Airway Structural Changes Research Articles

Remodeling in Asthma

Airway remodeling refers to the structural changes that occur in both the large and the small airways of miscellaneous diseases, including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, enlargement of glands, neovascularization, and epithelial alterations. Although controversial, airway remodeling is commonly attributed to the underlying chronic inflammatory process. These remodeling changes contribute to thickening of airway walls and consequently lead to airway narrowing, bronchial hyperresponsiveness, airway edema, and mucous hypersecretion. Airway remodeling is associated with poorer clinical outcome among patients with asthma. Early diagnosis and prevention of airway remodeling has the potential to decrease disease severity, to improve control, and to prevent disease expression. In this article, we briefly provide an update on the characteristic features of airway remodeling observed in asthma and their clinical consequences.

Pengembangan Model Mencit Alergi dengan Paparan Kronik Ovalbumin

ABSTRACTHistology expression in asthma show inflammatory processes and airway structural changes. Treatmentdevelopment in asthma needs appropriate animal models but most animal models use short term allergenexposure. The aim of this research was to create develop allergic mouse model with allergic inflammationand structural changes histology expression. Eight female BALB/c mice, 6-12 weeks old, 80-100 gramswere divided into two groups. The first group were exposed to a normal saline solution where the secondgroup received ovalbumin. Mice were sensitized by intraperitoneal injection of ovalbumin on day 0 and 14and challenged by nebulization of 1% ovalbumin three times weekly for 6 weeks. Twenty four hours afterfinal exposure, the mice were sacrificed by lethal cardiac puncture. The level of total IgE in serum weremeasured by ELISA and IL-4 receptor expression were examinated by immunohistochemistry.Morphometric analysis was performed to count inflammatory cells, eosinophil, goblet cells, epithel andsmooth muscle thickness. Differences between the control and exposed mice were analyzed by Mann-Whitney test. There were a significant differences in total IgE serum and expression IL-4 receptor betweenthe two groups (P < 0,05). The morphometric analyzing also demonstrated significant differences betweenthese two groups (P < 0,05). Chronic ovalbumin exposure through inhalation produced allergicinflammation and airway structural changes.Keywords: allergic inflammation, mouse models, chronic exposure, ovalbumin

Irreversiblity of Remodeled Features on High-Resolution Computerized Tomography Scans of Asthmatic Patients on Conventional Therapy: A 6-Year Longitudinal Study

Airway remodeling can be assessed using high-resolution computerized tomography (HRCT) scanning of both parenchymal-and airway abnormalities in patients with asthma. The aim of this study was to examine structural changes in large and small airways of asthmatic patients using HRCT to determine if remodeling changes had occurred after prolonged use of conventional anti-asthma therapy. HRCT scans were evaluated prospectively for evidence of the following abnormalities: bronchial wall thickening (BWT), bronchiectasis, mucoid impactions, small centrilobular opacities, thick linear opacities, focal hyperlucency, and emphysema. Fifty mild and moderate asthmatics were enrolled in the study group. These abnormalities were re-evaluated in the patients after the passage of 6 years of regular anti-asthma medication. Forty-six of the patients completed the study. The probability of finding at least one abnormality by HRCT investigation was statistically higher in the second scan than in the first (26 patients [56.5%] versus 18 patients [39.1%], p = 0.02]. Irreversibility ratios of abnormalities were 80%, 100%, 75%, 87.7%, 77.8%, and 100% for BWT, bronchiectasis, small centrilobular opacities, focal hyperlucency, thick linear opacity, and emphysema, respectively. The ratios for newly detected structural abnormalities were 25%, 2.5%, 0%, 7.9%, 8.1%, and 0% for BWT, bronchiectasis, small centrilobular opacities, focal hyperlucency, thick linear opacity, and emphysema, respectively. New occurrences and progression in BWT are associated with the duration of asthma affliction (p = 0.03). The results of our study indicate that HRCT remodeling features, once occurring, are irreversible in most of the patients, and new remodeling features also occur despite administering the standard asthma treatment.

Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

Chronic obstructive pulmonary disease (COPD) and bronchial asthma are common respiratory diseases that are caused by chronic inflammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-alpha) and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF) plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-alpha and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma.

