Enzymatic defense, inflammation and chronic lung disease

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(Applicant's Abstract) Chronic lung disease (CLD) of the preterm infant is characterized by a chronic fibroproliferative process associated with inflammation and disruption of normal alveolarization. Multiple cytokines and chemokines have been linked to the chronic inflammatory response leading to the development of CLD in humans as well as in animal models of this disease. Collaborative efforts from the group have shown that exposure of mice to extremes of oxygen tension (from 10% to 95% oxygen) resulted in lung injury characterized by a pronounced inflammatory response with mononuclear cell infiltration and dramatic induction of inflammatory cytokines/chemokines. Of interest, hypoxic mice overexpressing heme oxygenase-1 in the lung were completely protected from both inflammation as well as pulmonary vascular remodeling, a later consequence of hypoxia. Moreover, induction of inflammatory cytokines/chemokines was drastically suppressed in HO-1 transgenic mice. In this section of the SCOR application, the investigators propose 3 specific aims to extend these studies: In Aim 1, they will characterize the developmental response of the lung to injury leading to CLD. Using the newborn mouse model, they will characterize the inflammatory and architectural changes in response to hyperoxia, hypoxia, and infection that lead to CLD-like injury and analyze the effects of HO-1 induction in these developmental responses. In Aim 2, the investigators will investigate signaling pathways and molecular mechanisms by which HO-1 modulates cellular inflammatory responses. Using molecular biological techniques, they propose to analyze specific kinase pathways and transcriptional activities mediating cellular responses to injury. In Aim 3, the investigators characterize potential crosstalk between HO-1 signaling and CLD-relevant pathways in collaboration with SCOR investigators. Using transgenic mice or knockout models characterized by each member of the SCOR, they will investigate mechanisms of airway hyper-responsiveness in response to hypoxia, hyperoxia and infection; evaluate the role of chemokines in the animal models of CLD-like injury; and validate the animal findings to human disease by correlating HO activity with incidence, severity and complications of CLD in ventilated premature newborns. In achieving these aims, they will gain a better understanding of the immature lung?s defenses to injury and may be able to identify specific genes and pathways to target therapy for CLD.