GEOMETRICAL MICROSTRUCTURE AND FUNCTION IN DIAPHRAGM

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The diaphragm is the principal muscle of inspiration. In respiratory disease, the degree of ventilatory and physical impairment is related, in part, to changes of diaphragm function. Treatment of chronic respiratory diseases e.g., emphysema is incumbent on our ability to better understand diaphragm function in health and the manner in which this normal function is impacted by the disease state. The interrelationships between diaphragm structure and function are in many respects poorly understood. For example, knowledge of sarcomere length and changes in sarcomere length during acute respiratory maneuvers and chronic diseases (e.g., emphysema, fibrosis) can provide insights into muscle contractile function, energetic demands, inter- and intra-regional fiber deformation, microvascular function and O2 exchange potential of the capillary bed. To date, however, there are almost no measurements of sarcomere length in the in situ diaphragm. The proposed investigations will test the hypothesis that the diaphragm operates over a "night- shifted" range of sarcomere lengths such that lengths sufficiently short to substantially impair tension development (i.e., <2.3 microns) are not attained, even at total lung capacity (TLC). One microcirculatory consequence of this behavior at lung volumes below TLC (i.e., diaphragm sarcomere length >2.3 microns) is that vessels will be stretched, their diameter decreased and consequently their flow dynamics and O2 delivery capacity impaired. The competing hypothesis is that sarcomere length will become sufficiently short at high lung volumes to potentially limit tension development, but at low lung volumes the microvasculature will not be stretched. Chronic lung diseases i.e., fibrosis, emphysema are expected to change specific aspects of diaphragm capillary-to-fiber geometrical relationships. For instance, the reduced lung volumes in fibrosis will increase sarcomere length and stretch the capillary bed thereby impairing flow, increasing flow heterogeneity and reducing O2 delivery. In emphysema, neither microvascular flow nor capillary length or volume would be expected to change. However, intrafiber diffusion distances will increase consequent to fiber hypertrophy. These investigations will apply recently developed morphometric techniques and novel physiologic approaches (i.e., microvascular PO2 determination by phosphorescence quenching, intravital microscopy) to identify acute and chronic structural changes in diaphragm capillary and fiber geometry and test the effect of these changes on microvascular flow and PO2 and also provide data necessary for modelling PO2. The ultimate goal of these investigations is to provide significant new information to facilitate a better understanding of the interrelationships between diaphragm fiber geometry and muscular and microvascular function under conditions of health and disease. This knowledge is intrinsic to our understanding of structure-function relationships in diaphragm and will enable improved treatment of patients with chronic respiratory disease.