Adjuvant effect of di-(2-ethylhexyl) phthalate on asthma-like pathological changes in ovalbumin-immunised rats

Pollution of phthalates, including di-(2-ethylhexyl)phthalate (DEHP), is widespread because of their use in plastics and other daily consumer products. Epidemiological studies have shown that the largest source of general population exposure to DEHP is on dietary. Studies have suggested an association between exposure to phthalate plasticisers, and increased prevalence of asthma. To investigate the adjuvant effect of DEHP on asthmatic pathological changes in ovalbumin-immunised rat model. Wistar rats were randomly divided into five groups (eight rats of each group): (1) saline; (2) ovalbumin (OVA); (3) OVA+DEHP 0.7mg·kg−1·d−1; (4) OVA+DEHP 70 mg·kg−1·d−1; and (5) DEHP 70 mg·kg−1·d−1. DEHP treatment groups which were administered to 0.7 mg and 70 mg DEHP/kg/d by gastric gavage for 30d before and during the process of OVA immunisation or saline treatment. The in vivo pulmonary function analysis, bronchoalveolar lavage (BAL) fluid collection and section histological observation were conducted. DEHP exposure could significantly increase airway hyperresponsiveness, airway remolding, and eosinophil infiltration in the OVA-immunised rats. But the DEHP exposure alone group does not show significant airway structural change and inflammatory cell infiltration, compared with control group. DEHP administered by gastric gavage play an adjuvant effect on respiratory systems in ovalbumin-immunised rat model.

Effect of valsartan on the expression of angiotensin II receptors in the lung of chronic antigen exposure rats

Many studies have suggested that angiotensin II (Ang II) and its receptors may be involved in the development of asthma. However, the expression of angiotensin II receptors (AGTR) is not clear in the lung tissue of chronic asthmatics. This study was designed to determine the relationship between airway remodeling, dysfunction and the expression of AGTRs in a rat model of asthma. Rats were sensitized with ovalbumin (OVA) for 2 weeks. Sixty minutes before an inhalation challenge, the rats were pretreated either with valsartan (15, 30, 50 mg x kg(-1) x d(-1)) or saline intragastrically. Then the rats received an OVA challenge for 30 alternative days. Acetylcholine (Ach)-induced bronchoconstriction was measured after the final antigen challenge. White cell counts in bronchoalveolar lavage fluid (BALF) and morphological changes in the airways were then assessed. The levels of transforming growth factor-beta 1 (TGF-beta(1)) and platelet-derived growth factor (PDGF) in BALF were detected by ELISA. The levels of AGTR1 and AGTR2 mRNA and protein in lung tissues were measured by RT-PCR and Western blotting. AGTR1 mRNA and protein levels in repeatedly OVA-challenged rats were significantly increased as compared with negative controls. The AGTR1 mRNA expression versus white cell counts of BALF and airway wall thickness (mainly in small airways) in lungs of chronic antigen-exposed rats were positively correlated. Valsartan decreased the level of AGTR1 in repeatedly OVA-challenged rats. However, AGTR2 mRNA and protein levels in the OVA-challenged rats and high-dose valsartan-treated rats (50 mg x kg(-1) x d(-1)) were also increased. Valsartan significantly decreased inflammatory cell accumulation and attenuated Ach-evoked bronchoconstriction in repeatedly antigen-challenged rats. Valsartan also decreased allergen-induced structural changes in rat airway (including total airway wall thickness and smooth muscle area) and the levels of TGF-beta(1) and PDGF in BALF. AGTR1 expression is potentially associated with airway remodeling and dysfunction in asthma. Ang II and AGTR1 may participate in airway inflammation and airway remodeling of chronic antigen-exposed rats. Valsartan, a AGTR1 antagonist, could inhibit AGTR1 expression and partially inhibits structural airway changes as well as airway inflammation in chronic OVA-exposed rats.

