus production, plasma exudation, and BHR. Increased expression of T-helper 2 (Th2)-derived cytokines such as interleukin-4 and 5 (IL-4,5) have been observed in the airway mucosa, and these may cause IgE production and terminal differentiation of eosinophils. Chemoattractant cytokines (chemokines) such as eotaxin may be responsible for the chemoattraction of eosinophils to the airways. The initiating events are unclear but may be genetically determined and may be linked to the development of a Th2-skewed allergen-specific immunological memory. The use of molecular biology techniques on tissues obtained from asthmatics is increasing our understanding of the pathophysiology of asthma. With the application of functional genomics and the ability to transfer or delete genes, important pathyways underlying the cause if asthma will be unraveled. The important outcome of this is that new preventive and curative treatments may ensue.     

Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis.

We studied whether different bronchial responses to allergen in asthma and rhinitis are associated with different bronchial inflammation and remodeling or airway mechanics. Nine subjects with mild asthma and eight with rhinitis alone underwent methacholine and allergen inhalation challenges. The latter was preceded and followed by bronchoalveolar lavage and bronchial biopsy. The response to methacholine was positive in all asthmatic but in only two rhinitic subjects. The response to allergen was positive in all asthmatic and most, i.e., five, rhinitic subjects. No significant differences between groups were found in airway inflammatory cells or basement membrane thickness either at baseline or after allergen. The ability of deep inhalation to dilate methacholine-constricted airways was greater in rhinitis than in asthma, but it was progressively reduced in rhinitis during allergen challenge. We conclude that 1) rhinitic subjects may develop similar airway inflammation and remodeling as the asthmatic subjects do and 2) the difference in bronchial response to allergen between asthma and rhinitis is associated with different airway mechanics.     

Nitric oxide paradox in asthma

Asthma results from allergen-driven intrapulmonary Th2 response, and is characterized by intermittent airway obstruction, airway hyperreactivity (AHR), and airway inflammation. Accumulating evidence indicates that inflammatory diseases of the respiratory tract are commonly associated with elevated production of nitric oxide (NO). It has been shown that exhaled NO may be derived from constitutive NO synthase (NOS) such as endothelial (NOS 3) and neural (NOS 1) in normal airways, while increased levels of NO in asthma appear to be derived from inducible NOS2 expressed in the inflamed airways. Nevertheless, the functional role of NO and NOS isoforms in the regulation of AHR and airway inflammation in human or experimental models of asthma is still highly controversial. In the present commentary we will discuss the role of lipopolysaccharides contamination of allergens as key element in the controversy related to the regulation of NOS2 activity in experimental asthma.     

Asthma, viruses, and nitric oxide

Over the last two decades there has been a worldwide increase in the morbidity and mortality associated with asthma, a chronic inflammatory disease of the airways. There is a growing body of evidence that suggests there is an association between upper respiratory viral infections, particularly rhinovirus infections, and asthma exacerbations. Virally induced airways hyperreactivity has been associated with elevated numbers of inflammatory cells in the bronchial mucosa. Upon virus infection, respiratory epithelial cells produce proinflammatory cytokines, including IL-6, IL-8, RANTES, and GM-CSF, which could contribute to the increased inflammatory cell recruitment noted in the airways. Whether or not a viral infection triggers an asthma attack may depend upon many factors, including the types of inflammatory cells recruited to the airways, the viral load, and variations in the host antiviral response. There is evidence to support the idea that eosinophils from asthmatic and symptomatic atopic subjects may be primed to respond to chemotactic cytokines produced by infected epithelial cells. Rhinovirus infections may therefore enhance airway eosinophilia in asthmatics, leading to airway hyperresponsiveness and impaired pulmonary function. Nitric oxide is a potent inhibitor of both rhinovirus-induced cytokine production and viral replication and may play an important role in the host response to viral infections. Based upon these observations, we speculate that nitric oxide donors may represent a novel therapeutic approach for the treatment of rhinovirus infections and viral exacerbations of asthma.     

Impact of rhinitis on airway inflammation: biological and therapeutic implications

There is increasing evidence for a close link between the upper and the lower respiratory tracts and the fact that rhinitis has an important impact on asthma. Several clinical and experimental observations suggest a similar immunopathology between the upper and lower airways in allergic subjects. The common inflammatory process that develops in the respiratory tract explains some of the complex interactions among different clinical diseases such as rhinitis, sinusitis, asthma, bronchial hyperresponsiveness and viral infections. There are also non-inflammatory mechanisms that may contribute to the link between rhinitis and asthma. Moreover, the outcomes of various pharmacological treatments of rhinitis have recently provided further support for the hypothesis of the united airways. We discuss some of the recent observations on the nose-lung interaction and some of the novel therapeutic approaches used to treat rhinitis and asthma that arise from this.     

