The role of neutrophil elastase in the pathogenesis of pulmonary fibrosis

• Main Author: Chua, Felix
• Published: University College London (University of London) 2006
• Subjects: 616.2407
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429168

Pulmonary fibrosis is the clinico-pathological outcome of excessive lung extracellular matrix accumulation. Although it may complicate a variety of lung diseases, the circumstances that lead to the development of pulmonary fibrosis remain poorly understood. In particular, many regulatory events controlling the inception and progression of pulmonary fibrosis remain unclear. Neutrophil elastase is a potent serine proteinase historically associated with alveolar destruction in pulmonary emphysema. However, elevated levels of neutrophil elastase have been reported in fibrotic lung disease, and pharmacological inhibition of its activity in animal models is associated with attenuated fibrotic lung damage. These observations have led to the hypothesis that excessive neutrophil elastase activity may be important to the pathogenesis of pulmonary fibrosis. In the present studies, the potential to ameliorate pulmonary fibrosis was investigated by subjecting neutrophil elastase null (NE7) mice to bleomycin treatment. Instillation of 0.05U bleomycin into these animals failed to increase lung collagen content or to induce the formation of fibrotic lung lesions. This protective effect lasted for at least 60 days following bleomycin administration. Neutrophil elastase deficiency itself was not associated with reduced severity of bleomycin-induced early lung injury or lung neutrophil influx. However, quantities of active transforming growth factor-beta (TGF-p) were significantly decreased in the lungs of bleomycin- treated NE7 mice. This finding correlated with increased lung tissue reserves of activatable TGF- P which indicates an abnormality at the level of stored latent TGF-p. The initial section of this dissertation will detail the phenotypic characteristics of bleomycin- treated neutrophil elastase null mice. Temporal changes in collagen accumulation, lung histology and indices of lung injury will be presented in subsequent chapters. The final section will contain a thorough analysis of TGF-p production, localisation and activation in the lungs of bleomycin- treated NE7" mice. Here, the hitherto unreported observation that pulmonary TGF-p activation is inhibited in vivo in the absence of neutrophil elastase will be presented. In light of these data, a novel proteolytic role for neutrophil elastase in generating active TGF-P within the repairing lung extracellular matrix will be discussed. These findings support the hypothesis that neutrophil elastase increases TGF-P activity in the repairing lung by mobilising preformed latent TGF-p stored in the extracellular matrix. Conversion of this pool of activatable TGF-P allows an augmented fibrotic response to be focused at sites of lung connective tissue repair.