Characteristic Feature Of Asthma Research Articles

Interleukin-4 and Interleukin-13 Enhance Human Bronchial Smooth Muscle Cell Proliferation

Background: T_H2 inflammation and bronchial smooth muscle cell (BSMC) hyperplasia are characteristic features of asthma, but whether these phenomena are linked remains unknown. This study aims to define the effect of the T_H2 cytokines IL-4 and IL-13 on human BSMC proliferation when administered alone or in combination with the fibroblast growth factor 2 (FGF2) growth factor. In addition, the effects of the proinflammatory mediators TNFα and IL-1β and the involvement of members of the well-known family of platelet-derived growth factor (PDGF) mitogens were tested. Methods: BSMC proliferation was measured by crystal violet staining and PDGF and PDGF receptor (PDGFR) expression were determined by RT-PCR, immunocytochemistry, ELISA, flow cytometry and dot plot analysis. Results: Neither IL-4 nor IL-13 alone induced BSMC proliferation, despite both being potent inducers of PDGF-CC. However, following a pretreatment with FGF2, which increased PDGFR α chain expression, both IL-4 and IL-13 increased FGF2-induced BSMC proliferation in a time- and concentration-dependent manner. TNFα and IL-1β did not affect basal or FGF2-induced BSMC proliferation, but both proinflammatory mediators enhanced the proliferative synergism between FGF2 and the T_H2 cytokines. Conclusions: IL-4 and IL-13 potently induce FGF2-primed BSMC proliferation via an autocrine loop involving PDGFRα and PDGF-CC, and this proliferative synergism is amplified by proinflammatory cytokines.

CpG-ODN inhibits airway inflammation at effector phase through down-regulation of antigen-specific Th2-cell migration into lung

Allergic airway inflammation is one of the most typical characteristic features of bronchial asthma. T(h)2 cells, which produce IL-4, IL-5 and IL-13, are well known as major effector lymphocytes of the inflammation. In the present work, we found that subcutaneous injection of Toll-like receptor-9-ligand, CpG-oligodeoxynucleotides (CpG-ODN), remarkably suppressed eosinophilia and mucus hyper-production in T(h)2 cell-dependent airway inflammation model at the effector phase. The injection of CpG-ODN significantly blocked T(h)2 cell migration into lung. The inhibitory effects of CpG-ODN were observed even when IFN-gamma-deficient T(h)2 cells were transferred into IFN-gamma(-/-) mice. In contrast, the administration of neutralizing mAbs against type I cytokines such as IFN-alpha, IFN-beta and IL-12 significantly suppressed the inhibitory effect of CpG-ODN on airway inflammation and T(h)2 cell migration into the lung. We further demonstrated that the production of T(h)2 chemokines, thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), was significantly reduced by the CpG-ODN. The reduction of both TARC and MDC was also inhibited by the blockade of IFN-alpha, IFN-beta and IL-12 with mAbs. Thus, we revealed here that IFN-alpha, IFN-beta and IL-12, but not IFN-gamma, were required for the inhibitory effect of CpG-ODN in T(h)2 cell-mediated allergic airway inflammation. The present evidence strongly suggest that induction of type I cytokines would be promising therapeutic targets in T(h)2-dependent allergic diseases such as bronchial asthma.

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Eosinophilic inflammation is a characteristic feature of asthma. Integrins are highly versatile cellular receptors that regulate extravasation of eosinophils from the postcapillary segment of the bronchial circulation to the airway wall and airspace. Such movement into the asthmatic lung is described as a sequential, multistep paradigm, whereby integrins on circulating eosinophils become activated, eosinophils tether in flow and roll on bronchial endothelial cells, integrins on rolling eosinophils become further activated as a result of exposure to cytokines, eosinophils arrest firmly to adhesive ligands on activated endothelium, and eosinophils transmigrate to the airway in response to chemoattractants. Eosinophils express seven integrin heterodimeric adhesion molecules: alpha 4 beta 1 (CD49d/29), alpha 6 beta 1 (CD49f/29), alpha M beta 2 (CD11b/18), alpha L beta 2 (CD11a/18), alpha X beta 2 (CD11c/18), alpha D beta2 (CD11d/18), and alpha 4 beta 7 (CD49d/beta 7). The role of these integrins in eosinophil recruitment has been elucidated by major advances in the understanding of integrin structure, integrin function, and modulators of integrins. Such findings have been facilitated by cellular experiments of eosinophils in vitro, studies of allergic asthma in humans and animal models in vivo, and crystal structures of integrins. Here, we elaborate on how integrins cooperate to mediate eosinophil movement to the asthmatic airway. Antagonists that target integrins represent potentially promising therapies in the treatment of asthma.

