RESUMO
OBJECTIVES: Eosinophilic esophagitis (EoE) is a food-triggered disease associated with esophageal fibrosis and stricture formation in a subset of patients. In the present study we used a murine model of egg (ovalbumin [OVA])-induced EoE to determine whether inhibiting transforming growth factor-ß1 (TGF-ß1) signaling through the Smad3 pathway would inhibit features of esophageal remodeling including fibrosis, angiogenesis, and basal zone hyperplasia. METHODS: Wild-type (WT) and Smad3-deficient (KO [knockout]) mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA for 1 month. Levels of esophageal eosinophils, esophageal TGF-ß1+ and vascular endothelial growth factor (VEGF)+ cells, and features of esophageal remodeling (fibrosis, angiogenesis, basal zone hyperplasia) were quantitated by immunohistochemistry and image analysis. RESULTS: OVA challenge induced a similar increase in the levels of esophageal major basic protein (MBP)+ eosinophils and esophageal TGF-ß1+ cells in WT and Smad3 KO mice. Smad3 KO mice challenged with OVA had significantly less esophageal fibrosis and esophageal angiogenesis compared with OVA-challenged WT mice. The reduced esophageal angiogenesis in Smad3 KO mice was associated with reduced numbers of VEGF+ cells in the esophagus. There was a trend toward OVA-challenged Smad3 KO to have reduced basal zone hyperplasia, but this was not statistically significant. CONCLUSIONS: In a mouse model of egg-induced EoE, Smad3-deficient mice have significantly less esophageal remodeling, especially fibrosis and angiogenesis that is associated with reduced expression of VEGF. Targeting the TGF-ß1/Smad3 pathway may be a novel strategy to reduce esophageal fibrosis and its associated complications such as esophageal strictures in EoE.
Assuntos
Esofagite Eosinofílica/metabolismo , Esofagite Eosinofílica/patologia , Esôfago/metabolismo , Esôfago/patologia , Proteína Smad3/deficiência , Animais , Modelos Animais de Doenças , Proteína Básica Maior de Eosinófilos/metabolismo , Esofagite Eosinofílica/induzido quimicamente , Eosinófilos/química , Esôfago/irrigação sanguínea , Feminino , Fibrose , Hiperplasia , Camundongos , Camundongos Knockout , Neovascularização Patológica/patologia , Ovalbumina , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Studies of AMCase inhibition in mouse models of lung eosinophilic inflammation have produced conflicting results with some studies demonstrating inhibition of eosinophilic inflammation and others not. No studies have investigated the role of AMCase inhibition in eosinophilic esophagitis (EoE). We have used a mouse model of egg (OVA) induced EoE to determine whether pharmacologic inhibition of AMCase with allosamidin reduced eosinophilic inflammation and remodeling in the esophagus in EoE. Administration of intra-esophageal OVA for 6weeks to BALB/c mice induced increased levels of esophageal eosinophils, mast cells, and features of esophageal remodeling (fibrosis, basal zone hyperplasia, deposition of the extracellular matrix protein fibronectin). Administration of intraperitoneal (ip) allosamidin to BALB/c mice significantly inhibited AMCase enzymatic activity in the esophagus. Pharmacologic inhibition of AMCase with ip allosamidin inhibited both OVA induced increases in esophageal eosinophilic inflammation and OVA induced esophageal remodeling (fibrosis, epithelial basal zone hyperplasia, extracellular matrix deposition of fibronectin). This inhibition of eosinophilic inflammation in the esophagus by ip allosamidin was associated with reduced eotaxin-1 expression in the esophagus. Oral allosamidin inhibited eosinophilic inflammation in the epithelium but did not inhibit esophageal remodeling. These studies suggest that pharmacologic inhibition of AMCase results in inhibition of eosinophilic inflammation and remodeling in the esophagus in a mouse model of egg induced EoE partially through effects in the esophagus on reducing chemokines (i.e. eotaxin-1) implicated in the pathogenesis of EoE.