2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model

Patients with asthma experience airway structural changes, termed airway remodeling, in response to persistent inflammation. 2-Methoxyestradiol (2-ME) is an anti-angiogenic agent and downregulates hypoxia-inducible factor 1 (HIF-1) and inhibits HIF-1α-induced transcriptional activation of vascular endothelial growth factor (VEGF) expression. We hypothesized that 2-ME may interfere with the development of the clinical manifestations of asthma. We used a chronic murine model of allergic airway inflammation with subepithelial fibrosis in BALB/c mice. Mice were sensitized with ovalbumin (OVA) that was administered intraperitoneally at days 0–5 and challenged intratracheally (IT) with OVA on days 12–22. The mice received 2-ME IT at days 24, 26 and 28 and sacrificed at day 32. The sensitized/challenged mice developed an extensive cell inflammatory response of the airways. 2-ME administration significantly reduced the cellular infiltrate in the perivascular and peribronchial lung tissues, reduced goblet mucous production, reduced airway fibrosis and thickness of smooth muscle and blood vessels, and reduced eosinophil infiltration. Mice treated with 2-ME had a significant decrease of HIF-1 and VEGF expression in the perivascular, peribronchial, and interstitium of lung tissues. Collagen IV expression was also significantly reduced in 2-ME treated mice compared to untreated mice. The 2-ME treatment was associated with a significant decrease of OVA-specific IgE antibodies. These findings provide the first indication that IT administration of 2-ME is effective in preventing and reversing antigen-induced airway remodeling in the OVA allergen inflammatory murine model. The potential role of 2-ME in patients is discussed.

Aging increases upper airway collapsibility in Fischer 344 rats

The upper airway muscles play an important role in maintaining upper airway collapsibility, and the incidence of sleep-disordered breathing increases with age. We hypothesize that the increase in airway collapsibility with increasing age can be linked to changes in upper airway muscle mechanics and structure. Eight young (Y: 6 mo) and eight old (O: 30 mo) Fischer 344 rats were anesthetized and mechanically ventilated, and the pharyngeal pressure associated with flow limitation (Pcrit) was measured 1) with the hypoglossal (cnXII) nerve intact, 2) following bilateral cnXII denervation, and 3) during cnXII stimulation. With the cnXII intact, the upper airways of older rats were more collapsible compared with their younger counterparts [Pcrit = -7.1 +/- 0.6 (SE) vs. -9.5 +/- 0.7 cmH2O, respectively; P = 0.033]. CnXII denervation resulted in an increase in Pcrit such that Pcrit became similar in both groups (O: -4.2 +/- 0.5 cmH2O; Y: -5.4 +/- 0.5 cmH2O). In all rats, cnXII stimulation decreased Pcrit (less collapsible) in both groups (O: -11.3 +/- 1.0 cmH2O; Y: -10.2 +/- 1.0 cmH2O). The myosin heavy chain composition of the genioglossus muscle demonstrated a decrease in the percentage of the IIb isoform (38.3 +/- 2.5 vs. 21.7 +/- 1.7%; P < 0.001); in contrast, the sternohyoid muscle demonstrated an increase in the percentage of the IIb isoform (72.2 +/- 2.5 vs. 58.4 +/- 2.3%; P = 0.001) with age. We conclude that the upper airway becomes more collapsible with age and that the increase in upper airway collapsibility with age is likely related to altered neural control rather than to primary alterations in upper airway muscle structure and function.

Bronchoalveolar Lavage MMP-9 and TIMP-1 in Preschool Wheezers and Their Relationship to Persistent Wheeze

Atopic preschool children are more likely to develop persistent wheezing, which could be a consequence of early airway remodeling. Protease-antiprotease balance between MMP-9 and its cognate inhibitor TIMP-1 may be involved in this process. Our hypothesis was that atopic wheezing preschool children would have an imbalance of MMP-9 to TIMP-1 in bronchoalveolar lavage (BAL). BAL from 52 preschool wheezers was compared with 14 controls without wheeze. A subgroup completed an International Study of Asthma and Allergy in Childhood symptom questionnaire 2 y later. Molar ratios of MMP-9/TIMP-1 were higher in wheezy children (p < 0.001; median 4.0%, range 0-8.7) than controls (0.6%, 0-1.8), and showed an excess of TIMP-1 in the airway. BAL TIMP-1 was raised in children with persistent wheezing (p = 0.028; 34.4 ng/mL, 9.1-93.1 compared with 10.6 ng/mL 6.1-18.6), as was serum levels of intercellular adhesion molecule-1 (p = 0.027). The absolute concentration of TIMP-1 in the airway, rather than its molar ratio with MMP-9, was associated with persistent wheezing. The processes involved with airway remodeling are complex but excess TIMP-1 may impede matrix protein turnover and thereby contribute to persistent changes in airway structure and wheezing.

