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Background
Bronchopulmonary dysplasia (BPD) still represents a major morbidity of preterm birth [1]. It has been deemed an evolving process of chronic lung inflammation and lung injury. Besides structural immaturity, pre- and postnatal inflammation has been considered a principle mechanism in the initiation and aggravation of BPD. Various adverse conditions, such as mechanical ventilation, may amplify the inflammatory response and contribute to severe lung injury [2-9]. The latter is characterized by impaired alveolarization and impaired vascular development and culminates in severe airway remodeling with interstitial and vascular fibrosis [10-13].
Connective tissue growth factor (CTGF), also known as CCN family protein 2 (CCN2), is a matricellular protein, that plays a key role in tissue development and remodeling, interacting with a variety of other growth factors, such as transforming growth factor (TGF)-? [14]. It has been deemed a critical role in the pathogenesis of various forms of adult pulmonary fibrosis and vascular disease [15, 16]. Both growth factors have been acknowledged as central mediators promoting and accelerating fibrosis as well as pathological airway remodeling [12, 17, 18]. In pulmonary fibrosis, CTGF seems to be predominantly localized to proliferating alveolar type II (ATII) cells and activated fibroblasts [19] and, thus, may play a central part as pro-fibrotic mediator. In the neonatal lung, increased expression of CTGF seems to be induced by mechanical ventilation and hyperoxia, suggesting that CTGF may contribute to the pathogenesis of BPD [20-22]. In addition, in neonatal mice, a conditional overexpression of CTGF in ATII cells was shown to induce lung fibrosis, resulting in a BPD-like architecture [10]. These data may underline a key role of CTGF in tissue fibrosis and airway remodeling, both displaying important features of BPD. However, underlying mechanisms of the transcriptional modulation of CTGF, considered to be its predominant form of regulation [23], may be complex and might depend on the particular disease or the affected organ [24]. While TGF-? seems to induce CTGF gene expression [23], tumor necrosis factor alpha (TNF-?), among other factors, has been shown to reduce expression of CTGF [25].
Besides, there is considerable evidence of an even more complex interplay of CTGF and TGF-? [26]. CTGF seems to enhance the impact of TGF-? in the context of pro-inflammation [27]. It may act as a co-factor for...