Comparative study to elucidate the mechanism underlying the difference in airway hyperresponsiveness between two mouse strains

The mechanism underlying airway hyperresponsiveness (AHR), a characteristic feature of asthma, remains obscure. We attempted to elucidate the mechanism responsible for the different degrees of AHR in two mouse strains, BALB/c and C57BL/6, following exposure to an anaphylactic trigger. When ovalbumin (OVA)-sensitized mice were challenged daily with OVA for up to three consecutive days, the BALB/c mice showed a higher degree of airway responsiveness to methacholine than did C57BL/6. Following the OVA challenge, eosinophils and macrophages in bronchoalveolar lavage fluid (BALF) from BALB/c increased significantly in number compared to those from C57BL/6. BALB/c mice also exhibited a higher serum IgE level than that of C57BL/6 after OVA challenge. The enhanced AHR and eosinophilic infiltration in BALF were significantly reduced by pretreatment with a selective cysteinyl-leukotriene type 1 receptor (cysLT 1R) antagonist, montelukast. In the in vitro study, cysLT production was significantly lower in the dissected lung tissue from BALB/c than in tissue from C57BL/6 when both groups were stimulated with saline. The lungs from BALB/c generated significantly larger amounts of cysLTs on incubation with OVA rather than with saline, while the lungs from C57BL/6 did not show any significant increase in cysLTs with antigen stimulation. Significant upregulation of cysLT 1R and cysLT 2R mRNA expression was induced by OVA challenge in the lungs of BALB/c, but not in those of C57BL/6. It is suggested that, after an anaphylactic reaction, the degree of AHR is dependent on the genetic background and that cysLTs play an important role in the mechanism involved.

Structural basis for exaggerated airway narrowingThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

Airway hyperresponsiveness, particularly the ability of airways to narrow excessively in response to stimuli that normally cause little airway narrowing in nonasthmatic subjects, is a characteristic feature of asthma and the basis of its symptoms. Although airway hyperresponsiveness may be partly the result of alterations in the contractile phenotype of the airway smooth muscle, there is evidence that it may also be caused by structural changes in the airway wall, collectively termed airway remodeling. Airway remodeling is defined as changes in composition, quantity, and (or) organization of cellular and molecular constituents of the airway wall. Airway wall remodeling that occurs in asthma can result in functional alterations because of quantitative changes in airway wall compartments, and (or) because of changes in the biochemical composition or material properties of the various constituents of the airway wall. This brief review summarizes the quantitative changes in the dimensions and organization of the airway wall compartments that have been described and explains how structural alterations may lead to the exaggerated airway narrowing.

Bronchial responsiveness to methacholine and adenosine 5′‐monophosphate in young children with asthma: their relationship with blood eosinophils and serum eosinophil cationic protein

