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In this article, we explain why from our perspective as the largest academic medical center in the country, we consider it to be part of our mission to contribute to the elaboration of a value-based health care organization system. We describe our hospital quality management system and how we think that this can deliver added value by introducing lean principles in the care process. We also reflect on the importance of hospital accreditation and external benchmarking in the continuous quality improvement culture within the hospital. more...

In vivo animal models can offer valuable information on several aspects of asthma pathogenesis and treatment. The mouse is increasingly used in these models, mainly because this species allows for the application in vivo of a broad range of immunological tools, including gene deletion technology. Mice, therefore, seem particularly useful to further elucidate factors influencing the response to inhaled allergens. Examples include: the role of immunoregulatory mechanisms that protect against T-helper cell type 2 cell development; the trafficking of T-cells; and the contribution of the innate immunity. However, as for other animal species, murine models also have limitations. Mice do not spontaneously develop asthma and no model mimics the entire asthma phenotype. Instead, mice should be used to model specific traits of the human disease. The present task force report draws attention to specific aspects of lung structure and function that need to be borne in mind when developing such models and interpreting the results. In particular, efforts should be made to develop models that mimic the lung function changes characteristic of asthma as closely as possible. A large section of this report is therefore devoted to an overview of airway function and its measurement in mice. more...

Antagonizing the effect of interleukin (IL)-5 is a potential new treatment strategy in allergic disorders. We evaluated the safety, biological activity, and pharmacokinetics of SCH55700, a humanized anti-human IL-5 antibody, in subjects with severe persistent asthma treated with oral or high doses of inhaled steroids. In a double-blind, randomized, multicenter trial, a rising single dose of SCH55700 (0.03 mg/kg [n = 2], 0.1 mg/kg [n = 4], 0.3 mg/kg [n = 6], or 1.0 mg/kg [n = 12]) or placebo (n = 8) was administered intravenously. SCH55700 dose dependently reduced circulating eosinophil counts. At a dose of 1.0 mg/kg, the decrease remained significant up to Day 30 [(0.07 +/- 0.01) x 10(9)/L versus (0.23 +/- 0.04) x 10(9)/L at baseline] (mean +/- SEM) (p = 0.05). After administration of SCH55700 at 0.3 and 1.0 mg/kg, a trend toward improvement in baseline FEV1 was observed, which reached significance 24 hours after the 0.3-mg/kg dose (p = 0.019 versus placebo). No significant changes occurred in other clinical indices of disease activity. Adverse events were not different between active treatment and placebo. We conclude that SCH55700 is a biologically active anti-human IL-5 antibody that can be safely used in severe steroid-treated asthma. Its therapeutic potential needs to be addressed in specifically designed efficacy trials. more...

Asthma is currently defined as a chronic inflammatory disorder of the airways. The exact relationship between this inflammatory process and altered airway behavior in asthma remains to be fully established. More specifically, the question remains as to the exact causal relationship between airway inflammation and bronchial hyperresponsiveness (BHR), which constitutes the predominant lung function abnormality in asthma. The two main determinants of BHR are the hypersensitivity and the hyperreactivity of the airways. Hypersensitivity is reflected in a leftward shift of the dose response curve to the bronchoconstrictor effect of agonists such as histamine. More important from a clinical perspective is the hyperreactivity of the airways, which is characterized by excessive airway narrowing. The airway wall consists of three compartments, namely the inner airway wall area between the airway lumen and the smooth muscle layer, the airway smooth muscle layer and the outer airway wall area between the smooth muscle layer and the lung parenchyma. Mathematical models have calculated that changes within each of these compartments can contribute to airway hyperreactivity. Morphometric analysis of asthmatic airways confirm thickening of each of these three airway wall compartments. The contribution of airway inflammation to the thickening of each of these compartments and their relative functional impact on BHR remains to be further elucidated. Asthmatic airways display signs both of the acute and the chronic phase of an inflammatory reaction. The acute allergic inflammation is characterized by the presence of increased amounts of inflammatory cells including eosinophils, mast cells, macrophages, dendritic cells and T helper 2 (Th2) lymphocytes, and is regulated by a complex network of mutually interacting cytokines. The Th2 lymphocyte plays a crucial role within this network. Based, amongst other observations, on in vivo animal models, the hypothesis can be formulated that through the release of a range of cytokines, Th2 cells affect directly airway responsiveness. It would appear that neither crosslinking of IgE and subsequent mast cell degranulation nor eosinophil influx into the airways play a crucial role in this process. Asthmatic airways also display signs of a chronic inflammatory process, that results in more structural alterations, the so-called airway remodeling. This includes increased deposition of collagen and fibronectin, in addition to airway smooth muscle hypertrophy and hyperplasia. In vivo animal models indicate that these structural alterations have a more profound impact on BHR than the acute inflammation. These models also illustrate that depending on the exact extent and location of structural changes throughout the various airway wall compartments, remodeling can enhance but also protect against excessive airway narrowing, despite the presence of acute inflammation. These results illustrate the necessity to take into account the full extent of histological alterations throughout the airway wall, when evaluating the effect of individual cells and cytokines involved in the acute and chronic inflammatory response in asthma. more...

