The role of macrophage derived matrix metalloproteinase 1, 2 and 9 in the development of primary spontaneous pneumothorax : cause or consequence

Primary spontaneous pneumothorax (PSP) is a common clinical problem affecting previously healthy individuals. It is a condition in which air is present in the pleural space in the absence of a precipitating event such as trauma or lung disease (Painter et al., 2005). The pathogenesis is poorly understood but is related to the rupture of apical pleural blebs. The tissue injury that accumulates within the lung prior to PSP is thought to arise through the action of activated alveolar macrophages. These cells, once stimulated, release matrix degrading metalloproteinases within the lung postulated to result in increased breakdown of collagen and elastin causing alveolar destruction, distal emphysema and formation of blebs. The proteases of most interest are a family of zinc dependant proteinases, collectively known as matrix metalloproteinases, (MMP' s). Of particular interest in this setting are MMP's 1, 2 and 9 due to their association with matrix degradation and remodelling and their ability to digest both type I and type IV Collagen. The study aims to investigate whether PSP occurs as a result of increased expression of MMP-1, MMP-2 and MMP-9 from activated alveolar macrophages. Immunohistochemistry was performed on apical lung tissue samples from 51 patients presenting with PSP to determine the level of expression of MMP-1, MMP-2 and MMP-9. Semiquantitative analysis revealed decreased expression ofMMP-2 and MMP-9 in comparison to controls. No alteration in MMP-1 expression was observed in comparison to controls. In vitro experiments were conducted using two cell lines; A549 a lung type 11 epithelial cell line and U937 a human macrophage cell line to map physiological responses to varying environmental stimuli, postulated to represent risk factors of PSP. In addition evaluation of cytokine expression was performed on these samples to further assess the effects of the cellular stimulation The A549 cell line was most sensitive to treatments with CO2 and tobacco particulate while the U937 cell line showed fluctuating responses to all of the treatments investigated. Despite this, it was not possible to positively correlate the production ofMMP-l, 2 and 9 in the individual cell treatments with that observed for the in-vivo patient samples. Measurement of cytokine expression demonstrated a varying response in both A549 and U937 cell lines, the greatest of which was observed for Interleukin 8 (IL-8) and Tumour Necrosis Factor a (TNF-a). Decreased levels ofMMP-2 and MMP-9 may limit the deposition of matrix construct causing a weakness in type IV collagen. This decrease in MMP activity may alter the proteolysis/antiproteolysis balance reflecting defective repair of the extracellular matrix. Sustained production of MMP-l under these conditions may further contribute, pushing the remodelling process towards matrix destruction further promoting the tissue damage associated with bleb formation.EThOS - Electronic Theses Online ServiceGBUnited Kingdo