Bronchial hyperresponsiveness is a characteristic feature of asthma, and is usually measured by bronchial challenges using direct or indirect stimuli. Blood eosinophil numbers and serum levels of eosinophil cationic protein (ECP) are considered as indirect measures of airway inflammation in asthma. The aim of this study was to investigate whether bronchial responsiveness to adenosine 5'-monophosphate (AMP) is more closely associated with blood eosinophil markers, compared with that to methacholine, in young children with asthma. Methacholine and AMP bronchial challenges were performed in 4- to 6-year-old children with asthma (n = 77) and in healthy controls (n = 32), using a modified auscultation method. The end-point was defined as the appearance of wheezing and/or oxygen desaturation. The peripheral blood eosinophil counts and serum ECP concentrations were determined in each subject. A positive response to methacholine (end-point concentration < or =8mg/ml) and to AMP (end-point concentration < or =200 mg/ml) was observed in 74 (96.1%) and 66 asthmatic children (85.7%), respectively. A majority of controls was unresponsive to both challenges. In the asthma group, there was no significant correlation between methacholine end-point concentration and the eosinophil counts (r = -0.111, P = 0.337) or serum ECP levels (r = -0.126, P = 0.274). In contrast, AMP end-point concentration correlated significantly with the eosinophil counts (r = -0.372, P = 0.001) and with serum ECP levels (r = -0.371, P = 0.001). Our results suggest that bronchial responsiveness to AMP is more closely related to airway inflammation, compared with that to methacholine, and support the potential usefulness of AMP challenges in detecting inflammatory changes in young children with asthma.

Short-term variability of airway caliber—a marker of asthma?

Variability in airway caliber is a characteristic feature of asthma. Previous studies reported that the variability in respiratory system impedance (Zrs), measured by the forced oscillation technique during several minutes of tidal breathing, is increased in asthma and may be a marker of inherent instability of the airways. The aims of this study were to determine if short-term variability in impedance correlates with peak expiratory flow (PEF) variability or airway hyperresponsiveness (AHR). The SD of log-transformed impedance (lnZrsSD) was measured as a marker of short-term variability and compared with the diurnal variability of PEF over 2 wk in 28 asthmatic and 7 nonasthmatic subjects and with AHR to histamine in a cohort of 17 asthmatic and 82 nonasthmatic subjects. In addition, lnZrsSD was measured in eight nonasthmatic subjects before and after methacholine challenge in the upright and supine positions. There were no significant differences in lnZrsSD between asthmatic and nonasthmatic subjects (P = 0.68). Furthermore, in asthmatic subjects, lnZrsSD did not correlate with diurnal variability of PEF (rs = -0.12 P = 0.54) or with AHR to histamine (r = 0.10, P = 0.71). Neither methacholine challenge nor supine posture caused any significant change in lnZrsSD. We conclude that our findings do not support previous reports about the utility of short-term variability of impedance. Our findings suggest that, using standard methods for forced oscillometry, impedance variability does not provide clinically useful information about the severity of asthma.

Airway resistance variability and response to bronchodilator in children with asthma

Variability of airway function is a feature of asthma, spanning timescales from months to seconds. Short-term variation in airway resistance (R(rs)) is elevated in asthma and is thought to be due to increased variation in the contractile activation of airway smooth muscle. If true, then variation in R(rs) should decrease in response to bronchodilators, but this has not been investigated. Using the forced oscillation technique, R(rs) and the variation in R(rs) from 4-34 Hz were measured in 39 children with well-controlled mild-to-moderate asthma and 31 healthy controls (7-13 yrs) before and after an inhaled bronchodilator (200 microg salbutamol) or placebo. In agreement with other findings, baseline R(rs) at all frequencies and the sd of R(rs) (R(rs) sd) below 14 Hz were found to be elevated in asthma while neither forced expiratory volume in one second nor the mean forced expiratory flow between 25 and 75% of forced vital capacity were different compared with controls. The present authors found that R(rs) sd changed the most of any measurement in asthma, and this was the only measurement that changed significantly more in children with asthma following bronchodilator administration. The present results show that like airway narrowing, short-term airway variability of resistance may be a characteristic feature of asthma that may be useful for monitoring response to therapy.

Role of Insulin-like Growth Factor (IGF)-I in Human and Experimental Asthma

RATIONALE: One characteristic feature of bronchial asthma is airway inflammation elicited by inflammatory cells such as T cells and eosinophils. The chronic inflammation leads to epithelial remodeling which is an important mechanism of irreversible airway obstruction. Insulin-like growth factor (IGF)-I acts on fibroblasts as a progression factor to push cells toward proliferation and activation to synthesize collagen. Although PDGF is involved in remodeling of asthma, the role of IGF-I is unclear so far.

