Our overall hypothesis is that BLP is an early mediator of lung injury, arrested alveolarization and immunodeficiency in BPD. Urine BLP levels are elevated shortly after birth in infants who develop BPD. BLP can mediate lung injury: anti-BLP blocking antibody 2A11 protects against BPD in both baboon models. We are exploring the mechanisms by which this occurs, especially pro-inflammatory cascades. Our recent data suggest that immunodeficiency might contribute to BPD: 2A11 treatment abrogates thymic cortical involution and increases thymic nurse cells, which function in negative selection against self-reactive T cells. We will test our hypothesis using five Specific Aims:
AIM 1 : To determine the optimal dosage schedule and dose-response for 2A11 in the 125d/PRN x 21 days model of BPD. We will compare 2A11 to a humanized antibombesin antibody.
AIM 2 : To determine long-term outcomes at 6 months after giving anti-BLP antibodies in the 125d/PRN model of BPD using the optimal dose and treatment schedule.
AIM 3 : To analyze normal ontogeny of the baboon immune system in lung, spleen and thymus, including both innate and acquired immunity [macrophage/dendritic cells (M/DC), endothelial cells, and T cells. Functional assays may include cell proliferation, apoptosis, expression of cell differentiation markers, cytokine production, chemotaxis, respiratory burst, phagocytosis and antigen presentation in vitro. We will also assess RNA levels for the three BLP receptors and other markers as indicated.
AIM 4 : To test the hypotheses that 125d/PRN baboons are immunodeficient, that this contributes to BPD, and that 2A11 abrogates this immunodeficiency. We will establish functional baboon immune systems in vivo in immunodeficient mice (scid-boon): Baboon immunity will be tested in the host mice + BLP, 2A11, antioxidants, or other interventions for BPD.
In AIM 5 we will determine whether greater therapeutic efficacy can be achieved using combinations of treatments shown to individually improve outcomes in the 125d/PRN model of BPD: 2A11, antioxidant mimetics, and nitric oxide (NO). We also plan collaborative studies to determine mechanisms by which 2A11 restores microvasculature formation in developing lung. This investigation should further clarify underlying cellular defects in BPD and permit the introduction of novel multi-modality treatments.
| Bao, Erik L; Chystsiakova, Anastasiya; Brahmajothi, Mulugu V et al. (2016) Bronchopulmonary dysplasia impairs L-type amino acid transporter-1 expression in human and baboon lung. Pediatr Pulmonol 51:1048-1056 |
| Subramaniam, Meera; Bausch, Christine; Twomey, Anne et al. (2007) Bombesin-like peptides modulate alveolarization and angiogenesis in bronchopulmonary dysplasia. Am J Respir Crit Care Med 176:902-12 |
| Ashour, Khalid; Shan, Lin; Lee, Jong Hwan et al. (2006) Bombesin inhibits alveolarization and promotes pulmonary fibrosis in newborn mice. Am J Respir Crit Care Med 173:1377-85 |
| Rosen, Dennis; Lee, Jong-Hwan; Cuttitta, Frank et al. (2006) Accelerated thymic maturation and autoreactive T cells in bronchopulmonary dysplasia. Am J Respir Crit Care Med 174:75-83 |
| Shan, Lin; Emanuel, Rodica L; Dewald, Denise et al. (2004) Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung. Am J Physiol Lung Cell Mol Physiol 286:L165-73 |
| Chang, Ling-Yi L; Subramaniam, Meera; Yoder, Bradley A et al. (2003) A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia. Am J Respir Crit Care Med 167:57-64 |
