Modulators of inflammation in Bronchopulmonary Dysplasia

Abstract

Over 50 years after its first description, Bronchopulmonary Dysplasia (BPD) remains a devastating pulmonary complication in preterm infants with respiratory failure and develops in 30-50% of infants less than 1000-gram birth weight. It is thought to involve ventilator- and oxygen-induced damage to an immature lung that results in an inflammatory response and ends in aberrant lung development with dysregulated angiogenesis and alveolarization. Significant morbidity and mortality are associated with this most common chronic lung disease of childhood. Thus, any therapies that decrease the incidence or severity of this condition would have significant impact on morbidity, mortality, human costs, and healthcare expenditure. It is clear that an inflammatory response and the elaboration of growth factors and cytokines are associated with the development of BPD. Numerous approaches to control the inflammatory process leading to the development of BPD have been attempted. This review will examine the anti-inflammatory approaches that are established or hold promise for the prevention or treatment of BPD.

Figure 1:. Pathogenesis of BPD and anti-inflammatory Interventions

Lung development occurs in five distinct but overlapping phases. Several antenatal factors can adversely influence lung development and include intrauterine growth restriction (IUGR), prolonged preterm rupture of membranes (PPROM) and chorioamnionitis. These factors all appear to activate the innate immune system and increase the expression of cytokines that result in inflammation. Among a multitude of effects, antenatal corticosteroid therapy accelerates lung development, in particular, the surfactant system. Preterm birth is often associated with initiation of ventilation and exposure to oxygen and an increased incidence of infections, all of which also result in the activation of the innate immune system and the elaboration of cytokines that drive inflammation. Lung development now has to occur ex-utero, is influenced by this inflammatory milieu, and results in an inhibition of alveolar and vascular development recognized as BPD. A number of strategies and approaches have been investigated to abrogate or dampen the inflammatory response. These are indicated in bold boxes in the figure and are discussed in the review. For additional abbreviations, please the text.

Figure 2:. Activation of the NLRP3 inflammasome and the utility of its blockade in the prevention of BPD

Interleukin 1 beta (IL1ß) is a master regulator of inflammation. Endogenous danger associated molecular patterns (DAMPs) activate the innate immune system to elaborate IL1ß. One such DAMP is low molecular weight hyaluronan (LMW HA), which is formed by the fragmentation of HMW HA by oxidative stress. Acting through the HA receptors RHAMM and CD44, LMW HA activates the transcription factor NFκB to transcriptionally upregulate pro-IL1ß. At the same time, the NLRP3 inflammasome is also activated which results in the formation of active caspase 1 which cleaves pro-IL1ß to IL1ß to initiate inflammation. The development of HA-binding peptides holds promise in interfering with the LMW HA-RHAMM-CD44 complex to prevent activation of the NLRP3 inflammasome system, which would be predicted to prevent the formation of IL1ß. Recombinant IL1 receptor antagonist will block the effects of IL1ß to also prevent its downstream actions. For additional abbreviations, please see the text.