The Potential Role of Nitric Oxide in Substrate Switching in Eosinophil Peroxidase

Eosinophil recruitment and enhanced nitric oxide (NO) production are characteristic features of asthma and other airway diseases. Eosinophil peroxidase (EPO), a highly cationic hemoprotein secreted by activation of eosinophils, is believed to play a central role in host defense against invading pathogens. The enzyme uses hydrogen peroxide (H2O2) and bromide (Br-), a preferred cosubstrate of EPO, to generate the cytotoxic oxidant hypobromous acid. The aim of this work was to determine whether NO can compete with plasma levels of Br- and steer the enzyme reaction from a 2e- oxidation to a 1e- oxidation pathway. Rapid kinetic measurements were utilized to measure the rate of EPO compounds I and II formation, duration, and decay at 412 and 432 nm, respectively, at 10 degrees C. An EPO-Fe(III) solution supplemented with increasing Br- concentrations was rapidly mixed with fixed amounts of H2O2 in the absence and in the presence of increasing NO concentrations. In the absence of NO, EPO-Fe(III) primarily converted to compound I and, upon H2O2 exhaustion, it decayed rapidly to the ferric form. NO caused a significant increase in the accumulation of EPO compound II, along with a proportional increase in its rate of formation and duration as determined by the time elapsed during catalysis. The time courses for these events have been incorporated into a comprehensive kinetic model. Computer simulations carried out supported the involvement of a conformational intermediate in the EPO compound II complex decay. Collectively, our results demonstrated that NO displays the potential capacity to promote substrate switching by modulating substrate selectivity of EPO.

Obesity and asthma: lessons from animal models

Epidemiological data indicate that obesity is a risk factor for asthma. These data are supported by observations in several murine models of obesity. Ob/ob, db/db, and Cpe(fat) mice each exhibit innate airway hyperresponsiveness, a characteristic feature of asthma. These mice also respond more vigorously to common asthma triggers, including ozone. Here we discuss the implications of these data with respect to several mechanisms proposed to explain the relationship between obesity and asthma: 1) common etiologies; 2) comorbidities; 3) mechanical factors; and 4) adipokines. We focus on the role of adipokines, especially TNF-alpha, IL-6, leptin, and adiponectin. Understanding the mechanistic basis for the relationship between obesity and asthma may lead to novel therapeutic strategies for treatment of the obese asthmatic subject.

Levosalbutamol in the treatment of asthma

With the exception of levosalbutamol, all of the β2-agonists that are currently in use are racemic mixtures that are composed in equal amounts of (R)- and (S)-enantiomers. Clinical and mechanistic studies have demonstrated that (R)-salbutamol alone provides the β2-agonist activity that is needed for the relief of bronchoconstriction, as well as the β2-adrenergically mediated side effects. (S)-Salbutamol, on the other hand, has minimal binding affinity for the β2-receptor, indicating that its effects are likely to be mediated through another site. Furthermore, there is evidence that (S)-salbutamol opposes the desirable effects of (R)-salbutamol in the racemic mixture and contributes to the development of characteristic features of asthma, such as airway obstruction, bronchial hyperresponsiveness and airway inflammation. Evidence from clinical studies shows delayed recovery from exacerbation of asthma by patients who are exposed to high concentrations of (S)-salbutamol.

Serum Interleukin-7 Levels In Patients With Allergic Asthma Keskin Goksal ∗, Inal Ali, Musabak Ugur, Sengul Ali ∗Ankara Etlik Ihtisas Hospital, Immunology Department