Diffuse parenchymal lung disorders (DPLD) can develop in a variety of systemic disorders. Schematically grouped, these include connective tissue disorders, vasculitis, neoplastic disorders, sarcoidosis and a group of inherited or other rare miscellaneous disorders. This overview focuses on sarcoidosis, systemic sclerosis and Churg Strauss vasculitis. Pulmonary involvement occurs in more than 90% of all patients with sarcodosis. Grading into 4 stages is based on the chest radiograph. Forms characterised by an acute clinical onset or a low grade lung involvement have the highest spontaneous remission rate. The cause of sarcoidosis remains unknown. The diagnosis therefore is descriptive, based on the combination of clinical observations, chest X ray, and the histological documentation of non-caseating epitheloid granulomas in tissue biopsies. Treatment with steroids is only indicated if organ involvement leads to functional impairment. Lung fibrosis is the most important complication of both the "limited" and "diffuse cutaneous form" of systemic sclerosis, involving 90% of all patients. The histological pattern is that of "Usual Interstitial Pneumonia" (UIP) or "Non-specific Interstitial Pneumonia" (NSIP). The pathogenesis of the disorder is thought to consist of an abnormal, excessive regenerative response to an auto-immune mediated lung injury. Churg Strauss vasculitis is characterised by asthma, blood eosinophilia and vasculitis of the small vessels. The affected vessels wall shows signs of fibrinoid necrosis and are infiltrated by eosinophils. pANCA (anti-myeloperoxidase) is considered to play a role in the pathogenesis of the disease. Concern has risen that CysLT1 receptor antagonists might induce production of pANCA. To date, this has not been substantiated. more...

15-lipoxygenase (15-LO) has been implicated in the inflammation of chronic bronchitis (CB), but it is unclear which of its isoforms, 15-LOa or 15-LOb, is primarily involved. To detect 15-LO gene (mRNA) and protein expression, we have applied in situ hybridization (ISH) and immunohistochemistry (IHC), respectively, to bronchial biopsies obtained from 7 healthy nonsmokers (HNS), 5 healthy smokers (HS), and 8 smokers with CB, and additionally include the airways of lungs resected from 11 asymptomatic smokers (AS) and 11 smokers with CB. Compared with HNS, biopsies in CB demonstrated increased numbers of 15-LOa mRNA+ cells (median: HNS = 31.3/mm(2) versus CB = 84.9/mm(2), P < 0.01) and protein+ cells (HNS = 2.9/mm(2) versus CB = 32.1/mm(2), P < 0.01). The HS group also showed a significant increase in protein+ cells (HNS = 2.9/mm(2) versus HS = 14/mm(2), P < 0.05). In the resected airways, 15-LOa protein+ cells in the submucosal glands of the CB group were more numerous than in the AS group (AS = 33/mm(2) versus CB = 208/mm(2); P < 0.001). 15-LOa mRNA+ and protein+ cells consistently outnumbered 15-LOb by approximately 7- and 5-fold, respectively (P < 0.01). Quantitative reverse transcriptase polymerase chain reaction of complementary biopsies confirmed the increased levels of 15-LOa in CB compared with that in either HNS or HS (P < 0.05). There was no difference between the subject groups with respect to 15-LOb expression. The numbers of cells expressing mRNA for 15-LOa in CB showed a positive association with those expressing interleukin (IL)-4 mRNA (r = 0.80; P < 0.01). We conclude that the upregulation of 15-LO activity in the airways of HS and of smokers with CB primarily involves the 15-LOa isoform: the functional consequences of its association the upregulation of IL-4 in chronic bronchitis requires further study. more...