What can we learn about airway smooth muscle from the company it keeps?: Fig. 1—

In severe and fatal asthma dramatic changes in airway structure have been described, collectively referred to as remodelling 1, 2. Current dogma dictates that remodelling reflects aberrant repair in response to ongoing inflammation and injury. However, the interplay between inflammation and remodelling, and, more importantly, between airway structure and function remains elusive, such that we remain uncertain whether these changes protect the airways from the effects of inflammation or are integral to disease progression. To begin to unravel this conundrum we need to recognise the complexity and heterogeneity of asthma. The asthma paradigm comprises several domains, including ongoing symptoms, the presence of variable airflow obstruction and airway hyperresponsiveness. Together with such disordered airway physiology, most subjects with asthma have evidence of a chronic inflammatory response that is typically, but not exclusively, eosinophilic, with the presence of mast cells within the airway smooth muscle bundle 3–5. In addition, there is often evidence of structural remodelling of the airway wall with thickening of the reticular lamina, mucus gland hyperplasia, increased vasculature, and increased airway smooth muscle hyperplasia and hypertrophy. Importantly, some features of remodelling, particularly thickening of the lamina reticularis, can occur early on in disease and even in some children prior to the onset of asthma 6. In contrast, other aspects of the remodelling process have been associated with disease duration 7. In addition to structural and inflammatory cells, the airway wall is comprised of extracellular matrix, the composition of which varies between different compartments in the airway wall, between asthma versus health, and across disease severity. This matrix is not a benign bystander that simply constitutes the scaffold to build airway structures and allow inflammatory cell trafficking, but can alter …

Small airways: an important but neglected target in the treatment of obstructive airway diseases

Changes in the structure and function of the small airways (<2mm diameter) are now recognized to play a major role in airflow limitation in both chronic obstructive pulmonary disease (COPD) and severe asthma. Increased thickness of the small airway wall causes lumenal narrowing, which can be further occluded by mucus and/or inflammatory cell exudate. This leads to increased peripheral resistance, air trapping and shortness of breath on exertion. Studies in animal models and in subjects with COPD have suggested that oxidant-driven transforming growth factor (TGF)-beta1 activation and subsequent increased airway wall collagen synthesis might be central to the changes in small airway structure. However, it remains difficult to measure small airway function in patients, and delivery of inhaled drugs to peripheral airways has not yet been optimised. The increased understanding of the processes underlying the development of small airways disease should facilitate pharmacological intervention targeted at this hitherto neglected compartment.

Airway remodeling is correlated with obstruction in children with severe asthma

Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern. Two groups of children with severe asthma and persistent symptoms, 5-14 years old were included, 15 with persistent obstructive pattern (group O) and 10 without obstructive pattern (group N). Persistent obstructive pattern was defined as a forced expiratory volume in 1 s (FEV(1)) less than 80% of the predicted value after a course of systemic corticosteroids and no significant improvement after bronchodilator. We examined bronchial biopsies by pathological and immunochemical methods and quantified airway smooth muscle (ASM) and mucus gland areas, reticular basement membrane (RBM) thickening, distance between ASM and RBM, muscle light chain kinase (MLCK) expression and number of vessels (CD31 expression). Surface area of ASM (P = 0.009), MLCK expression (P = 0.03) and number of vessels (P = 0.0008) were increased in group O compared with group N. Distance of RBM-ASM was shorter in group O (P = 0.007). FEV(1) negatively correlated with ASM area (r = -0.6; P = 0.002), MLCK expression (r = -0.45; P = 0.02) and CD31 expression (r = -0.7; P = 0.0003), and positively correlated with the distance of RBM-ASM (r = 0.5; P = 0.007). Structural abnormalities of airway remodeling are present in children with severe asthma. Only an increase in surface area of ASM and the density of the vascular network are more pronounced in children with persistent obstructive pattern, while RBM thickening is similar. These results are concordant with longitudinal studies which emphasize the precocity of bronchial obstruction.