Assuntos
Acetilglucosamina/análogos & derivados , Quitinases/metabolismo , Inibidores Enzimáticos/administração & dosagem , Esofagite Eosinofílica/tratamento farmacológico , Esôfago/patologia , Hipersensibilidade Imediata/tratamento farmacológico , Trissacarídeos/administração & dosagem , Acetilglucosamina/administração & dosagem , Alérgenos/imunologia , Animais , Células Cultivadas , Quimiocina CCL11/genética , Quimiocina CCL11/metabolismo , Modelos Animais de Doenças , Ovos/efeitos adversos , Esofagite Eosinofílica/induzido quimicamente , Esofagite Eosinofílica/imunologia , Esôfago/efeitos dos fármacos , Esôfago/imunologia , Feminino , Fibrose , Humanos , Hiperplasia , Hipersensibilidade Imediata/induzido quimicamente , Hipersensibilidade Imediata/imunologia , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Ovalbumina/efeitos adversos , Ovalbumina/imunologiaRESUMO
Sialic acid-binding, Ig-like lectin (Siglec)-F is highly expressed on mouse eosinophils and plays an important role in regulating levels of eosinophilic lung inflammation. In this study we investigated the mechanism of constitutive and inducible Siglec-F ligand expression by lung airway epithelial cells and inflammatory cells in wild-type (WT) and genetically altered mice (ST3Gal-III heterozygotes, Fuc-TIV/VII double null, STAT6 null). Flow cytometry demonstrated that Siglec-F ligands are constitutively expressed in vitro and in vivo in selected lung cell types (epithelial cells, eosinophils, macrophages, and mast cells, but not CD4, CD8, or B cells) and are induced in response to divergent stimuli, including innate stimuli (TLR ligands, Alternaria), Th2 cytokines (IL-4, IL-13), and adaptive immune stimuli (OVA allergen). Furthermore, studies of deficient mice demonstrated the greater importance of the sialyltransferase ST3Gal-III compared with fucosyltransferases Fuc-TIV/VII in the synthesis of the constitutive and inducible Siglec-F ligands by lung epithelial and nonepithelial cells. In keeping with this, ST3Gal-III heterozygote mice (deficient in expression of Siglec-F ligands) also had significantly enhanced OVA-induced eosinophilic airway inflammation associated with reduced eosinophil apoptosis. Reduced eosinophil apoptosis in the lung of ST3Gal-III-deficient mice is likely mediated by reduced epithelial expression of Siglec-F ligands as WT eosinophils (which highly express Siglec-F) cultured with ST3Gal-III-deficient epithelial cells (which do not express Siglec-F ligand) showed reduced eosinophil apoptosis compared with WT eosinophils cultured with WT epithelial cells. Overall, these studies demonstrate that ST3Gal-III plays an important role in Siglec-F ligand formation and eosinophil apoptosis with resultant effects on eosinophilic inflammation in the lung.
Assuntos
Antígenos de Diferenciação Mielomonocítica/imunologia , Eosinofilia/imunologia , Pneumonia/imunologia , Sialiltransferases/imunologia , Animais , Antígenos de Diferenciação Mielomonocítica/metabolismo , Apoptose/imunologia , Separação Celular , Eosinofilia/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Citometria de Fluxo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Reação em Cadeia da Polimerase , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Sialiltransferases/metabolismo , beta-Galactosídeo alfa-2,3-SialiltransferaseRESUMO
Whether hypoxia contributes to airway inflammation and remodeling in asthma is unknown. In this study we used mice exposed to a hypoxic environment during allergen challenge (simulating hypoxia during an asthma exacerbation) to investigate the contribution of hypoxia to airway inflammation and remodeling. Although neither hypoxia alone, nor OVA allergen alone, induced significant neutrophil influx into the lung, the combination of OVA and hypoxia induced a synergistic 27 fold increase in peribronchial neutrophils, enhanced expression of HIF-1α and one of its target genes, the CXC-family neutrophil chemokine KC. The combination of hypoxia and OVA allergen increased eotaxin-1, peribronchial eosinophils, lung TGB-ß1 expression, and indices of airway remodeling (fibrosis and smooth muscle) compared to either stimulus alone. As hypoxia is present in >90% of severe asthma exacerbations, these findings underscore the potential of hypoxia to potentiate the airway inflammatory response, remodeling, and accelerate the decline of lung function in asthma exacerbations.