In subjects insufficiently controlled with low to moderate doses of inhaled corticosteroids, adding beta-agonists is clinically more beneficial than increasing the dose of inhaled corticosteroids. In the present study, we investigated the effect of adding salmeterol to fluticasone on allergen-induced airway inflammation and remodeling. Sensitized rats, in which characteristics of remodeling had been induced by ovalbumin exposure every 2 days from Days 14 to 28, were further exposed to ovalbumin or PBS from Days 29 to 42. During the last 2 weeks, before allergen exposure, rats were treated with aerosolized fluticasone propionate (10 mg), salmeterol (1 mg), salmeterol (1 mg) plus fluticasone propionate (10 mg), or placebo. After 4 weeks of ovalbumin exposure, the airways showed inflammatory changes, goblet cell hyperplasia, and enhanced fibronectin and collagen deposition. Salmeterol in monotherapy decreased bronchoalveolar lavage fluid eosinophil number but had no influence on structural changes. Combining salmeterol with fluticasone propionate counteracted goblet cell hyperplasia, but increased the amount of fibronectin and collagen in the airway wall. These effects of salmeterol did not influence airway responsiveness. We conclude that the combination of salmeterol and fluticasone propionate enhances aspects of allergen-induced airway remodeling. This is not accompanied by changes in airway responsiveness. more...

To examine whether fluticasone propionate (FP) dose-dependently inhibits inflammatory as well as structural changes, Brown Norway rats were sensitised to ovalbumin (OA) on day 0 and 7. From day 14-28, rats were exposed to aerosolised OA (1%) or phosphate buffered saline every 2 days. Thirty minutes before each allergen exposure, animals were pre-treated with aerosolised placebo or FP (0.1, 1 or 10 mg) or prednisolone 3 mg x kg(-1) i.p. At day 29, 0.1 mg FP had no measurable effect, either on inflammatory or structural changes, such as goblet cell hyperplasia and airway wall thickening. The allergen-induced increase in eosinophilic inflammation in bronchoalveolar lavage fluid and in the airway mucosa, as well as increased fibronectin deposition, were inhibited by treatment with FP from a dose of 1 mg onwards. Inhibition of goblet cell hyperplasia and thickening of the airway wall required 10 mg inhaled FP. At this dose, systemic effects were observed. However, for a comparable degree of systemic activity, prednisolone was far less effective at preventing airway changes. The dose of inhaled fluticasone propionate required to inhibit allergen-induced structural alterations was higher than to prevent eosinophil influx, and caused systemic side-effects. However, for a similar systemic activity, prednisolone was ineffective in preventing airway remodelling. more...

Increased or altered collagen deposition in the airway wall is one of the characteristics of airway remodelling in asthma. The mechanisms underlying this increase, and its functional consequences remain to be established further. Representative in vivo animal models might be useful in this respect. In the present study, collagen deposition after prolonged allergen exposure was characterised in the airway wall of Brown Norway rats. Sensitised rats were repeatedly exposed to ovalbumin (OA) or phosphate-buffered saline during 2 and 12 weeks. The deposition of collagen type I, III, IV, V and VI was not altered in animals exposed to OA for 2 weeks. After 12 weeks of OA exposure, more collagen type I was deposited in the inner and outer airway wall and more type V and VI collagen was observed in the outer airway wall. At 12 weeks the number of vessels, identified via type IV collagen staining was not increased, but the total vessel area was. In conclusion, prolonged allergen exposure in sensitised rats is associated with enhanced deposition of type I, V and VI collagens and increased vascularity. This suggests that some aspects of airway remodelling in asthma could be driven by long-term allergen exposure. more...

Background: Inhaled corticosteroids are widely used as first-line therapy in patients with asthma. The concept of early introduction is more and more accepted., Objective: In our rat model of airway remodelling, we investigated whether treatment with inhaled fluticasone propionate can inhibit further progression of established structural airway changes., Methods: Sensitized Brown Norway rats were exposed to aerosolized ovalbumin (1%) from day 14 to 42. From day 28 to 42, animals were treated with inhaled fluticasone or placebo 30 min before each allergen challenge. One control group was exposed to PBS from day 28 to 42, a second control group throughout the whole experiment., Results: Exposure to ovalbumin during 2 weeks induced structural airway changes, including epithelial cell proliferation, increase in airway wall area and fibronectin deposition. Goblet cell number was increased, although not significantly compared with PBS. Continuing allergen exposure for 2 weeks further enhanced each of these features. In addition, the amount of collagen in the airway wall was enhanced by 4 weeks allergen exposure compared with PBS-exposed animals. These additional increases were inhibited by treatment with fluticasone during the last 2 weeks., Conclusion: The progression of established allergen-induced structural airway changes in sensitized rats can be inhibited by treatment with fluticasone. more...