Understanding airway pathophysiology with computed tomograpy.

Conventional pulmonary function tests are limited in the mechanistic insight that they can provide by the fact that they can only provide average measures of lung function. For example, a measurement of decreased expiratory flow assessed with conventional spirometry could result from narrowed large airways, narrowed small airways, closed airways, altered elasticity, or regional heterogeneities in parenchyma or airways. To examine specific mechanisms and pathology in the airways, a method is required that can actually look at specific individual airways. Over the past decade, several more direct methods of assessing specific mechanisms and structural alterations in normal airways and airway pathology in asthma have become available for such purposes. One such method is high-resolution computed tomography (HRCT), a method that allows the study of multiple individual airways during either contraction to closure or relaxation in real time, as well as changes in airway size with changes in lung volume. Although other imaging modalities have the potential to image airways in vivo, none presently has the convenience and the accessibility coupled with the resolution required to visualize the parenchymal airways in vivo. Although HRCT may never be widely utilized for routine measurements or screening, because of radiation exposure, cost issues, and a limited ability to follow changes over extended time periods, the method has distinct and unique advantages in quantifying the behavior of airways in vivo. In this mini-review, we focus on these capabilities of HRCT by briefly reviewing highlights of experimental results from several canine and human studies.     

Circadian Variation in Allergen and Nonspecific Bronchial Responsiveness in Asthma

In a majority of patients, exacerbations of asthma occur more frequently during the night than day. Many hypotheses have been proposed to explain such variation in asthma. The airways of asthmatic persons are characterized by an abnormal degree of inflammation and bronchial hyperre-sponsiveness to both nonspecific and specific challenges. Studies of both children and adults with asthma document marked circadian rhythmicity in the response of airways to bronchial challenges with histamine, methacho-line, acetylcholine, saline, and house dust mite. Taken together, the findings of these investigations indicate that the hyperreactivity of airways to these agents is more profound and prolonged following evening and overnight tests compared to tests conducted in the midday and afternoon. The temporal pattern in bronchial response to the hyperventilation of cold dry air is different. The hyperresponsiveness of airways to this challenge is greatest in the afternoon. The amplitude of the circadian rhythm in airway hyperreactivity seems to be correlated to the amplitude of the circadian rhythm of pulmonary function; the greater the day-night difference in bronchial reactivity is, the greater is the day-night difference in flow rates.     

Bronchial Thermoplasty: A Novel Therapeutic Approach to Severe Asthma

Bronchial thermoplasty is a non-drug procedure for severe persistent asthma that delivers thermal energy to the airway wall in a precisely controlled manner to reduce excessive airway smooth muscle. Reducing airway smooth muscle decreases the ability of the airways to constrict, thereby reducing the frequency of asthma attacks. Bronchial thermoplasty is delivered by the Alair System and is performed in three outpatient procedure visits, each scheduled approximately three weeks apart. The first procedure treats the airways of the right lower lobe, the second treats the airways of the left lower lobe and the third and final procedure treats the airways in both upper lobes. After all three procedures are performed the bronchial thermoplasty treatment is complete.Bronchial thermoplasty is performed during bronchoscopy with the patient under moderate sedation. All accessible airways distal to the mainstem bronchi between 3 and 10 mm in diameter, with the exception of the right middle lobe, are treated under bronchoscopic visualization. Contiguous and non-overlapping activations of the device are used, moving from distal to proximal along the length of the airway, and systematically from airway to airway as described previously. Although conceptually straightforward, the actual execution of bronchial thermoplasty is quite intricate and procedural duration for the treatment of a single lobe is often substantially longer than encountered during routine bronchoscopy. As such, bronchial thermoplasty should be considered a complex interventional bronchoscopy and is intended for the experienced bronchoscopist. Optimal patient management is critical in any such complex and longer duration bronchoscopic procedure. This article discusses the importance of careful patient selection, patient preparation, patient management, procedure duration, postoperative care and follow-up to ensure that bronchial thermoplasty is performed safely.Bronchial thermoplasty is expected to complement asthma maintenance medications by providing long-lasting asthma control and improving asthma-related quality of life of patients with severe asthma. In addition, bronchial thermoplasty has been demonstrated to reduce severe exacerbations (asthma attacks) emergency rooms visits for respiratory symptoms, and time lost from work, school and other daily activities due to asthma.Download video file.^{(90M, mov)}     