RATIONALE: Airway inflammation is a characteristic feature of asthma. Many inflammatory cells and cytokines contribute to airway inflammation in astma, including Th2 lymphocytes and IL-4, IL-5 and IL-13. Interleukin-7 is secreted by bone marrow stromal cells and it stimulates survival and expansion of immature precursors of B and T lymphocytes. Recently, It has reported that the production of IgE induced by IL-7 in human peripheral blood mononuclear cells was potentiated by the presence of T cells. Lymphocytes proliferation, specifically associated with allergic astma are regulated by several cytokines, so we studied serum IL-7 levels in patients with allergic asthma.The study included 38 patients with allergic asthma (27 female, 11 male; mean age 36.00 ± 4.28 years, disease duration 10.32 ± 4,42 years), 15 patients with allergic rhinitis (13 female, 2 male; mean age 33.2 ± 5.22 years, disease duration 6.74 ± 2.45 years) and 14 healthy controls (11 female, 3 male; mean age 34.72 ± 3.12 years). The levels of serum IL-7 were measured with EIA.The mean IL-7 levels in the sera of patients with allergic asthma was 164.30 ± 35.88 ng/ml, allergic rhinitis was 108.33 ± 14.65 ng/ml and healthy controls was 91 ± 22,18 ng/ml. The levels of serum IL-7 were significantly elevated in patients with allergic asthma compared to allergic rhinitis and healthy controls (P= 0.023 and P=0.018 respectively). Serum IL-7 levels were similar in the patients with allergic rhinitis and healthy controls (P=0.349).As a result; serum IL-7 levels were increased in patients with allergic asthma. RATIONALE: Airway inflammation is a characteristic feature of asthma. Many inflammatory cells and cytokines contribute to airway inflammation in astma, including Th2 lymphocytes and IL-4, IL-5 and IL-13. Interleukin-7 is secreted by bone marrow stromal cells and it stimulates survival and expansion of immature precursors of B and T lymphocytes. Recently, It has reported that the production of IgE induced by IL-7 in human peripheral blood mononuclear cells was potentiated by the presence of T cells. Lymphocytes proliferation, specifically associated with allergic astma are regulated by several cytokines, so we studied serum IL-7 levels in patients with allergic asthma. The study included 38 patients with allergic asthma (27 female, 11 male; mean age 36.00 ± 4.28 years, disease duration 10.32 ± 4,42 years), 15 patients with allergic rhinitis (13 female, 2 male; mean age 33.2 ± 5.22 years, disease duration 6.74 ± 2.45 years) and 14 healthy controls (11 female, 3 male; mean age 34.72 ± 3.12 years). The levels of serum IL-7 were measured with EIA. The mean IL-7 levels in the sera of patients with allergic asthma was 164.30 ± 35.88 ng/ml, allergic rhinitis was 108.33 ± 14.65 ng/ml and healthy controls was 91 ± 22,18 ng/ml. The levels of serum IL-7 were significantly elevated in patients with allergic asthma compared to allergic rhinitis and healthy controls (P= 0.023 and P=0.018 respectively). Serum IL-7 levels were similar in the patients with allergic rhinitis and healthy controls (P=0.349). As a result; serum IL-7 levels were increased in patients with allergic asthma.

Augmentation of Endothelin-1-Induced Phosphorylation of CPI-17 and Myosin Light Chain in Bronchial Smooth Muscle from Airway Hyperresponsive Rats

Airway hyperresponsiveness (AHR) associated with heightened airway resistance and inflammation is a characteristic feature of bronchial asthma. It has been demonstrated that contraclile responsiveness to endothelin-1 (ET-1) in repeated antigen challenge-induced airway hyperresponsive bronchial preparation was significantly increased. ET-1 is a potent contracting substance for various smooth muscles including airways. In addition to the classical Ca(2+)-mediated contraction, ET-1 also induced Ca(2+) sensitization of contraction. However, it is not clear whether ET-1 stimulation also activates the CPI-17 (PKC-potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kDa) pathway in airway smooth muscles. Therefore, the changes in ET-1-induced activation/phosphorylation of CPI-17 and myosin light chain (MLC) in bronchial smooth muscle of repeatedly antigen-challenged rats were examined. The levels of ET-1-induced phosphorylation of CPI-17 and MLC were increased much more markedly in the AHR group than in the sensitized control animals. It might be suggested that the augmented activation of CPI-17 observed in the hyperresponsive bronchial smooth muscle is responsible for the enhanced agonists-induced contraction of bronchial smooth muscle in AHR rats.