It remains to be fully established whether allergen-induced airway inflammation and remodeling are influenced by age. The aim of the present study was to compare allergen-induced airway changes in young and adult rats. Brown Norway rats were sensitized at 4 weeks of age (young) or 13 weeks of age (adult) and exposed to aerosolized ovalbumin (OA) or phosphate-buffered saline for 2 weeks. In both age groups OA exposure induced an increase in OA-specific Immunoglobulin E and in the number of peribronchial eosinophils. OA-challenged animals also developed an increase in total airway wall area, enhanced fibronectin deposition, and goblet cell hyperplasia. Both inflammatory and structural alterations were more pronounced in the airways of young compared with adult OA-exposed rats. The number of peribronchial eosinophils was increased in young animals (685.4 +/- 75.0 versus 389.9 +/- 37.8/mm2 in adult rats; p < 0.001). A higher degree of goblet cell hyperplasia was observed in young rats (65.37 +/- 4.68 versus 34.74 +/- 3.68/mm basement membrane in adult rats; p < 0.001) and area of fibronectin deposition in the airway wall was higher in young compared with adult animals (5.08 +/- 0.46 versus 3.62 +/- 0.29 microm2/microm basement membrane; p < 0.005). In conclusion, in young rats airways are more susceptible to allergen-induced inflammatory and structural airway changes. more...

We wished to determine if the inflammatory cells surrounding the airway mucus-secreting glands in chronic bronchitis (CB) were associated with interleukin (IL)-4 and IL-5 mRNA expression and whether the CD8 T cell population expressed these cytokines. Digoxigenin-labeled IL-4 and IL-5 antisense RNA probes were used to detect gene expression in 11 asymptomic smokers (AS), 11 smokers with CB alone with normal lung function, and 10 smokers with chronic bronchitis and coexisting chronic obstructive pulmonary disease (CB+COPD; FEV(1)% of predicted of 43-77% and FEV(1)/ FVC of 51-68%). There were approximately three times as many IL-4 than IL-5 mRNA(+) cells. The highest number of IL-4 mRNA(+) cells were in the submucosal glands of the CB group with normal lung function (216/mm(2)), significantly higher than the values in either the AS (63/mm(2)) or the CB+COPD (87/mm(2)) groups, respectively (p < 0.01). There were similar group differences when the total numbers of inflammatory cells were compared. Accordingly, there was a positive correlation between the number of IL-4 mRNA(+) cells and the total number of inflammatory cells in both the subepithelium and glandular compartments (r = 0.60; p = 0.01 and r = 0.70; p = 0.02, respectively). There were no significant associations between the numbers of CD8(+) and IL-4 or IL-5 mRNA(+) cells. Of 1328 IL-4(+) and 1404 CD8(+) cells counted none was double labeled. Of 727 IL-5(+) and 1569 CD8(+) cells, none was double labeled. In contrast, as a positive control, 34% of tumor necrosis factor (TNF)-alpha(+) cells were also CD8(+) and 15% of CD8(+) cells were TNF-alpha positive. Thus, cells other than the CD8(+) phenotype produce IL-4 and IL-5 in CB. We conclude that there is increased inflammation and IL-4 gene expression in the mucus-secreting glands and the airway mucosa of smokers with bronchitis: both are lower in those with CB and coexisting COPD suggesting that airway inflammation in CB is reduced when airway obstruction develops. more...

The airway inflammation underlying asthma is regulated by a network of mutually interacting cytokines. The exact functional role of each individual cytokine in the pathogenesis of the disease remains to be fully established. Type 2 T-helper cells are currently considered to play a crucial role in this process. In vivo animal data suggest a sequential involvement of interleukin (IL)-4 and IL-5 in the induction of allergen-induced airway changes. The potential role of other type 2 T-helper cell-like cytokines in asthma is increasingly being recognized. In particular, IL-4 and -13 display a large degree of redundancy. Whereas IL-4 seems to be crucial in the primary allergen sensitization process, IL-13 might be more important during secondary exposure to aerosolized allergen. Animal models also indicate that T-cell-derived cytokine production, rather than eosinophil influx or immunoglobulin-E synthesis, is causally related to altered airway behaviour. An important aspect when evaluating the functional role of cytokines in a complex disease such as asthma is the interaction with other cytokines in the microenvironment. Increased expression of pro-inflammatory cytokines such as tumour necrosis factor-alpha can further enhance the inflammatory process, and is increasingly linked to disease severity. In addition, decreased expression of immunoregulatory cytokines, including interleukin-12, interleukin-18 or interferon gamma could also strengthen the type 2 T-helper cell-driven inflammatory process. more...

The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-gamma after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype. more...

