An imbalance in C/EBPs and increased mitochondrial activity in asthmatic airway smooth muscle cells: novel targets in asthma therapy?

Abstract

The asthma prevalence was increasing over the past two decades worldwide. Allergic asthma, caused by inhaled allergens of different origin or by food, is mediated by inflammatory mechanisms. The action of non-allergic asthma, induced by cold air, humidity, temperature or exercise, is not well understood. Asthma affects up to 15% of the population and is treated with anti-inflammatory and muscle relaxing drugs which allow symptom control. Asthma was first defined as a malfunction of the airway smooth muscle, later as an imbalanced immune response of the lung. Recent studies placed the airway smooth muscle again into the focus. Here we summarize the molecular biological basis of the deregulated function of the human airway smooth muscle cell as a cause or important contributor to the pathology of asthma. In the asthmatic human airway smooth muscle cells, there is: (i) a deregulation of cell differentiation due to low levels of maturation-regulating transcription factors such as CCAAT/enhancer binding proteins and peroxisome proliferator-activated receptors, thereby reducing the cells threshold to proliferate and to secrete pro-inflammatory cytokines under certain conditions; (ii) a higher basal energy turnover that is due to increased number and activity of mitochondria; and (iii) a modified feedback mechanism between cells and the extracellular matrix they are embedded in. All these cellular pathologies are linked to each other and to the innate immune response of the lung, but the sequence of events is unclear and needs further investigation. However, these findings may present the basis for the development of novel curative asthma drugs.

Figure 1

The contribution of airway smooth muscle cells to the pathology of asthma. Dotted arrows with a question mark indicate that this possible link is hypothetical at this stage. C/EBP, CCAAT/enhancer binding protein; CTGF, connective tissue growth factor; IgE, immunoglobulin E.

Figure 2

The possible impact of dysregulated mitochondria on asthma and their regulation by C/EBP-isoforms. ADP, adenosinediphosphate; C/EBP, CCAAT/enhancer binding protein; mTOR, mammalian target of rapamycin; NAD, nicotinamidadenindinucleotid; NADPH, nicotinamidadenindinucleotidphosphate; ROS, reactive oxygen species.