Assuntos
Remodelação das Vias Aéreas/imunologia , Quimiocinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Ovalbumina/imunologia , Sistema Respiratório/imunologia , Fator de Crescimento Transformador beta1/imunologia , Alérgenos/imunologia , Animais , Asma/genética , Asma/imunologia , Asma/metabolismo , Brônquios/imunologia , Brônquios/metabolismo , Brônquios/patologia , Quimiocina CCL11/imunologia , Quimiocina CCL11/metabolismo , Quimiocinas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Fibrose , Expressão Gênica/imunologia , Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Neutrófilos/metabolismo , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Hypoxia-inducible factor (HIF)-1α is a master regulator of inflammatory activities of myeloid cells, including neutrophils and macrophages. These studies examine the role of myeloid cell HIF-1α in regulating asthma induction and pathogenesis, and for the first time, evaluate the roles of HIF-1α and HIF-2α in the chemotactic properties of eosinophils, the myeloid cells most associated with asthma. Wild-type (WT) and myeloid cell-specific HIF-1α knockout (KO) C57BL/6 mice were studied in an ovalbumin (OVA) model of asthma. Administration of the pharmacological HIF-1α antagonist YC-1 was used to corroborate findings from the genetic model. WT, HIF-1α, and HIF-2α KO eosinophils underwent in vitro chemotaxis assays. We found that deletion of HIF-1α in myeloid cells and systemic treatment with YC-1 during asthma induction decreased airway hyperresponsiveness (AHR). Deletion of HIF-1α in myeloid cells in OVA-induced asthma also reduced eosinophil infiltration, goblet cell hyperplasia, and levels of cytokines IL-4, IL-5, and IL-13 in the lung. HIF-1α inhibition with YC-1 during asthma induction decreased eosinophilia in bronchoalveolar lavage, lung parenchyma, and blood, as well as decreased total lung inflammation, IL-5, and serum OVA-specific IgE levels. Deletion of HIF-1α in eosinophils decreased their chemotaxis, while deletion of the isoform HIF-2α led to increased chemotaxis. This work demonstrates that HIF-1α in myeloid cells plays a role in asthma pathogenesis, particularly in AHR development. Additionally, treatment with HIF-1α inhibitors during asthma induction decreases AHR and eosinophilia. Finally, we show that HIF-1α and HIF-2α regulate eosinophil migration in opposing ways.
Assuntos
Asma/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Eosinófilos/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/imunologia , Resistência das Vias Respiratórias/imunologia , Animais , Asma/induzido quimicamente , Asma/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Eosinófilos/patologia , Feminino , Regulação da Expressão Gênica , Células Caliciformes/imunologia , Células Caliciformes/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Indazóis/farmacologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Transdução de SinaisRESUMO
Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6-deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.
Assuntos
2',5'-Oligoadenilato Sintetase/metabolismo , Fator 6 Ativador da Transcrição/metabolismo , Quimiocinas/metabolismo , Pulmão/metabolismo , Proteínas de Membrana/metabolismo , Metaloproteases/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , Fator 6 Ativador da Transcrição/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Quimiocinas/genética , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Células Epiteliais/metabolismo , Epitélio/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Interleucina-13/farmacologia , Interleucina-4/farmacologia , Pulmão/citologia , Proteínas de Membrana/genética , Metaloproteases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/farmacologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/genéticaRESUMO
The fungal allergen, Alternaria, is specifically associated with severe asthma, including life-threatening exacerbations. To better understand the acute innate airway response to Alternaria, naive wild-type (WT) mice were challenged once intranasally with Alternaria. Naive WT mice developed significant bronchoalveolar lavage eosinophilia following Alternaria challenge when analyzed 24 h later. In contrast to Alternaria, neither Aspergillus nor Candida induced bronchoalveolar lavage eosinophilia. Gene microarray analysis of airway epithelial cell brushings demonstrated that Alternaria-challenged naive WT mice had a >20-fold increase in the level of expression of found in inflammatory zone 1 (FIZZ1/Retnla), a resistin-like molecule. Lung immunostaining confirmed strong airway epithelial FIZZ1 expression as early as 3 h after a single Alternaria challenge that persisted for ≥5 d and was significantly reduced in STAT6-deficient, but not protease-activated receptor 2-deficient mice. Bone marrow chimera studies revealed that STAT6 expressed in lung cells was required for epithelial FIZZ1 expression, whereas STAT6 present in bone marrow-derived cells contributed to airway eosinophilia. Studies investigating which cells in the nonchallenged lung bind FIZZ1 demonstrated that CD45(+)CD11c(+) cells (macrophages and dendritic cells), as well as collagen-1-producing CD45(-) cells (fibroblasts), can bind to FIZZ1. Importantly, direct administration of recombinant FIZZ1 to naive WT mice led to airway eosinophilia, peribronchial fibrosis, and increased thickness of the airway epithelium. Thus, Alternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness. This may provide some insight into the uniquely pathogenic aspects of Alternaria-associated asthma.