Puberty and upper airway dynamics during sleep.

The upper airway compensatory response to subatmospheric pressure loading declines with age. The epidemiology of obstructive sleep apnea suggests that sex hormones play a role in modulating upper airway function. Sex hormones increase gradually during puberty, from minimally detectable to adult levels. We hypothesized that the upper airway response to subatmospheric pressure loading decreased with increasing pubertal Tanner stage in males but remained stable during puberty in females. Upper airway dynamic function during sleep was measured over the course of puberty. Normal subjects of Tanner stages 1 to 5. During sleep, maximal inspiratory airflow was measured while varying the level of nasal pressure. The slope of the upstream pressure-flow relationship (SPF) was measured. The SPF correlated with age and Tanner stage. However, the relationship with Tanner stage became nonsignificant when the correlation due to the mutual association with age was removed. Females had a lower SPF than males. In both sexes, the upper airway compensatory response to subatmospheric pressure loading decreased with age rather than degree of pubertal development. Thus, changes in sex hormones are unlikely to be a primary modulator of upper airway function during the transition from childhood to adulthood. Although further studies of upper airway structural changes during puberty are needed, we speculate that the changes in upper airway function with age are due to the depressant effect of age on ventilatory drive, leading to a decrease in upper airway neuromotor tone.

Longitudinal study of airway dimensions in chronic obstructive pulmonary disease using computed tomography

Chest CT has been widely used for the evaluation of structural changes in lung parenchyma and airways in cross-sectional studies. There has been no report on the annual changes in airway dimensions as assessed by CT in COPD patients. The objective of this study was to investigate the annual changes in airway dimensions and lung attenuation using CT in patients with COPD and to evaluate the correlations among annual changes in CT measurements and pulmonary function. Eighty-three men with COPD had completed five annual assessments of CT scans and pulmonary function tests over 4 years. Airway dimensions of the basal segment bronchi and lung attenuation on CT images were analysed in 38 subjects in whom the same airway could be measured at least three times, including at entry and at the end of the study. Mean annual decline in FEV(1) was 21 mL/year. Annual changes in the percentage of low attenuation areas were not significantly correlated with decline in FEV(1). On the other hand, annual changes in the percentage of wall area (WA%/year) were significantly inversely correlated with annual changes in FEV(1) (r = -0.363, P = 0.025), whereas WA%/year did not differ among severity stages at entry and did not correlate with baseline FEV(1). The results showing that annual changes in airway thickening correlated with annual decline in air flow limitation suggests the importance of treatment of airway inflammation in COPD. CT is a useful tool for quantitative estimation not only of emphysema but also of airway lesions in longitudinal studies.

Reduced Lung Function in a Chronic Asthma Model Is Associated with Prolonged Inflammation, but Independent of Peribronchial Fibrosis

BackgroundIn asthma, mechanisms contributing to chronicity remain to be determined. Recent models of sensitisation with prolonged airway allergen challenges reproduce typical features of chronic asthma. However, the interplay between inflammation, structural changes and lung function is poorly understood. This study was performed to delineate functional, structural and immunological airway changes after cessation of long term challenges to elucidate factors contributing to the development of prolonged lung function changes.Methodology/Principal FindingsMice sensitised systemically were consecutively challenged intranasally with ovalbumin for two or eight weeks. After the end of challenges, lung function, airway inflammation, features of airway remodelling, local T-cell cytokines and systemic ovalbumin-specific antibodies were monitored. Long term challenges resulted in airway hyperresponsiveness lasting 2 weeks and reduced baseline lung function for 6 weeks after their cessation. In contrast, these changes resolved within one week after short term challenges. Prolonged transforming growth factor beta (TGF-β)1 production and marked peribronchial fibrosis were only induced by long term challenges. Importantly, fibrosis became apparent only after the onset of lung function changes and outlasted them. Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response. In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.ConclusionsProlonged lung function changes after long term allergen challenges seem to develop and resolve independently of the persistent peribronchial fibrosis. They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-β1 production in the airways and a Th1 immune response.