Bronchial responsiveness to methacholine and adenosine 5′-monophosphate (AMP) in young children with post-infectious bronchiolitis obliterans

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, but it is also frequently demonstrated by children and adults with chronic obstructive lung diseases. BHR is usually measured by bronchial challenges using direct or indirect stimuli. The aim of this study was to compare these two types of bronchial challenge in young children with post-infectious bronchiolitis obliterans (BO). Methacholine and adenosine 5'-monophosphate (AMP) bronchial challenges were performed on preschool children with post-infectious BO (n=18), those with asthma (n=23) and in controls (n=20), using a modified auscultation method. The endpoint was defined as the appearance of wheezing and/or oxygen desaturation. A positive response to methacholine (an endpoint concentration < or = 8 mg/ml) was observed in 88.9% (16/18) of the patients with post-infectious BO, but a positive response to AMP (an endpoint concentration < or = 200 mg/ml) was observed in only 22.2% (4/18). All patients with asthma responded positively to methacholine, and most (21/23, 91.3%) of them also responded positively to AMP. The majority of the controls were insensitive to both challenges. BHR to methacholine is a frequent, but by no means universal, finding in young children with post-infectious BO, but is usually not accompanied by BHR to AMP.

Bronchial responsiveness to methacholine and adenosine 5′-monophosphate in preschool children with bronchopulmonary dysplasia

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, but it is also frequently present in children and adults with chronic obstructive lung diseases. Bronchopulmonary dysplasia (BPD) is a chronic lung disease, most commonly developing after mechanical ventilation and oxygen therapy in premature infants. BHR is usually measured by bronchial challenges, using direct or indirect stimuli. The aim of this study was to evaluate BHR to direct and indirect stimuli in young children with BPD. Methacholine and adenosine 5'-monophosphate (AMP) bronchial challenges were performed on preschool children with BPD (n = 19), using a modified auscultation method. The endpoint was defined as the appearance of wheezing and/or oxygen desaturation. The results obtained were then compared with those of asthmatic (n = 25) and control (n = 23) preschool children. A positive response to methacholine (endpoint concentration, < or = 8 mg/ml) was observed in 89.5% (17/19) of patients with BPD, but a positive response to AMP (endpoint concentration, < or = 200 mg/ml) was observed only in 21.1% (4/19). All patients with asthma responded positively to methacholine, and most (23/25, 92.0%) of them also responded positively to AMP. The majority of controls were unresponsive to both challenges. BHR to methacholine is a frequent finding in preschool-age survivors of BPD, but is usually not accompanied by BHR to AMP. This suggests that most patients with BPD do not have the inflammatory airway response which is characteristic of asthmatic patients.

Bronchial responsiveness to methacholine and adenosine 5′‐monophosphate (AMP) in young children with post‐infectious bronchiolitis obliterans

Abstract Aim: Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, but it is also frequently demonstrated by children and adults with chronic obstructive lung diseases. BHR is usually measured by bronchial challenges using direct or indirect stimuli. The aim of this study was to compare these two types of bronchial challenge in young children with post‐infectious bronchiolitis obliterans (BO). Methods: Methacholine and adenosine 5′‐monophosphate (AMP) bronchial challenges were performed on preschool children with post‐infectious BO (n=18), those with asthma (n=23) and in controls (n=20), using a modified auscultation method. The endpoint was defined as the appearance of wheezing and/or oxygen desaturation. Results: A positive response to methacholine (an endpoint concentration ≤8 mg/ml) was observed in 88.9% (16/18) of the patients with post‐infectious BO, but a positive response to AMP (an endpoint concentration ≤200 mg/ml) was observed in only 22.2% (4/18). All patients with asthma responded positively to methacholine, and most (21/23, 91.3%) of them also responded positively to AMP. The majority of the controls were insensitive to both challenges. Conclusion: BHR to methacholine is a frequent, but by no means universal, finding in young children with post‐infectious BO, but is usually not accompanied by BHR to AMP.