Assuntos
Alternariose/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Eosinofilia Pulmonar/patologia , Fibrose Pulmonar/patologia , Fator de Transcrição STAT6/metabolismo , Alternaria/imunologia , Alternariose/imunologia , Alternariose/metabolismo , Animais , Separação Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/metabolismo , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT6/imunologiaRESUMO
Airway remodeling in asthma is a result of persistent inflammation and epithelial damage in response to repetitive injury. Recent studies have identified several important mediators associated with airway remodeling in asthma, including transforming growth factor-ß, interleukin (IL)-5, basic fibroblast growth factor, vascular endothelial growth factor, LIGHT, tumor necrosis factor (TNF)-α, thymic stromal lymphopoietin, IL-33, and IL-25. In addition, the epithelium mesenchymal transformation (EMT) induced by environmental factors may play an important role in initiating this process. Diagnostic methods using sputum and blood biomarkers as well as radiological interventions have been developed to distinguish between asthma sub-phenotypes. Human clinical trials have been conducted to evaluate biological therapies that target individual inflammatory cells or mediators including anti IgE, anti IL-5, and anti TNF-α. Furthermore, new drugs such as c-kit/platelet-derived growth factor receptor kinase inhibitors, endothelin-1 receptor antagonists, calcium channel inhibitors, and HMG-CoA reductase inhibitors have been developed to treat asthma-related symptoms. In addition to targeting specific inflammatory cells or mediators, preventing the initiation of EMT may be important for targeted treatment. Interestingly, bronchial thermoplasty reduces smooth muscle mass in patients with severe asthma and improves asthma-specific quality of life, particularly by reducing severe exacerbation and healthcare use. A wide range of different therapeutic approaches has been developed to address the immunological processes of asthma and to treat this complex chronic illness. An important future direction may be to investigate the role of mediators involved in the development of airway remodeling to enhance asthma therapy.
Assuntos
Resistência das Vias Respiratórias/imunologia , Asma/patologia , Inflamação/patologia , Asma/imunologia , Asma/terapia , Terapia Biológica , Citocinas , Eosinófilos , Epitélio , Humanos , Inflamação/imunologia , Inflamação/terapia , Interleucina-5 , Fator de Necrose Tumoral alfaRESUMO
OBJECTIVES: Eosinophilic esophagitis (EoE) is a disorder characterized histologically by tissue eosinophilia. Sialic acid-binding immunoglobulin-like lectin (Siglec-F) is a receptor highly expressed on mouse eosinophils and mediates eosinophilic apoptosis. We investigated whether administration of an anti-Siglec-F Ab would reduce esophageal eosinophilic inflammation and remodeling in a mouse model of egg ovalbumin (OVA)-induced EoE. SUBJECTS AND METHODS: Three groups of mice were studied (no OVA, OVA + anti-Siglec-F Ab, and OVA + isotype control Ab). Mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA. Levels of esophageal eosinophils and features of remodeling (angiogenesis, vascular endothelial growth factor expression, deposition of fibronectin, basal zone hyperplasia, and fibrosis) were quantitated by immunohistochemistry and image analysis. RESULTS: Administration of an anti-Siglec-F Ab to OVA-challenged mice significantly reduced levels of esophageal eosinophils, down to levels noted in non-OVA-challenged mice. The anti-Siglec-F Ab also reduced features of OVA-induced remodeling, including angiogenesis, basal zone hyperplasia, and fibronectin deposition. The reduced angiogenesis in anti-Siglec-F Ab-treated mice was associated with reduced numbers of vascular endothelial growth factor-positive cells in the esophagus. The anti-Siglec-F antibody did not significantly reduce esophageal fibrosis as assessed by trichrome staining. CONCLUSIONS: Administration of an anti-Siglec-F antibody significantly decreased the number of eosinophils in the esophagus in a mouse model of OVA-induced EoE. The reduction in eosinophilic inflammation was associated with a significant decrease in levels of angiogenesis, deposition of fibronectin, and basal zone hyperplasia. Studies in this pre-clinical model of EoE suggest that Siglec-F (and its human paralog Siglec-8) may be novel therapeutic targets to reduce eosinophilic inflammation in EoE.
Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos/farmacologia , Antígenos de Diferenciação Mielomonocítica/metabolismo , Esofagite Eosinofílica/terapia , Eosinófilos/patologia , Animais , Antígenos de Diferenciação Mielomonocítica/imunologia , Apoptose , Modelos Animais de Doenças , Esofagite Eosinofílica/sangue , Esofagite Eosinofílica/patologia , Eosinófilos/efeitos dos fármacos , Feminino , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica , Ovalbumina/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin ß receptor (LTßR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-ß (TGF-ß) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.
