IL-17A in the peripheral lung of patients with severe to very severe COPD may contribute to disease progression and development of lymphoid follicles via activation of CXCL12.

Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-β1) levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (α-SMA) and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease.

IL-17A is induced during NTHi-associated AECOPD. Functionally, IL-1R1-dependent IL-17A is required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke. Targeting IL-17A in AECOPD may thus be beneficial to reduce neutrophil recruitment to the airways.

The link between respiratory complications in prematurely born infants and susceptibility for developing chronic obstructive pulmonary disease (COPD) is receiving increasing attention. We have previously found that CCAAT/enhancer binding protein (C/EBP) activity in airway epithelial cells of COPD patients is decreased compared to healthy smokers, suggesting a previously unknown role for C/EBPs in COPD pathogenesis.To investigate the role of the transcription factor C/EBPa in lung development and its potential role in COPD, mice with a lung epithelial-specific disruption of the C/EBPa gene (Cebpa DLE ) were generated using Cre-mediated excision, and the resulting pathology was studied during development and into adulthood. Cebpa DLE mice exhibit impaired lung development and epithelial differentiation, as well as affected vascularity. Furthermore, Cebpa DLE mice that survive until adulthood develop a severe pathological picture with irregular emphysema; bronchiolitis, including goblet cell hyperplasia, bronchiolar metaplasia, fibrosis and mucus plugging; and an inflammatory cell and gene expression profile similar to COPD. Cebpa DLE mice display lung immaturity during development, and adult Cebpa DLE mice develop a majority of the histopathological and inflammatory characteristics of COPD. Cebpa DLE mice could thus provide new valuable insights into understanding the long-term consequences of lung immaturity and the link to susceptibility of developing COPD.

BackgroundFractional exhaled nitric oxide is elevated in allergen-provoked asthma. The cellular and molecular source of the elevated fractional exhaled nitric oxide is, however, uncertain.ObjectiveTo investigate whether fractional exhaled nitric oxide is associated with increased airway epithelial inducible nitric oxide synthase (iNOS) in allergen-provoked asthma.MethodsFractional exhaled nitric oxide was measured in healthy controls (n = 14) and allergic asthmatics (n = 12), before and after bronchial provocation to birch pollen out of season. Bronchoscopy was performed before and 24 hours after allergen provocation. Bronchial biopsies and brush biopsies were processed for nitric oxide synthase activity staining with nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), iNOS immunostaining, or gene expression analysis of iNOS by real-time PCR. NADPH-d and iNOS staining were quantified using automated morphometric analysis.ResultsFractional exhaled nitric oxide and expression of iNOS mRNA were significantly higher in un-provoked asthmatics, compared to healthy controls. Allergic asthmatics exhibited a significant elevation of fractional exhaled nitric oxide after allergen provocation, as well as an accumulation of airway eosinophils. Moreover, nitric oxide synthase activity and expression of iNOS was significantly increased in the bronchial epithelium of asthmatics following allergen provocation. Fractional exhaled nitric oxide correlated with eosinophils and iNOS expression.ConclusionHigher fractional exhaled nitric oxide concentration among asthmatics is associated with elevated iNOS mRNA in the bronchial epithelium. Furthermore, our data demonstrates for the first time increased expression and activity of iNOS in the bronchial epithelium after allergen provocation, and thus provide a mechanistic explanation for elevated fractional exhaled nitric oxide in allergen-provoked asthma.

Cigarette smoke has a broad impact on the mucosal environment with the ability to alter host defense mechanisms. Within the context of a bacterial infection, this altered host response is often accompanied by exacerbated cellular inflammation, characterized by increased neutrophilia. The current study investigated the mechanisms of neutrophil recruitment in a murine model of cigarette smoke exposure and, subsequently, a model of both cigarette smoke exposure and bacterial infection. We investigated the role of IL-1 signaling in neutrophil recruitment and found that cigarette smoke-induced neutrophilia was dependent on IL-1α produced by alveolar macrophages. In addition to being the crucial source of IL-1α, alveolar macrophages isolated from smoke-exposed mice were primed for excessive IL-1α production in response to bacterial ligands. To test the relevance of exaggerated IL-1α production in neutrophil recruitment, a model of cigarette smoke exposure and nontypeable Haemophilus influenzae infection was developed. Mice exposed to cigarette smoke elaborated an exacerbated CXCR2-dependent neutrophilia in response to nontypeable Haemophilus influenzae. Exacerbated neutrophilia was dependent on IL-1α priming of the pulmonary environment by cigarette smoke as exaggerated neutrophilia was dependent on IL-1 signaling. These data characterize a novel mechanism of cigarette smoke priming the lung mucosa toward greater IL-1–driven neutrophilic responses to bacteria, with a central role for the alveolar macrophage in this process.

Our data suggest a previously unknown role for C/EBPβ and the airway epithelium in mediating inflammatory and innate immune responses to cigarette smoke.

Background: CCAAT/enhancer‐binding protein (C/EBP)α is crucial for lung development and differentiation of the pulmonary epithelium. Conversely, no lung defects have been observed in C/EBPβ‐deficient mice, although C/EBPβ trans‐activate pulmonary genes by binding to virtually identical DNA‐sequences as C/EBPα. Thus, the pulmonary phenotype of mice lacking C/EBPβ could be explained by functional replacement with C/EBPα. We investigated whether C/EBPα and C/EBPβ have overlapping functions in regulating lung epithelial differentiation during organogenesis. Epithelial differentiation was assessed in mice with a lung epithelial–specific (SFTPC‐Cre‐mediated) deletion of C/EBPα (CebpaΔLE), C/EBPβ (CebpbΔLE), or both genes (CebpaΔLE; CebpbΔLE). Results: Both CebpaΔLE mice and CebpaΔLE; CebpbΔLE mice demonstrated severe pulmonary immaturity compared to wild‐type littermates, while no differences in lung histology or epithelial differentiation were observed in CebpbΔLE mice. In contrast to CebpaΔLE mice, CebpaΔLE; CebpbΔLE mice also displayed undifferentiated Clara cells with markedly impaired protein and mRNA expression of Clara cell secretory protein (SCGB1A1), compared to wild‐type littermates. In addition, ectopic mucus‐producing cells were observed in the conducting airways of CebpaΔLE; CebpbΔLE mice. Conclusions: Our findings demonstrate that C/EBPα and C/EBPβ play pivotal, and partly overlapping roles in determining airway epithelial differentiation, with possible implications for tissue regeneration in lung homeostasis and disease. Developmental Dynamics 241:911–923, 2012. © 2012 Wiley Periodicals, Inc.