Methacholine and adenosine 5'-monophosphate challenges in children with post-infectious bronchiolitis obliterans

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, but is also frequently demonstrated by children and adults with chronic obstructive lung diseases. AHR is usually measured by bronchial challenges using direct or indirect stimuli. The aim of this study was to compare these two types of bronchial challenge in children with post-infectious bronchiolitis obliterans (BO). Methacholine and adenosine 5'-monophosphate (AMP) challenges were used as tools for the evaluation of AHR to direct and indirect stimuli, respectively, in children with post-infectious BO (n = 28). These results were compared with those of asthmatic (n = 30) and control children (n = 25). Altogether, twenty-two patients (78.6%) with post-infectious BO were hyperreactive to methacholine with a provocative concentration causing a 20% fall in forced expiratory volume in one second (PC20) of <16 mg x mL(-1), but only six (21.4%) were hyperreactive to AMP with a PC20 of <200 mg x mL(-1). All patients with asthma responded positively to methacholine, and most (28, 93.3%) also responded positively to AMP. The majority of controls were insensitive to both challenges. Airway hyperresponsiveness to methacholine is a frequent, but by no means universal, finding in children with post-infectious bronchiolitis obliterans, but is usually not accompanied by airway hyperresponsiveness to adenosine 5'-monophosphate. This finding suggests that airway hyperresponsiveness in patients with post-infectious bronchiolitis obliterans has characteristics that differ from those of asthmatic subjects.

β&lt;sub&gt;2&lt;/sub&gt;-Agonists and Bronchial Hyperresponsiveness

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, and individuals with this disease respond to a range of physiological and chemical insults that are otherwise innocuous to healthy subjects, suggesting that the mechanisms underlying this phenomenon are characteristic of the asthma phenotype. BHR can be increased following exposure to environmental allergens in suitably sensitized individuals, pollutants, and certain viruses and can also be exacerbated by exposure to certain drugs, including nonsteroidal anti-inflammatory agents and beta-blockers. Although beta2-agonists administered acutely remain the treatment for the symptoms of asthma, paradoxically, regular treatment with these drugs can result in an increase in BHR, and this has been suggested to contribute to the increase in asthma morbidity and mortality that has been reported by numerous investigators. This article highlights our current understanding of this phenomenon and examines the potential mechanisms responsible for this effect.

Airway Hyperresponsiveness to Methacholine in Chemical Warfare Victims

Background: The lung is one of the most exposable organs to chemical warfare agents such as sulfur mustard gas. Pulmonary complications as a result of this gas range from severe bronchial stenosis to mild or no symptoms. Airway hyperresponsiveness (AHR) which is usually assessed as response to inhaled methacholine is the most characteristic feature of asthma. AHR is reported in chronic obstructive pulmonary disease patients and smokers, and may also show in chemical warfare victims. However, there are little reports regarding AHR in chemical warfare victims. Objective: Therefore, in this study, airway responsiveness to methacholine in victims of chemical warfare was examined. Methods: The threshold concentrations of inhaled methacholine required for a 20% change in forced expiratory flow in 1 s (FEV₁; PC₂₀) or a 35% change in specific airway conductance (PC₃₅) were measured in 15 chemical war victims and 15 normal control subjects. Results: In 10 out of 15 chemical warfare victims (two thirds), PC₂₀ and PC₃₅ methacholine could be measured and subjects were called responders. AHR to methacholine in responder chemical war victims (PC₂₀ = 0.41 and PC₃₅ = 0.82 g/l) was significantly lower than in normal subjects (PC₂₀ = 5.69 and PC₃₅ = 4.60 g/l, p < 0.001 for both cases). There was a significant correlation between FEV₁ and PC₂₀ methacholine (r = 0.688, p < 0.001). The correlations between PC₂₀ and PC₃₅ were statistically significant as well (r = 0.856, p < 0.001). Conclusion: Results showed increased airway responsiveness of most chemical warfare victims to methacholine which correlated with the FEV₁ value and which may be related to chronic airway inflammation or irreversible airway changes.