Assuntos
Remodelação das Vias Aéreas/fisiologia , Asma/fisiopatologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologia , Animais , Asma/etiologia , Asma/patologia , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/fisiologia , Interleucina-13/fisiologia , Pulmão/patologia , Pulmão/fisiopatologia , Heterotrímero de Linfotoxina alfa1 e beta2/antagonistas & inibidores , Heterotrímero de Linfotoxina alfa1 e beta2/fisiologia , Camundongos , Camundongos Knockout , Transdução de Sinais , Fator de Crescimento Transformador beta/fisiologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/deficiência , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
The role of tumor necrosis factor-α (TNF-α) in contributing to allergen induced airway remodeling in asthma is unknown. In this study we have utilized a mouse model of chronic OVA allergen induced airway remodeling to determine whether TNF p55/p75 receptor deficient mice (abbreviated TNF-R KO) had reduced levels of airway remodeling. Chronic OVA challenged WT mice had significantly increased levels of lung eosinophilic inflammation as well as features of airway remodeling including increased peribronchial fibrosis, thickness of the peribronchial smooth muscle layer, mucus expression, and deposition of extracellular matrix proteins. In contrast, TNF-R KO mice had significantly reduced levels of major basic protein positive peribronchial eosinophils and significantly reduced peribronchial fibrosis assessed by quantitating the area of peribronchial trichrome staining and total lung collagen. In addition, TNF-R KO mice had significantly reduced thickness of the peribronchial smooth muscle layer, area of peribronchial α-smooth muscle actin immunostaining, and levels of the extracellular matrix protein fibronectin. There was a non-significant trend for reduced mucus expression in TNF-R KO mice. Levels of peribronchial cells immunostaining positive for TGF-ß1 were significantly reduced in TNF-R KO mice suggesting that reduced levels of TGF-ß1 expression in TNF-R KO mice may contribute to reduced airway remodeling. Overall, this study suggests an important role for TNF-α in contributing to many features of allergen induced airway remodeling including changes in levels of peribronchial smooth muscle, subepithelial fibrosis, and deposition of extracellular matrix.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Alérgenos/farmacologia , Ovalbumina/farmacologia , Eosinofilia Pulmonar/metabolismo , Eosinofilia Pulmonar/patologia , Receptores Tipo II do Fator de Necrose Tumoral/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Receptores Chamariz do Fator de Necrose Tumoral/deficiência , Animais , Asma/metabolismo , Asma/patologia , Brônquios/metabolismo , Brônquios/patologia , Colágeno/metabolismo , Eosinófilos/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Imunoglobulina E/sangue , Interleucina-5/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muco/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/imunologia , Músculo Liso/metabolismo , Músculo Liso/patologia , Eosinofilia Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/metabolismo , Receptores Chamariz do Fator de Necrose Tumoral/imunologia , Receptores Chamariz do Fator de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Basic fibroblast growth factor (bFGF) is a cytokine that is mitogenic for fibroblasts and smooth muscle and may play a role in airway remodeling in asthma. We have used a mouse model of chronic ovalbumin (OVA) allergen-induced airway remodeling to determine whether bFGF and fibroblast growth factor receptor-1 are expressed and regulated by corticosteroids in the airway, as well as to determine whether bFGF mediates expression of another proremodeling cytokine, transforming growth factor (TGF)-ß1. METHODS: The airway levels and localization of bFGF, FGF receptor-1 and TGF-ß1 were determined by ELISA, immunohistology and image analysis in the remodeled airways of chronic OVA-challenged mice treated with either corticosteroids or diluent. In vitro cultures of bone narrow-derived macrophages were used to determine whether bFGF induced TGF-ß1 expression. RESULTS: Mice chronically challenged with OVA developed significant airway remodeling that was associated with significantly increased levels of bFGF and TGF-ß1. Immunohistochemistry demonstrated significantly increased bFGF and FGF receptor-1 expression by peri- bronchial F4/80+ cells. Double-label immunofluorescence microscopy studies demonstrated that peribronchial macrophages coexpressed bFGF and TGF-ß1. In vitro studies demonstrated that incubation of bone marrow-derived macrophages with bFGF induced expression of TGF-ß1. Mice treated with corticosteroids and subjected to chronic OVA challenge had significantly reduced levels of bFGF, FGF receptor-1, peribronchial TGF-ß1+ cells and airway remodeling. CONCLUSIONS: Overall, this study demonstrates that allergen challenge stimulates peribronchial macrophages to coexpress bFGF and TGF-ß1 and that bFGF may potentiate macrophage release of TGF-ß1 through autocrine and/or paracrine pathways.
