The long-term objective of this project is to develop new, safe and effective anti-inflammatory medication for the prevention or treatment of bronchopulmonary dysplasia (BPD). Our preliminary work, in vitro, suggests that exogenous interleukin-10 (IL-10) may be a novel substitute for the effective but unsafe regimens of past dexamethasone (DEX) therapy for BPD. The early development of BPD involves the recruitment of polymorphonuclear leukocytes (PMNs), followed by monocytes (MONOs), in association with chemokine release. Our preliminary work in LPSstimulated PMNs and MONOs of the newborn, has demonstrated that IL-10 is as potent as DEX, on an equimolar basis, with regard to inhibition of chemokine release. We have also shown that nuclear factor-KB (NF- KB), a pro-inflammatory and anti-apoptotic, pivotal transcription factor is activated by LPS, involving different mechanisms in PMNs compared to MONOs. Furthermore DEX but not IL-10 inhibits NF-KB activity, but paradoxically DEX inhibits PMN apoptosis, while the effect of IL-10 on apoptosis in the newborn is unknown. Our central hypothesis is that IL-10, via its selective molecular actions, as well as selective properties of apoptosis, will lead to more effective and safer therapy for newborns developing BPD compared to DEX. The first specific aim is to test the hypothesis that IL-10 promotes apoptosis, in vitro, as opposed to DEX, in LPS-stimulated PMNs and MONOs of the newborn. Apoptotis will be measured by cell morphology (light microscopy), caspase-3 activity, and annexin binding (flow cytometry). The second specific aim is to test the hypothesis that IL-10 is a more selective regulator of genes that control inflammation and apoptosis, compared to DEX, in LPS-activated PMNs and MONOs of the newborn. High density oligoarrays correlating to timepoints and doses of dexamethasone or IL-10 used in specific aim 1 and our preliminary chemokine studies will be employed. Our studies will provide the urgently needed, scientific underpinnings, that may advance pre-clinical testing of IL-10 for BPD or lead to further molecular studies that define critical anti-inflammatory and apoptic genes in PMNs and MONOs of the newborn. ? ?
| Kasat, K; Patel, H; Predtechenska, O et al. (2014) Anti-inflammatory actions of endogenous and exogenous interleukin-10 versus glucocorticoids on macrophage functions of the newly born. J Perinatol 34:380-5 |
| Davidson, Dennis; Zaytseva, Alla; Miskolci, Veronika et al. (2013) Gene expression profile of endotoxin-stimulated leukocytes of the term new born: control of cytokine gene expression by interleukin-10. PLoS One 8:e53641 |
| Chusid, Lina A; Pereira-Argenziano, Lucy; Miskolci, Veronika et al. (2010) Transcriptional control of cytokine release from monocytes of the newborn: effects of endogenous and exogenous interleukin-10 versus dexamethasone. Neonatology 97:108-16 |
| Citarella, Brett V; Miskolci, Veronika; Vancurova, Ivana et al. (2009) Interleukin-10 versus dexamethasone: effects on polymorphonuclear leukocyte functions of the newborn. Pediatr Res 65:425-9 |