ABCs of Asthma

Asthma results from chronic airway inflammation involving a diversity of activated cells including mast cells, eosinophils, T-lymphocytes, neutrophils, macrophages, and epithelial cells. These cells release proinflammatory cytokine mediators that augment and regulate airway inflammation, leading to airway hyperresponsiveness responsible for the chronic asthma symptoms of dyspnea, wheezing, and chest tightness. It is hypothesized, but unproven, that inflammatory effects can lead to irreversible structural and functional airway changes. Early intervention with anti-inflammatory agents mitigates inflammatory changes, reverses airway obstruction, and may possibly prevent progression of airway remodeling. Current asthma guidelines recommend that initial management should be based on pretreatment assessments of asthma severity as determined by measures of clinical and spirometric impairment in individual patients; subsequent adjustments of pharmacotherapy and avoidance recommendations should be performed at regular follow-up visits and guided by frequent assessments of asthma control. Physicians and providers should continually educate asthmatic patients about proper use of asthma controller medications, avoidance of asthma triggers, and self-management of asthma exacerbations.

Endothelin-1 in exhaled breath condensate of stable and unstable asthma patients

Endothelins are proinflammatory, profibrotic, broncho- and vasoconstrictive peptides, which play an important role in the development of airway inflammation and remodeling in asthma. The study was undertaken to evaluate the endothelin-1 (ET-1) levels in exhaled breath condensate (EBC) of asthmatics with different degree in asthma severity. EBC was collected from 31 patients with allergic asthma (11 with steroid-naïve mild asthma, 10 with ICS-treated, stable mild-to-moderate asthma, 10 with ICS-treated unstable, severe asthma) and 7 healthy volunteers. In the three groups of asthmatics, ET-1 concentrations in EBC were significantly higher than in healthy volunteers. ET-1 levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. There was a significant correlation between ET-1 levels and FENO in the three groups of asthmatics and between ET-1 and blood eosinophil counts in the group of patients with unstable asthma. Measurements of ET-1 in EBC may provide another useful diagnostic tool for detecting and monitoring inflammation in patients with asthma.

Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary diseases (COPD), comprised of pulmonary emphysema, chronic bronchitis, and structural and inflammatory changes of small airways, is a leading cause of morbidity and mortality in the world. A better understanding of the pathobiology of COPD is critical for the developing of novel therapies, as the majority of patients with the disease have little therapeutic options at the present time. The pathobiology of COPD encompasses multiple injurious processes including inflammation (excessive or inappropriate innate and adaptive immunity), cellular apoptosis, altered cellular and molecular alveolar maintenance program, abnormal cell repair, extracellular matrix destruction (protease and anti-protease imbalance), and oxidative stress (oxidant and antioxidant imbalance). These processes are triggered by urban and rural air pollutants and active and/or passive cigarette smoke and modified by cellular senescence and infection. A series of receptor-mediated signal transduction pathways are activated by reactive oxygen species and tobacco components, resulting in impairment of a variety of cell signaling and cytokine networks, subsequently leading to chronic airway responses with mucus production, airway remodeling, and alveolar destruction. The authors provide an updated insight into the molecular and cellular pathobiology of COPD based on human and/or animal data.

Relaxin Plays an Important Role in the Regulation of Airway Structure and Function

Relaxin is a reproductive hormone with pleiotropic actions. In addition to airway fibrosis, relaxin deficiency results in airway structural changes (epithelial thickening) and increased lung recoil, suggesting that relaxin may impact other aspects of airway/lung structure and function beyond its ability to regulate collagen turnover. Furthermore, these structural changes associated with relaxin deficiency show marked similarity to the structural changes seen in asthma. The current study investigated the broader role of relaxin in regulating airway structure and function and examined the relationship between airway inflammation, structural changes, and airway hyperresponsiveness (AHR) using an ovalbumin (OVA)-induced model of allergic airways disease (AAD). The model of AAD was applied to 12-month-old relaxin-deficient (Rln(-/-)) mice with established airway fibrosis and age-matched wild-type (Rln(+/+)) controls. OVA-treated Rln(+/+) mice (induced inflammation) developed increased epithelial thickening (P < 0.05) and AHR (P < 0.05) but not airway fibrosis, compared with saline-treated Rln(+/+) controls. Saline-treated Rln(-/-) mice had significantly increased lung collagen deposition (existing fibrosis) and epithelial thickening and remarkably were found to have increased AHR that was equivalent to that in OVA-treated Rln(+/+) mice (all P < 0.05 vs. saline-treated Rln(+/+) controls). OVA-treated Rln(-/-) mice (existing fibrosis and induced inflammation) had increased airway/lung fibrosis (P < 0.05) but equivalent airway inflammation and AHR compared with OVA-treated Rln(+/+) animals. These findings demonstrate for the first time a role for relaxin in the regulation of airway responses using Rln(-/-) mice and suggest that airway fibrosis and/or epithelial thickening can result in increased AHR equivalent to that induced by airway inflammation in AAD.