Assuntos
Remodelação das Vias Aéreas/imunologia , Alérgenos/imunologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Macrófagos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Animais , Antígenos de Diferenciação/metabolismo , Asma/tratamento farmacológico , Asma/imunologia , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Modelos Animais de Doenças , Eosinófilos/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , VacinaçãoRESUMO
BACKGROUND: Tobacco smoking is a principal cause of COPD-emphysema (COPD-E). Whether discontinuing smoking for at least 4 years halts airway inflammation and progression of COPD-E in prior smokers is unknown. In this study we investigated whether discontinuing smoking for approximately 4 years in ex-smokers with GOLD (Global Initiative for Chronic Lung Disease) stage IIb (moderately severe) COPD-E stopped airway inflammation (ie, sputum biomarkers) and halted the progression of COPD-E on chest CT scan. METHODS: Ten ex-smokers with COPD-E who had quit smoking underwent chest CT scans to document the extent of COPD-E, assessment of lung function (FEV(1) and diffusing capacity of lung for carbon monoxide), sputum induction for biomarkers of inflammation (measured by enzyme-linked immunosorbent assay), and blood cotinine levels at baseline and approximately 4 years later. Normal healthy subjects (n = 7) and normal current smokers with no CT scan evidence of COPD-E (n = 8) served as sputum biomarker comparison groups. RESULTS: After approximately 4 years of not smoking (documented by cotinine levels), ex-smokers with COPD-E had persistent increased levels of mediators of inflammation in sputum (myeloperoxidase, leukotriene B4, IL-8, monocyte chemoattractant protein-1, matrix metalloprotease-9), which was associated with significant progression of COPD-E on chest CT scan. CONCLUSIONS: Cessation of tobacco smoking in heavy smokers with moderately severe COPD-E is associated with evidence of persistent airway inflammation and progression of COPD-E on CT scan 4 years later. Discontinuing smoking may slow the rate of progression of moderate severity COPD-E, but it does not prevent persistent airway inflammation and significant progression of COPD-E on CT scan.
Assuntos
Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Abandono do Hábito de Fumar , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Fumar/efeitos adversos , Fumar/metabolismo , Fumar/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: In this study we examined the role of Siglec-F, a receptor highly expressed on eosinophils, in contributing to mucus expression, airway remodeling, and Siglec-F ligand expression utilizing Siglec-F deficient mice exposed to chronic allergen challenge. METHODS: Wild type (WT) and Siglec-F deficient mice were sensitized and challenged chronically with OVA for one month. Levels of airway inflammation (eosinophils), Siglec-F ligand expresion and remodeling (mucus, fibrosis, smooth muscle thickness, extracellular matrix protein deposition) were assessed in lung sections by image analysis and immunohistology. Airway hyperreactivity to methacholine was assessed in intubated and ventilated mice. RESULTS: Siglec-F deficient mice challenged with OVA for one month had significantly increased numbers of BAL and peribronchial eosinophils compared to WT mice which was associated with a significant increase in mucus expression as assessed by the number of periodic acid Schiff positive airway epithelial cells. In addition, OVA challenged Siglec-F deficient mice had significantly increased levels of peribronchial fibrosis (total lung collagen, area of peribronchial trichrome staining), as well as increased numbers of peribronchial TGF-ß1+ cells, and increased levels of expression of the extracellular matrix protein fibronectin compared to OVA challenged WT mice. Lung sections immunostained with a Siglec-Fc to detect Siglec-F ligand expression demonstrated higher levels of expression of the Siglec-F ligand in the peribronchial region in OVA challenged Siglec-F deficient mice compared to WT mice. WT and Siglec-F deficient mice challenged intranasally with IL-4 or IL-13 had significantly increased levels of airway epithelial Siglec-F ligand expression, whereas this was not observed in WT or Siglec-F deficient mice challenged with TNF-α. There was a significant increase in the thickness of the peribronchial smooth muscle layer in OVA challenged Siglec-F deficient mice, but this was not associated with significant increased airway hyperreactivity compared to WT mice. CONCLUSIONS: Overall, this study demonstrates an important role for Siglec-F in modulating levels of chronic eosinophilic airway inflammation, peribronchial fibrosis, thickness of the smooth muscle layer, mucus expression, fibronectin, and levels of peribronchial Siglec-F ligands suggesting that Siglec-F may normally function to limit levels of chronic eosinophilic inflammation and remodeling. In addition, IL-4 and IL-13 are important regulators of Siglec-F ligand expression by airway epithelium.
Assuntos
Antígenos de Diferenciação Mielomonocítica/metabolismo , Eosinófilos/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pulmão/metabolismo , Muco/metabolismo , Ovalbumina/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologia , Animais , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Ligantes , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Adiponectin is a cytokine with both proinflammatory and anti-inflammatory properties that is expressed in epithelial cells in the airway in chronic obstructive pulmonary disease-emphysema (COPD-E). To determine whether adiponectin modulates levels of lung inflammation in tobacco smoke-induced COPD-E, we used a mouse model of COPD-E in which either adiponectin-deficient or wild-type (WT) mice were exposed to tobacco smoke for 6 mo. Outcomes associated with tobacco smoke-induced COPD-E were quantitated including lung inflammation [bronchoalveolar lavage (BAL) and total and differential cell count], lung mediators of inflammation (cytokines and chemokines), air space enlargement (i.e., linear intercept), and lung function (tissue elastance) in the different groups of mice. Whereas exposure of WT mice to tobacco smoke for 6 mo induced significant lung inflammation (increased total BAL cells, neutrophils, and macrophages), adiponectin-deficient mice had minimal BAL inflammation when exposed to tobacco smoke for 6 mo. In addition, whereas chronic tobacco-exposed WT mice had significantly increased levels of lung mediators of inflammation [i.e., TNF-α, keratinocyte-derived chemokine (KC), and adiponectin] as well as significantly increased air space enlargement (increased linear intercept) and decreased tissue elastance, exposure of adiponectin-deficient mice to chronic tobacco smoke resulted in no further increase in lung mediators, air space enlargement, or tissue elastance. In vitro studies demonstrated that BAL macrophages derived from adiponectin-deficient mice incubated in media containing tobacco smoke expressed minimal TNF-α or KC compared with BAL macrophages from WT mice. These studies suggest that adiponectin plays an important proinflammatory role in tobacco smoke-induced COPD-E.
