Quantitative pathophysiology in rabbit models of early onset scoliosis and expansion thoracoplasty
Olson, John Casey
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Early onset deformity of the spine and chest wall (initiated <8 years of age) is associated with declining respiratory function and increased morbidity at adulthood relative to adolescent onset deformity of comparable severity. In young children it is presumed that inhibition of thoracic growth during late stage alveolarization leads to an irreversible loss of pulmonary growth and thoracic function. Consequently there is clinical incentive to treat children with growth-preserving therapies as early as possible. In particular thoracic reconstruction surgeries have gained clinical acceptance over the last 15 years with encouraging results, however due to the delicate nature of these patients and the absence of a proper untreated control population there is limited prospective evidence to objectively evaluate the benefits of these surgeries on respiratory health. Additionally, controversy remains with regard to the proper timing of surgical intervention and if greater gains in growth and function are achieved with treatment at an earlier age. Thus the primary aims of this current study were 1) to develop a surgical rabbit model representing early onset thoracic deformity (onset at 3 weeks postnatal) from which to characterize the natural progression of thoracic deformity in association with pulmonary growth and function, and 2) to use deformity rabbits from aim 1 to evaluate effectiveness of thoracic reconstruction, via expansion thoracoplasty, to preserve thoracic growth, pulmonary growth, and respiratory function with particular consideration regarding post-natal timing of intervention by evaluating separate early (7 weeks of age) and late (11 weeks of age) treatment cohorts. All rabbits were evaluated longitudinally until skeletal maturity (28 weeks of age) via pulmonary function testing and computed tomography (CT) imaging. Secondary aims were 3) to characterize the functional and structural respiratory heterogeneity occurring in these rabbits through evaluation of regional specific volume distributions via CT deformable-image-registration and through estimation of dynamic heterogeneity via inverse modeling of the respiratory input impedance, and 4) to evaluate the response of biological mechanisms in the alveolar microstructure in these rabbits through postmortem immunohistochemical assays for growth factors associated with angiogenesis (VEGF pathway) and cell proliferation (Ki-67 antibody). Our findings highlight the nature of pulmonary hypoplasia under restrictive conditions; the extent of respiratory growth and function at maturity was highly predictable from thoracic geometry measured at 6 weeks in untreated deformity rabbits. From this predictive knowledge gains in growth and function associated with expansion thoracoplasty are determined, our evidence suggests that treatment benefits to lung growth are largely offset by detrimental effects of surgery and early surgery could only provide improvements in severe cases where expected outcomes are very poor, benefits to late treatment rabbits were inconclusive. A forward-inverse modeling approach to link empirical data on specific volume and respiratory impedance shows that inherent structural heterogeneity limits the sensitive detection of heterogeneity originating from a disease process. Lastly post-mortem evidence of increased cellular proliferation is shown in the pulmonary parenchyma of thoracoplasty treated rabbits.
Thesis (Ph.D.)--Boston University