Budesonide attenuates airway remodeling and modules the expression of Janus protein tyrosine kinase 1, and signal transducers and activators of transcription 6 in asthma: an experiment with mice

To investigate the effects of budesonide (BUD) on the airway remodeling and the expression of Janus protein tyrosine kinases 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6) in asthma. Thirty female Balb/c mice were randomly divided into 3 equal groups: control group; asthma group, sensitized on day 1, 8, and 15 and challenged from day 21 to 52 with periodically repeated intranasal drip of ovalbumin (OVA); and BUD treated group, undergoing intranasal drip of OVA as mentioned above and intranasal administration of BUD 2 hours before each OVA challenge. 24 h after the final OVA inhalation an invasive single-chamber whole body plethysmograph was used to assess the airway responsiveness. Then bronchoalveolar lavage fluid (BALF) was obtained and ELISA was used to measure the contents of interleukin (IL)-4 and IL-13. The mice were killed and their lungs taken out. HE staining and periodic acid Schiff (PAS) staining were used to observe the airway score of goblet cells. Peribronchiolar collagen deposition was imaged in Masson-stained lung sections. Biochemical assay was used to determine the total lung tissue level of collagen. Potass hydrolyse method was used to examine the content of hydroxyproline in the lung tissue. Western blotting was used to detect the protein expression of alpha-smooth muscle actin (SMA), JAK1, and STAT6. RT-PCR was used to detect the mRNA expression of alpha-SMA. The value of LogPC100 of the asthma group was 1.88 +/- 0.34, significantly higher than those of the BUD and control groups (1.79 +/- 0.18 and 0.82 +/- 0.78 respectively, both P = 0.000). The airway score of goblet cells of the asthma group was 3.05 +/- 0.23, significantly higher than those of the BUD and control groups (1.35 +/- 0.26 and 0.40 +/- 0.13 respectively, both P < 0.01). The hydroxyproline content of the asthma group was (459 +/- 47) microg/100 mg tissue, significantly higher than those of the BUD and control groups [(284 +/- 16) and (181 +/- 22) microg/100 mg tissue respectively, both P < 0.01]. The level of IL-4 of the asthma group was (14.4 +/- 1.12) ng/L, significantly higher than those of the BUD and control groups [(7.3 +/- 0.6) and (5.6 +/- 0.8) ng/L respectively, both P < 0.01]. The IL-13 level of the asthma group was (16.8 +/- 0.9) ng/L, significantly higher than those of the BUD and control groups [(10.6 +/- 0.9) and (5.6 +/- 0.8) ng/L respectively, both P < 0.01]. Treatment of BUD attenuated the allergen-induced airway hyperresponsiveness (AHR) and structural changes in airway, and decreased the values of the airway scores of goblet cells, and levels of hydroxyproline, IL-4, and IL-13 in comparison with the asthma group (all P < 0.01). Repeated OVA challenge resulted in an upregulation of the expression levels of alpha-SMA, JAK1 and STAT6 protein and alpha-SMA mRNA, while use of BUD suppressed these changes. The changes of JAK1 and STAT6 expression were correlated significantly with the changes in the airway score of goblet cells, hydroxyproline content, expression level of alpha-SMA, and levels of IL-4 and IL-13 in BALF (all P < 0.05). BUD ameliorates the progression of airway remodeling following prolonged allergen challenge via regulation of JAK1/STAT6 signal pathway.