Assuntos
Nicotiana/efeitos adversos , Pneumonia , Enfisema Pulmonar , Fumaça/efeitos adversos , Adiponectina/deficiência , Adiponectina/genética , Adiponectina/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/imunologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Elastase Pancreática/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/patologiaRESUMO
We have examined the role of NF-kappaB regulated genes in airway epithelium in mediating tobacco smoke induced airway inflammation in studies of CC10-Cre(tg)/Ikk beta(Delta/Delta) mice in which NF-kappaB signaling through I kappaB-kinase-beta (IKK-beta) is selectively ablated in epithelial cells in the airway. CC10-Cre(tg)/Ikk beta(Delta/Delta) mice exposed to tobacco smoke for seven days had a significant decrease in the number of BAL cells (total cells, neutrophils, and macrophages) as well as significantly reduced numbers of peribronchial cells (F4/80+ and myeloperoxidase+) compared to tobacco exposed WT mice. In addition to the reduction in peribronchial cells, CC10-Cre(tg)/Ikk beta(Delta/Delta) mice exposed to tobacco smoke had a significant decrease in the number of macrophages and neutrophils in the alveolar space suggesting that inactivation of NF-kappaB in the airway epithelium influenced the number of neutrophils and macrophages recruited to the alveolus. Levels of the NF-kappaB regulated chemokines KC and MCP-1 were significantly reduced in lungs of tobacco smoke exposed CC10-Cre(tg)/Ikk beta(Delta/Delta) mice compared to tobacco exposed WT mice. In contrast, there was no significant difference in levels of NF-kappaB regulated MIP-1 alpha between CC10-Cre(tg)/Ikk beta(Delta/Delta) and WT mice. Lung sections of tobacco smoke exposed CC10-Cre(tg)/Ikk beta(Delta/Delta) mice immunostained with KC or MCP-1 antibodies demonstrated reduced expression of these chemokines in the airway epithelium, but not in alveolar epithelium. Overall, these studies demonstrate an important role for NF-kappaB regulated genes in airway epithelium in contributing to acute tobacco smoke induced airway inflammation not only in the peribronchial space but also in the alveolar space.
Assuntos
Proteínas I-kappa B/metabolismo , Pneumonia/induzido quimicamente , Alvéolos Pulmonares/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Fumar/efeitos adversos , Animais , Contagem de Células , Células Cultivadas , Quimiocinas/biossíntese , Quimiocinas/genética , Proteínas I-kappa B/genética , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/imunologia , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pneumonia/genética , Pneumonia/metabolismo , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
As genetically engineered mutant mice deficient in single genes are usually generated on a C57BL/6 background, to study mast cell trafficking in mutant mice, we initially investigated whether mast cells accumulated in bronchi in C57BL/6 mice challenged with OVA allergen acutely or chronically for 1 to 3 months. The total number of bronchial mast cells were quantitated using toluidine blue staining in airways of different sizes, i.e. , small (<90 microm), medium (90-155 microm), or large (>150 microm) airways. Non-OVA challenged and acute OVA challenged mice (C57BL/6 and BALB/c) had no detectable bronchial mast cells. Chronic OVA challenge in BALB/c mice for 1 or 3 months induced a significant increase in the number of bronchial mast cells in small-, medium-, and large-sized airways but minimal change in the number of bronchial mast cells in C57BL/6 mice. Both BALB/c and C57BL/6 mice developed significant lung eosinophilia following acute or chronic OVA challenge. Studies of IL-9-deficient mice on a BALB/c background demonstrated a significant increase in the number of bronchial mast cells in IL-9-deficient mice suggesting that IL-9 was not required for the bronchial accumulation of mast cells. Overall, these studies demonstrate that the chronic OVA challenge protocol we have utilized in BALB/c mice provides a model to study the mechanism of bronchial mast cell accumulation and that bronchial mast cell accumulation in chronic OVA challenged mice is independent of IL-9 in this model.
