a-method-for-generating-pulmonary-neutrophilia-using-aerosolized

A Method for Generating Pulmonary Neutrophilia Using Aerosolized Lipopolysaccharide

Acute lung injury (ALI) is a severe disease characterized by alveolar neutrophilia, with limited treatment options and high mortality. Experimental models ...

Karolinska Institutet

Cigarette smoke is the major cause of chronic obstructive pulmonary disease and lung cancer. The mechanisms by which smoking induces pulmonary dysfunction are complex, involving stress from toxic components and inflammatory responses. Although CCCAAT/enhancer-binding protein (C/EBP)-β is known as a key intracellular regulator of inflammatory signaling, its role in pulmonary inflammation has not been established.

Lung epithelial CCAAT/enhancer-binding protein-β is necessary for the integrity of inflammatory responses to cigarette smoke.

Glucocorticoids (GCs) have been successfully used in the treatment of inflammatory diseases for decades. However, there is a relative GC resistance in several inflammatory lung disorders, such as chronic obstructive pulmonary disease (COPD), but still the mechanism(s) behind this unresponsiveness remains unknown. Interaction between transcription factors and the GC receptor contribute to GC effects but may also provide mechanisms explaining steroid resistance. CCAAT/enhancer-binding protein (C/EBP) transcription factors are important regulators of pulmonary gene expression and have been implicated in inflammatory lung diseases such as asthma, pulmonary fibrosis, cystic fibrosis, sarcoidosis, and COPD. In addition, several studies have indicated a role for C/EBPs in mediating GC effects. In this review, we discuss the different mechanisms of GC action as well as the function of the lung-enriched members of the C/EBP transcription factor family. We also summarize the current knowledge of the role of C/EBP transcription factors in mediating the effects of GCs, with emphasis on pulmonary effects, and their potential role in mediating GC resistance.

The emerging role of C/EBPs in glucocorticoid signaling: lessons from the lung.

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 (Cebpa(ΔLE) ), C/EBPβ (Cebpb(ΔLE) ), or both genes (Cebpa(ΔLE) ; Cebpb(ΔLE) ).

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ.

The inflammatory processes associated with pulmonary disorders remains incompletely understood. CCAAT/enhancer-binding protein (C/EBP)β is implicated in inflammatory lung disorders as well as in β(2)-adrenoceptor signaling. We hypothesized that C/EBPβ in the lung epithelium contributes to lipopolysaccharide (LPS)-induced airway neutrophilia and expression of neutrophil chemoattractant chemokine (C-X-C) motif ligand (CXCL)1, as well as the suppressive effects of long-acting β(2)-agonists (LABAs) and glucocorticoids (GCs). To investigate this, mice with a lung epithelial-specific deletion of C/EBPβ (Cebpb(ΔLE)) and control littermates (Cebpb(fl/fl)) were pre-treated with a LABA, formoterol and/or a GC, budesonide, and challenged with LPS. Inflammatory cell recruitment in bronchoalveolar lavage (BAL) fluid and pulmonary expression of inflammatory mediators were investigated. In addition, the ability of formoterol to increase C/EBP transactivation was assessed in vitro. LPS-challenged Cebpb(ΔLE) mice exhibited fewer BAL neutrophils and lower pulmonary expression of CXCL1 versus Cebpb(fl/fl) mice. Suppression of LPS-induced neutrophilia by formoterol was impaired in Cebpb(ΔLE) mice and Cxcl1 expression was increased. However, suppression of the neutrophilia by budesonide with/without formoterol was preserved. Further studies indicated that C/EBP transactivation was increased by the cAMP elevating agent forskolin and formoterol in a β(2)-adrenoceptor dependent manner. Thus, C/EBPβ in the lung epithelium contributes to LPS-induced CXCL1 expression and airway neutrophilia as well as to the suppressive effects of formoterol. Reduced C/EBPβ activity, observed in smokers with chronic obstructive pulmonary disease, may impair the responsiveness to LABAs when used without GCs.

Lung epithelial-C/EBPβ contributes to LPS-induced inflammation and its suppression by formoterol.

Premature infants frequently develop bronchopulmonary dysplasia (BPD). Lung immaturity and impaired epithelial differentiation contribute together with invasive oxygen treatment to BPD onset and disease progression. Substantial evidence suggests that prematurity is associated with long term pulmonary consequences. Moreover, there is increasing concern that lung immaturity at birth may increase the risk of developing chronic obstructive pulmonary disease (COPD). The mechanisms contributing to this phenomenon remains unknown, largely as a consequence of inadequate experimental models and clinical follow-up studies. Recent evidence suggests that defective transcriptional regulation of epithelial differentiation and maturation may contribute to BPD pathogenesis as well as early onset of COPD. The transcriptional regulators CCAAT/enhancer-binding protein (C/EBP)α and C/EBPβ, SMAD family member (Smad)3, GATA binding protein (GATA)6, and NK2 homeobox (NKX)2-1 are reported to be involved in processes contributing to pathogenesis of both BPD and COPD. Increased knowledge of the mechanisms contributing to early onset COPD among BPD survivors could translate into improved treatment strategies and reduced frequency of respiratory disorders among adult survivors of BPD. In this paper, we introduce critical transcriptional regulators in epithelial differentiation and summarize the current knowledge on the contribution of impaired epithelial maturation to the pathogenesis of inflammatory lung disorders.

A Relationship between Epithelial Maturation, Bronchopulmonary Dysplasia, and Chronic Obstructive Pulmonary Disease.

Fractional exhaled nitric oxide is elevated in allergen-provoked asthma. The cellular and molecular source of the elevated fractional exhaled nitric oxide is, however, uncertain.

Article	Year
Lung epithelial CCAAT/enhancer-binding protein-β is necessary for the integrity of inflammatory responses to cigarette smoke. American journal of respiratory and critical care medicine\| PubMed ID: 21562127	2011
The emerging role of C/EBPs in glucocorticoid signaling: lessons from the lung. The Journal of endocrinology\| PubMed ID: 22045755	2012
Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ. Developmental dynamics : an official publication of the American Association of Anatomists\| PubMed ID: 22411169	2012
Lung epithelial-C/EBPβ contributes to LPS-induced inflammation and its suppression by formoterol. Biochemical and biophysical research communications\| PubMed ID: 22634316	2012
A Relationship between Epithelial Maturation, Bronchopulmonary Dysplasia, and Chronic Obstructive Pulmonary Disease. Pulmonary medicine\| PubMed ID: 23320163	2012
Elevated exhaled nitric oxide in allergen-provoked asthma is associated with airway epithelial iNOS. PloS one\| PubMed ID: 24587191	2014

Abraham B. Roos

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