Background: Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma., Objective: The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10., Methods: C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both., Results: IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity., Conclusions: These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology. more...

Asthma is currently defined as a chronic inflammatory disorder of the airways. The central role of allergen-specific Th2 cells in the regulation of this mucosal airway inflammation has been highlighted. Hence, there is large interest in the therapeutic potential of an anti-Th2 cell approach. One of the strategies which has been developed, is to inhibit the effect of interleukin (IL)-4 or IL-5, two main Th2 cell derived cytokines. Interleukin-4 is pivotal in the pathogenesis of allergic disorders through its wide range of effects. An important observation, especially during secondary antigen exposure, is the possible redundancy with IL-13. Both cytokines share common elements in their receptor and intracellular signalling pathway. As a result, compounds can be developed that selectively inhibit the effect of either IL-4 or IL-13, or alternatively, by interfering with the common pathway, inhibit the effect of both cytokines. Eosinophils are generally seen as a particularly harmful element in the allergic inflammation. The importance of IL-5 on eosinophil biology has clearly been established. Conversely, in man, the biological effects of IL-5 are largely limited to eosinophil function. Therefore, IL-5 antagonists offer the unique opportunity of selectively neutralizing the effect of eosinophils. Several strategies have now been developed that successfully inhibit the biological effect of interleukin-4 or interleukin-5. Some of these compounds have proven to be biologically active in man. The challenge now is to establish their therapeutic role in asthma. more...

Ethical and technical reasons limit the possibility of evaluating the effects of inhaled corticosteroids on structural changes in airways of humans with asthma. We therefore evaluated whether fluticasone propionate (FP) modifies airway remodeling, induced by repeated allergen exposure in rats. Sensitized BN rats were exposed to aerosolized ovalbumin (OA) for 2 wk. To assess the effect of FP on the development of or on established airway remodeling, animals were treated with aerosolized FP or placebo during allergen exposure or for 2 wk afterward. Compared with animals exposed to phosphate-buffered saline (PBS), OA-challenged animals developed an increase in total airway wall area, enhanced fibronectin deposition, epithelial cell proliferation, goblet cell hyperplasia, and airway hyperresponsiveness. Concomitant treatment with FP decreased all allergen-induced structural changes without being able to reverse them to normal. Initiating FP treatment after the allergen exposure had no effect on any of the OA-induced structural airway changes. The increase in total airway wall area, enhanced fibronectin deposition, and epithelial cell proliferation persisted. The goblet cell hyperplasia disappeared spontaneously. In conclusion, concomitant treatment with FP partly inhibits structural airway changes as well as hyperresponsiveness induced by OA exposure. Post hoc treatment fails to reverse established airway remodeling. more...

Background: The airway inflammation observed in asthma is orchestrated by activated Th-2 lymphocytes relevant for the induction of altered airway responsiveness. An increasing body of evidence is accumulating that not only the pro-inflammatory cytokines interleukin (IL)-4 and IL-5 but also the immunomodulating cytokines IL-12 and possibly IL-10 are crucial for regulating the allergic airway inflammation., Objective: Since IL-10 is capable of downregulating a broad spectrum of pro-inflammatory cytokines, we wanted to address the role of endogenously produced IL-10 in vivo in allergic asthma., Methods: Knockout (IL-10(-/-)) mice (C57BL/6-IL10tm1Cgn) and wild-type (WT) counterparts were immunized (day 0) and exposed (day 14-21) to ovalbumin (OVA). Airway inflammation and reactivity (AR), serum allergen-specific IgE responses and cytokine profiles in the bronchoalveolar lavage fluid (BALF) were studied., Results: The IL-10(-/-) mice had more eosinophilic airway inflammation but comparable levels of allergen-specific serum IgE compared to the WT mice after allergen challenge. The AR was comparably increased in the OVA challenged WT and IL-10(-/-) mice vs sham-exposed WT, but not vs sham-exposed IL-10(-/-)mice since these showed a higher baseline AR. IFN gamma, IL-4 and IL-13 were comparable and IL-5 was even lower in the BALF of the in IL-10(-/-) mice compared to the similarly exposed WT mice., Conclusion: These results indicate that IL-10 plays an important and possibly direct role in the control of airway inflammation and responsiveness in an in vivo mouse model of allergy. more...

