Asbestosis is a debilitating interstitial lung disease caused by the inhalation of asbestos fibers and characterized by inflammation and fibrosis of the alveolar interstitium. The pathogenesis of asbestosis is not well understood, but studies have indicated that an oxidant-antioxidant imbalance in the lower respiratory tract plays a critical role in the pathogenesis of asbestos-induced pulmonary injury. Extracellular superoxide dismutase (EC-SOD) is expressed in especially high levels in mammalian lungs compared to other tissues. Although the reason for this high level of EC-SOD is not well understood, studies suggest that it may play an important role in protecting from lung injuries caused by oxidative stresses. EC-SOD has a positively charged binding domain that enables it to bind to negatively charged components in the extracellular matrix of tissues. Hyaluronan is a negatively charged, high molecular weight glycosaminoglycan, found predominantly in the extracellular matrix. It normally exists in its native high molecular weight form, however, under inflammatory conditions, hyaluronan has been shown to be more polydisperse, with a significant fraction of lower molecular weight fragments. The low molecular weight fragments of hyaluronan play an important role in regulating inflammatory cell function that may contribute to inflammation and tissue injury. The hypothesis of this proposal is that EC-SOD protects against asbestos-induced lung inflammation by preventing oxidative degradation of high molecular weight hyaluronan. This proposal will utilize biochemical and histological analyses to study the role of EC-SOD in regulating hyaluronan degradation in the lungs of asbestos-treated or control mice. In addition, EC-SOD knockout and transgenic overexpressing mice will be treated with asbestos to determine the importance of EC-SOD in regulating hyaluronan degradation. We will also utilize an in vitro system to generate reactive oxygen species in the presence of purified hyaluronan to test the hypothesis that reactive oxygen species will lead to hyaluronan degradation and that EC-SOD can inhibit this fragmentation. Furthermore, the chemoattractant effects of hyaluronan fragments will be tested and EC-SOD's protective effects will be evaluated to determine if it can inhibit these chemoattractive reseponses. The studies outlined above, when complete, will elucidate a mechanism in which EC-SOD mediates inflammation in response to asbestos induced pulmonary injury. This may lead to new therapeutic interventions in inhibiting lung inflammatory reactions that occur in response to environmental health related particle exposures and provide novel information to protect public health. [unreadable] [unreadable] [unreadable]
NIH ExPorter
NIH ExPorter