Assuntos
Alérgenos/administração & dosagem , Brônquios/imunologia , Brônquios/patologia , Interleucina-9/metabolismo , Mastócitos/imunologia , Mastócitos/patologia , Animais , Asma/etiologia , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-9/deficiência , Interleucina-9/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Eosinofilia Pulmonar/etiologia , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/patologia , Especificidade da EspécieRESUMO
BACKGROUND: As passive environmental tobacco smoke (ETS) exposure in nonsmokers can increase both asthma symptoms and the frequency of asthma exacerbations, we utilized a mouse model, in which ovalbumin (OVA) + ETS induce significantly increased levels of eosinophilic airway inflammation and remodeling compared to either stimulus alone, to determine whether a Toll-like receptor-9 (TLR-9) agonist could reduce levels of airway inflammation, airway remodeling and airway hyperreactivity (AHR). METHODS: Mice treated with or without a TLR-9 agonist were sensitized to OVA and challenged with OVA + ETS for 1 month. AHR to methacholine was assessed in intubated and ventilated mice. Lung Th2 cytokines and TGF-beta(1) were measured by ELISA. Lungs were processed for histology and immunohistology to quantify eosinophils, mucus, peribronchial fibrosis and smooth muscle changes using image analysis. RESULTS: Administration of a TLR-9 agonist to mice coexposed to chronic ETS and chronic OVA allergen significantly reduced levels of eosinophilic airway inflammation, mucus production, peribronchial fibrosis, the thickness of the peribronchial smooth muscle layer, and AHR. The reduced airway remodeling in mice treated with the TLR-9 agonist was associated with significantly reduced numbers of peribronchial MBP+ and peribronchial TGF-beta(1)+ cells, and with significantly reduced levels of lung Th2 cytokines [interleukin-5 and interleukin-13] and TGF-beta(1). CONCLUSION: These studies demonstrate that TLR-9-based therapies inhibit airway inflammation, remodeling and AHR in mice coexposed to ETS and allergen who exhibit enhanced airway inflammation and remodeling.
Assuntos
Asma/tratamento farmacológico , Asma/imunologia , Eosinófilos/efeitos dos fármacos , Pulmão/metabolismo , Oligodesoxirribonucleotídeos/administração & dosagem , Receptor Toll-Like 9/agonistas , Poluentes Atmosféricos/efeitos adversos , Remodelação das Vias Aéreas/efeitos dos fármacos , Alérgenos/imunologia , Animais , Asma/metabolismo , Movimento Celular/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fibrose Pulmonar , Fumar/efeitos adversos , Fator de Crescimento Transformador beta/metabolismoRESUMO
Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab')(2) fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V(+)/CCR3(+) bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein(+)/TGF-beta(+) cells, suggesting that reduced levels of eosinophil-derived TGF-beta in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos de Diferenciação Mielomonocítica/imunologia , Eosinofilia/terapia , Inflamação/terapia , Pulmão/imunologia , Alérgenos/imunologia , Animais , Apoptose/imunologia , Eosinofilia/patologia , Eosinófilos/imunologia , Fibrose , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Inflamação/patologia , Pulmão/patologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Muco/imunologia , Ovalbumina/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
The ability of corticosteroids to reduce airway inflammation and improve lung function is significantly reduced in asthmatics who are tobacco smokers compared with asthmatics who are nonsmokers. As not only high levels of tobacco smoke exposure in active smokers, but also significantly lower levels of tobacco smoke exposure from passive environmental tobacco smoke (ETS) exposure in nonsmokers can increase both asthma symptoms and the frequency of asthma exacerbations, we utilized a mouse model to determine whether corticosteroids can reduce levels of airway inflammation, airway remodeling, and airway hyperreactivity in mice exposed to the combination of chronic ETS and ovalbumin (OVA) allergen. Chronic ETS exposure alone did not induce increases in eosinophilic airway inflammation, airway remodeling, or airway hyperreactivity. Mice exposed to chronic OVA allergen had significantly increased levels of peribronchial fibrosis, increased thickening of the smooth muscle layer, increased mucus, and increased airway hyperreactivity, which was significantly enhanced by coexposure to the combination of chronic ETS and chronic OVA allergen. Administration of corticosteroids to mice exposed to chronic ETS and OVA allergen significantly reduced levels of eosinophilic airway inflammation, mucus production, peribronchial smooth muscle thickness, airway hyperreactivity, and the number of peribronchial TGF-beta1+ cells. Overall, this study demonstrates that corticosteroids can significantly reduce levels of eosinophilic inflammation, mucus expression, airway remodeling, and airway hyperreactivity in chronic ETS-exposed mice challenged with allergen.