The exact functional contribution of the various inflammatory cells, mediators, cytokines and growth factors present in asthmatic airways to bronchial hyperresponsiveness remains to be fully established. Gene knock-out in vivo animal models can provide valuable information in this respect. Obviously, the closer the animal models mimic human disease, the more relevant this information will be. This constitutes the major limitation of murine asthma models to date. Key characteristics of asthma include from a morphological point of view, signs of an acute allergic airway inflammation in combination with airway remodeling, and from a functional point of view, hypersensitivity and hyperreactivity of the airways. Neither of these two main characteristics are properly mimicked in currently developed animal models. The degree of airway hyperresponsiveness obtained in these models is generally small, when compared to the degree of hyperresponsiveness observed in asthmatics. This probably relates at least in part, to the differences in airway inflammation, as in most of the murine models, only acute inflammatory changes are induced without chronic structural changes that might affect responsiveness to a large degree. The shortcomings of these models notwithstanding, gene knock-out models of asthma have revealed some interesting observations. The majority of these models has evaluated the exact functional role of TH2 cells, interleukin-4, interleukin-5 and IgE in the pathogenesis of allergic airway inflammation and airway hyperresponsiveness. Overall, it can be argued that neither the IgE/mast cell axis, nor the IL-5/eosinophil axis, are the cause of airway hyperresponsiveness, but that the T-cell in its own right is the main determining factor in establishing the degree of bronchial hyperresponsiveness. more...

Adding inhaled long-acting beta(2)-agonists to a low dose of inhaled corticosteroids (ICS), results in better clinical asthma control than increasing the dose of ICS. However, this approach may mask underlying airway inflammation. In a double-blind parallel-group study, we evaluated the effect of adding formoterol to a low dose of budesonide, compared with a higher dose of budesonide, on the composition of induced sputum. After a 4-wk run-in period of treatment with budesonide (800 microg, twice daily), 60 patients with moderate asthma were randomly assigned to a 1-yr treatment with 400 microg of budesonide plus placebo, twice daily (BUD800), or 100 microg of budesonide plus 12 microg of formoterol, twice daily (BUD200+F). All drugs were administered via Turbuhaler. Budesonide (800 microg, twice daily) during run-in significantly reduced median sputum eosinophils from 4.5 to 0.68%. No significant changes in the proportion of eosinophils, EG2(+) cells, other inflammatory cells, or ECP levels in sputum were observed over the ensuing 1-yr treatment with BUD200+F or BUD800. Clinical asthma control was not significantly different between both groups. In conclusion, no significant differences in sputum markers of airway inflammation were observed during a 1-yr treatment with a low dose of inhaled budesonide plus formoterol compared with a higher dose of budesonide. more...

Study Objectives: We previously reported eight patients who developed Churg-Strauss syndrome in association with zafirlukast treatment for asthma and postulated that the syndrome resulted from unmasking of a previously existing condition due to corticosteroid withdrawal and not from a direct drug effect. The availability of montelukast, a new leukotriene receptor antagonist with a different molecular structure, permitted us to test this hypothesis. Our goals were to ascertain whether the Churg-Strauss syndrome developed in patients taking montelukast and other novel asthma medications, and to describe potential mechanisms for the syndrome., Design: Case series., Setting: Outpatient and hospital practices of pulmonologists in the United States and Belgium., Patients: Four adults (one man, three women) who received montelukast as treatment for asthma; two women who received salmeterol/fluticasone therapy, but not montelukast., Results: Churg-Strauss syndrome developed in the four asthmatic patients who received montelukast. In each case, there was a long history of difficult-to-control asthma characterized by multiple exacerbations that had required frequent courses of oral systemic corticosteroids or high doses of inhaled corticosteroids for control. Two other asthmatics who received fluticasone and salmeterol but not montelukast therapy developed the same syndrome with tapering doses of oral or high doses of inhaled corticosteroids., Conclusions: The occurrence of Churg-Strauss syndrome in asthmatic patients receiving leukotriene modifiers appears to be related to unmasking of an underlying vasculitic syndrome that is initially clinically recognized as moderate to severe asthma and treated with corticosteroids. Montelukast does not appear to directly cause the syndrome in these patients. more...

The pathogenesis and functional consequences of airway remodeling in asthma remain to be fully established. In the present study we evaluated the effect of prolonged allergen exposure on airway function and structure in rats. Sensitized Brown Norway rats were repeatedly exposed for periods of 2, 4, or 12 wk to aerosolized ovalbumin (OA) or phosphate-buffered saline (PBS). OA exposure induced a persistent increase in OA-specific serum IgE and in the number of peribronchial eosinophils. After 2 wk of OA exposure, airway histology revealed goblet-cell hyperplasia, an increase in bromodeoxyuridine-positive cells in airway epithelium, increased fibronectin deposition, and a thickening of the airway inner wall area. This coincided with airway hyperresponsiveness (AHR) to aerosolized carbachol. After OA exposure for 12 wk, increased fibronectin (p < 0.05 versus PBS) and collagen deposition (p < 0.05 versus PBS) were observed in the submucosa. After 12 wk of exposure, neither total nor inner wall area or airway responsiveness to carbachol were any longer significantly different from those of PBS-exposed animals. In conclusion, prolonged OA exposure in rats induces structural airway changes that bear similarities to airway remodeling in asthma. The study data further indicate that depending on the extent and distribution of remodeling, changes in the extracellular matrix can enhance or protect against AHR. more...

