| Summary: | Work presented in this thesis documents the effects of hyaluronan, a ubiquitous component of the extracellular matrix, and a major component of the provisional matrix, upon monocyte/macrophage cytokine production and survival. Specifically, hyaluronan exerted pro-inflammatory effects on monocytes, in terms of production and release of IL-1 and TNFα. This effect was not observed with other ECM components, including the proteins fibronectin, vitronectin, collagen I and the complex oligosaccharide heparan sulphate, which is structurally related to hyaluronan. Monocyte-derived macrophages also responded to hyaluronan with the production of TNFα. For macrophages, this response involved the principal hyaluronan receptor, CD44, expression of which was found to be increased during <I>in vitro</I> maturation. Hyaluronan was also found to inhibit the rate of monocyte apoptosis in the absence of other survival signals. These potentially pro-inflammatory effects of hyaluronan may have serious implications for the pathogenesis of many inflammatory disease states. The adult respiratory distress syndrome is an example of an acute inflammatory state that can progress to a chronic and maladaptive inflammatory response. Levels of hyaluronan in the bronchoalveolar lavage fluid from patients with ARDS were measured by ELISA, and were found to be significantly elevated. The presence of hyaluronan was also revealed in the alveolar interstitium of lung sections taken from patients with ARDS. Elevated levels of hyaluronan associated with ARDS may result in the escalation of inflammatory responses. One speculation based upon the work presented in this thesis is that the pro-inflammatory influence of hyaluronan on alveolar macrophage responses may be instrumental in the pathogenesis and progression of disease. Together the results presented in this thesis suggest a pivotal role for hyaluronan in the regulation of monocyte-macrophage inflammatory responses.
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