Modulation of lung inflammation of preterm ventilated infants: role of IL-6 trans-signalling and IL-8 isoforms

Chronic lung disease (CLD) is a common respiratory sequalae of infants born extremely premature (< 32 weeks gestational age). A persistent and poorly-resolving neutrophilic lung inflammation has been strongly implicated in the development of CLD. Pathways of resolution of lung inflammation have been poorly characterised in preterm infants. Interleukin-8 (IL-8) is an key neutrophil chemokine implicated in the pathogenesis of CLD. Longer, and less functionally potent, isoforms of IL-8 predominate the preterm circulation but their expression and function in the preterm lungs is not known. The complex of interleukin-6 (IL-6), along with the soluble IL-6 receptor (sIL-6R), initiates IL-6 trans-signalling which experimentally has demonstrated downregulation of IL-8 during acute inflammation. Expression of IL-6 trans-signalling cytokines and their functional activity in the preterm lungs have not been studied. My work shows that the concentration of sgp130, a specific inhibitor of IL-6 trans-signalling, was significantly increased in the bronchoalveolar lavage fluid (BALF) of preterm ventilated baboons, and human infants developing CLD later, compared to infants who did not. Although total IL-6 activity was detected in a specific functional assay, IL-6 trans-signalling activity could not be detected from the BALF samples or by using a complex from recombinant cytokines. I have shown that the long isoform of IL-8, IL-877 was a minor proportion of total IL-8 in the preterm ventilated BALF, although significant expression of IL-877 was detected in vitro from lung cells. Preterm BALF efficiently converted exogenously added recombinant IL-877 to shorter isoforms, mainly by the activity of serine proteases from neutrophils and the clotting cascade. BALF from CLD infants converted significantly more IL-877, compared to BALF from No-CLD infants. Among the neutrophil serine proteases, proteinase-3 (Pr-3) converted IL-877 to functionally more potent isoforms; Pr-3 antigen and thrombin activity was also significantly increased in BALF from CLD infants, making them attractive targets for intervention