Background: House dust mites (HDMs) are the major source of perennial allergens causing human allergic asthma. Animal models mimicking as closely as possible the allergic features observed in human asthma are therefore interesting tools for studying the immunological and pathophysiological mechanisms involved. Especially the role of eosinophils and allergen-specific immunoglobulin (Ig) E in the pathophysiology of airway hyperresponsiveness (AHR) remains a subject of intense debate., Objective: To develop a mouse model of allergic airway inflammation and hyperresponsiveness based on the use of purified house dust mite allergen (Der p 1) as clinical relevant allergen. Furthermore, we studied the effects of low dose allergen exposure on the airway eosinophilia and AHR., Methods: On day 0, C57Bl/6 mice were immunized with purified Der p 1 intraperitoneally. From day 14-20, the mice were exposed daily to a 30-min aerosol of different concentrations of house dust mite extract., Results: Mice, actively immunized with Der p 1 and subsequently exposed to HDM aerosols, developed AHR, eosinophil infiltration of the airways and allergen-specific IgE. Moreover, lowering the concentration of the HDM aerosol also induced AHR and IgE without apparent eosinophil influx into the airways. Der p 1-sensitized mice exposed to PBS produced IgE, but did not show AHR or eosinophil influx., Conclusion: This in vivo model of HDM-induced allergic airway changes suggests that AHR is not related to either eosinophil influx or allergen-specific serum IgE, thereby reducing the importance of these factors as essential elements for allergic AHR. more...

Asthma and chronic obstructive pulmonary disease are characterized by airway inflammation, which can be assessed by bronchoscopic techniques as well as by the analysis of induced sputum. A method to induce sputum with inhaled hypertonic saline was adapted for use in 21 chronic obstructive pulmonary disease (COPD) patients (mean baseline forced expiratory volume in one second (FEV1) 1.60 L, or 54% predicted) and in 16 healthy volunteers. The success rate and safety of the method, were investigated along with the reproducibility of cell counts and differences in cell counts between both groups. All subjects produced adequate samples and the procedure did not alter spirometric values. A marked sputum neutrophilia was noted in patients with COPD (74.9+/-4.7%), whereas mainly macrophages were seen in healthy volunteers (74.0+/-4.0%). Reliability of the cell counts was high, both within investigators (r=0.99 neutrophils, r=0.99 macrophages) and between investigators (r=0.95 neutrophils, r=0.77 macrophages). In patients with COPD, an inverse correlation was noted between percentage of neutrophils and FEV1 (r(s)=-0.48, p<0.05). Immunostaining revealed a large proportion of activated macrophages in both groups. It was concluded that induction of sputum is a safe and reproducible method to study the composition of airway secretions in patients with chronic obstructive pulmonary disease. more...

Views on the appropriate use of theophylline in asthma management have varied substantially over the past decades. The recent emphasis on potential anti-inflammatory effects of theophylline has only added to the debate. In current guidelines, theophylline has been positioned mainly as a form of "add-on" therapy in moderate to severe persistent asthma. The purpose of this review is to analyze whether recent developments have been made that allow for a further positioning of theophylline in the treatment of asthma. more...

Recent observations in asthmatics demonstrated anti-inflammatory and immunomodulatory activities of theophylline besides the bronchodilating effect. Theophylline inhibits the mediator release from mast cells, peripheral blood monocytes and alveolar macrophages. The proliferative response of T-cells as well as the influx of eosinophils in BAL fluid is inhibited by treatment with theophylline. The production and release of pro-inflammatory cytokines are affected by theophylline showing a potent inhibitory effect on the production of IL-1beta, TNF-alpha and IFN-gamma. The production of the anti-inflammatory cytokine IL-10 is increased. Evidence is mounting that the anti-inflammatory effects and immunomodulating actions are exerted at lower plasma concentrations than those required for bronchodilation. These activities are of relevance in the treatment of chronic obstructive pulmonary disease (COPD), a disease in which the inflammatory component is considered to be more important than previously thought. more...

