After pneumonectomy (PNX) in adult dogs, increased mechanical strain of the remaining lung provides the major signal for compensatory alveolar growth and tissue remodeling. The uniformity of strain and growth response in remaining lobes varies with the size and location of resection. At lower levels of resection and strain (e.g., left PNX) compensation occurs by recruitment of existing reserves and structural remodeling. A threshold of strain must be exceeded before new tissue growth is invoked. As lung strain exceeds this threshold (e.g., right PNX), recruitment of existing reserves, tissue remodeling and new alveolar tissue growth keep maximal O2 uptake above 80% of normal. As more lung is resected, alveolar septal volume and surface continue to expand while the number of conducting airways and blood vessels remain fixed, resulting in dissociated or """"""""dysanaptic"""""""" growth. As strain-induced growth approaches an upper limit (threshold), dysanaptic growth limits compensation by 1) raising power requirements of breathing and 2) reducing cardiac output. We have shown that post-PNX lobar strain varies widely within the remaining lung. The regional location of these 2 thresholds will also vary. In some lobes the threshold for alveolar growth initiation will not be reached. In other lobes the threshold for dysanaptic growth will be exceeded to limit further compensation. We hypothesize that a) non-uniform lobar strain distribution weakens the response of the remaining lung to a given mechanical signal; and b) exercise training promotes more uniform distribution of lobar strain thereby optimizing overall compensation. We will characterize lobar strain by serial CT scans in adult dogs before and after undergoing different degrees of lung resection. Lobar air, vascular and extravascular lung tissue volumes will be assessed along with dimensions of the airway and thorax. We will relate lobar strain to overall functional compensation, to regional activation of selected growth factor pathways and terminally to local changes in acinar and airway structure assessed by morphometry. Separate cohorts will be either exercise trained or remain sedentary for 6 months post-PNX to determine if training alters lobar strain distribution or structure-function adaptation. These studies will define fundamental signal-response relationships within a well-established model of strain-induced compensatory lung growth, and will explore a therapeutic intervention to potentially enhance the endogenous response.
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