In vitro effect of air pollutants on human bronchi

A useful approach for constructing dose–response relationships and for studying the underlying mechanisms by which a xenobiotic agent enhances airway reactivity is to measure the response of an isolated airway following ex vivo exposure to a pollutant. We have in this way determined the dose–response relationship between ex vivo exposure to pollutants such as nitrogen dioxide (NO₂), the aldehyde acrolein, and ozone (O₃) and the reactivity to agonists in human isolated bronchial smooth muscle. We have also investigated the underlying alteration in the cellular mechanisms of airway smooth-muscle contraction induced by such exposure and found that it is related to alteration in calcium signaling at the site of the airway smooth-muscle cell. Finally, although there is epidemiological evidence that an increase in allergic diseases such as asthma may be linked to air pollution, there are few experimental data to address this issue. The final aim of this study was therefore to investigate the interaction between passive sensitization and exposure to pollutants in human isolated airways. We have examined (i) the effect of a pre-exposure to pollutants on the contraction of sensitized bronchi in response to a specific antigen and (ii) the effect of passive sensitization on the contraction in response to nonspecific agonists in bronchi pre-exposed to pollutants. The results indicate a combined effect of immunological sensitization and exposure to pollutants; that is, passive sensitization and exposure to pollutants act in a synergistic manner on human bronchial smooth-muscle reactivity in response to both specific antigens and nonspecific agonists. This revised version was published online in August 2006 with corrections to the Cover Date.     

Local anaesthetic medication for the treatment of asthma

It is presumed that drugs able to prevent bronchial spasm and/or inflammation may have therapeutic potential to control asthma symptoms. The local anaesthetic lidocaine has recently received increased attention as an alternative form of treatment for asthmatic patients. This paper reviews the major findings on the topic and summarizes the putative mechanisms underlying the airway effects of local anaesthetic agents. We think that lidocaine extends the spectrum of options in asthma therapy, probably by counteracting both spasmogenic and inflammatory stimuli in the bronchial airways. The possibility of development of new anti-asthma compounds based on the synthesis of lidocaine derivatives is also on the horizon.     

Activation of smooth muscle in the airway wall, force production, and airway narrowing.

Airway narrowing depends on smooth muscle force production and muscle shortening, but the structural and geometric properties exhibited by individual generations of the bronchial tree largely determine the extent and characteristics of airway narrowing. Properties of major importance include the nature and integrity of the epithelium, the structural and mechanical properties of the airway wall, as well as airway diameter. The influence of these properties on airway narrowing measured as flow or flow resistance in large and small diameter segments of airways from pig lung is described using a novel preparation, the perfused bronchial segment.     

The effects of nociceptin peptide (N/OFQ)–receptor (NOP) system activation in the airways

The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide (NOP) receptor. It is cleaved from a larger precursor identified as prepronociceptin (ppN/OFQ). NOP is a member of the seven transmembrane-spanning G-protein coupled receptor (GPCR) family. ppN/OFQ and NOP receptors are widely distributed in different human tissues. Asthma is a complex heterogeneous disease characterized by variable airflow obstruction, bronchial hyper-responsiveness and chronic airway inflammation. Limited therapeutic effectiveness of currently available asthma therapies warrants identification of new drug compounds. Evidence from animal studies suggests that N/OFQ modulates airway contraction and inflammation. Interestingly up regulation of the N/OFQ–NOP system reduces airway hyper-responsiveness. In contrast, inflammatory cells central to the inflammatory response in asthma may be both sources of N/OFQ and respond to NOP activation. Hence paradoxical dysregulation of the N/OFQ–NOP system may potentially play an important role in regulating airway inflammation and airway tone. To date there is no data on N/OFQ–NOP expression in the human airways. Therefore, the potential role of N/OFQ–NOP system in asthma is unknown. This review focuses on its physiological effects within airways and potential value as a novel asthma therapy.     

In vivo evaluation of the effectiveness of bronchial thermoplasty with computed tomography.

A recent study has reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airway smooth muscle to shorten in response to methacholine (MCh)(Danek CJ, Lombard CM, Dungworth DL, Cox PG, Miller JD, Biggs MJ, Keast TM, Loomas BE, Wizeman WJ, Hogg JC, and Leff AR. J Appl Physiol 97: 1946-1953, 2004). If such a technique is successful, it has the potential to serve as a therapy to attenuate airway narrowing in asthmatic subjects regardless of the initiating cause that stimulates the smooth muscle. In the present study, we have applied high-resolution computed tomography to accurately quantify the changes in airway area before and after a standard MCh aerosol challenge in airways treated with bronchial thermoplasty. We studied a total of 193 airways ranging from 2 to 15 mm in six dogs. These were divided into treated and control populations. The MCh dose-response curves in untreated airways and soon-to-be-treated airways were superimposable. In contrast, the dose-response curves in treated airways were shifted upward at all points, showing a significantly decreased sensitivity to MCh at both 2 and 4 wk posttreatment. These results thus show that treated airways have significantly increased luminal area at any dose of inhaled MCh compared with untreated airways. The work in this study thus supports the underlying concept that impairing the smooth muscle may be an effective treatment for asthma.