Cytokines are very potent pro-inflammatory agents. Several cytokines are present in abnormal quantities in asthmatic airway tissues. In vitro and in vivo experiments demonstrate that these cytokines have biological effects relevant to the pathogenesis of asthma. We review the evidence that interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), interleukin-12 (IL-12) and interferon-gamma (IFNgamma) have the potential of playing a key role in the pathogenesis of asthma. Inhibition of the activity of IL-4 or IL-5 and enhancing or mimicking the action of IL-10, IL-12 or IFNgamma are therapeutic options in asthma that warrant further investigations. more...

T-helper 2 (Th2)-like cells are thought to play a crucial role in the pathogenesis of the eosinophilic airway inflammation observed in asthma. In a murine model of allergen-induced airway eosinophilia and bronchial hyperresponsiveness (BHR), we have shown that interleukin (IL)-12 can suppress antigen-induced airway changes despite the presence of circulating specific IgE. In the present study, we investigated the role of interferon-gamma (IFN-gamma) in the inhibitory effects of IL-12 on allergic airway inflammation. Repeated daily exposure of actively immunized mice to aerosolized ovalbumin (OVA), as compared with aerosolized saline (SAL), induced a significant increase in bronchoalveolar lavage fluid (BALF) eosinophilia and OVA-specific serum IgE in both IFN-gamma-receptor-deficient (IFN-gammaR KO) and wild-type mice. As compared with placebo (PLAC), administration of recombinant murine IL-12 (rmIL-12) during the daily aerosol exposure (but not at the time of immunization) significantly inhibited BALF eosinophilia in both IFN-gammaR KO mice and wild-type controls, without influencing the production of specific IgE. In contrast, administration of rmIL-12 during the active immunization inhibited both BALF eosinophilia and specific IgE in wild-type mice as compared with littermates given PLAC; however, treatment with rmIL-12 during immunization, in comparison with PLAC, caused a significant increase in BALF eosinophilia and specific IgE in IFN-gammaR KO mice. These results demonstrate that inhibition of the allergen-induced eosinophil influx in murine airways by IL-12 is IFN-gamma-dependent during the initial sensitization, but becomes IFN-gamma-independent during the secondary response. more...

We have developed in C57 Black 6 mice an in vivo model of allergic airway inflammation characterized by the presence of IgE antibodies to an inhaled antigen, peribronchial infiltrates with an increased number of eosinophils, and an increased airway responsiveness to nonantigenic bronchoconstrictor stimuli. In this animal model we have investigated the role of different cytokines in the development of IgE antibodies to inhaled antigen, eosinophilic airway inflammation, and airway hyperresponsiveness. The studies were performed by using knockout mice or by exogenous administration of cytokines or cytokine antagonists. Interleukin-4 (IL-4) knockout mice were unable to develop an allergic eosinophilic airway infiltration and did not produce specific IgE antibodies. Chronic aerosol exposure to antigen also did not induce an increase in airway responsiveness. In studies of wild-type mice, pretreatment with the combination of anti-IL5 and anti-IL-5 receptor antibodies, given in an attempt to fully inhibit the effect of endogenously released IL-5, caused a pronounced inhibition of the antigen-induced airway eosinophilia but did not prevent the increase in airway responsiveness. Treatment with IL-12 during the active immunization prevented airway eosinophilia, production of specific IgE antibodies, and the antigen-induced increase in airway responsiveness. In contrast, administration of IL-12 to actively immunized mice during the aerosol exposure abolished airway eosinophilia and airway hyperresponsiveness without affecting the production of specific IgE. more...

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise- and adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 +/- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E4 (LTE4) excretion at exercise was + 18.1 +/- 10.9% on placebo and -44.8 +/- 6.2% after ABT-761 (p = 0.017); changes at adenosine were + 38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges. more...

The idiopathic hypereosinophilic syndrome is empirically defined as the presence of prolonged eosinophilia without identifiable underlying cause, and with evidence of end-organ dysfunction. Virtually any organ system may be involved, most frequently the heart, the central and peripheral nervous system, the lungs and the skin. We report two cases where the diagnosis of hypereosinophilic syndrome was proposed although the classic criteria were not met. In the first case total peripheral eosinophil counts were relatively low, but pathological evidence clearly showed infiltration of eosinophils in the damaged tissues. An hypothesis to explain this discrepancy is formulated. The second case did not fulfil the first feature either, although the clinical presentation and disease course corresponded well with other cases reported in the literature. The delay in diagnosis was caused by early institution of corticosteroids, clearing all evidence of eosinophil involvement in the observed tissue damage. more...