Pulmonary Alveolar Proteinosis (PAP) is a rare disorder in the lung environment. It is characterized by intra-alveolar accumulation of a lipid-rich material. The present standard of care for PAP is whole lung lavage (WLL), which involves serious complications and invasive measures. More effective and less invasive therapies are needed for the management of PAP, but their development has been hampered by a limited understanding of the underlying pathophysiologic processes in PAP.
Part I. GM-CSF is required for the terminal differentiation and function of alveolar macrophages but not for those of other tissue macrophages, which may explain why PAP is primarily a lung disease. GM-CSF signaling plays a particular and unique role in alveolar macrophage function and pulmonary homeostasis. Activin A, a member of the transforming growth factor-β1 (TGF-β) superfamily and is an important molecule that has been shown to be involved in maintaining cellular homeostasis. Activin A is a multifunctional cytokine which regulates a broad range of activities. Recently, studies also have suggested a role for activin A in inflammatory processes. Documentation of activin A alteration in pulmonary disease is relatively recent. Mechanisms of activin regulation in alveolar macrophages are not known.
In the present study, we show that GM-CSF regulates the expression of activin A in murine alveolar macrophages. Utilizing the c57/BI6 mice to investigate mechanistic processes, we identify downstream elements that play roles in the GM-CSF induction of activin A expression in alveolar macrophages. Our results indicate that GM-CSF induces the activation of the extracellular signal-regulated kinases (ERK1/ERK2) and the nuclear factor κB (NF-κB) pathway. Importantly, the addition of PD98059 and MG132, synthetic inhibitors of ERK1/ERK2 and NF-κB respectively, decrease the GM-CSF-induced activin A expression in alveolar macrophages.
Part II. PAP is also considered to be an autoimmune disease characterized by high levels of neutralizing antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF). The etiology of idiopathic PAP is still unknown, but investigation of the B cell repertoire is currently underway. Rituximab, a chimeric murine-human monoclonal antibody, directed against the B lymphocyte specific antigen CD20, has shown promise in a number of autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the efficacy of rituximab as an alternative therapeutic option in PAP has not previously been studied. In this open label, prospective study, we hypothesized that rituximab would deplete B-lymphocytes in PAP and improve clinical symptoms. In contrast to other clinical trials, this clinical trial evaluated rituximab's efficacy in PAP without the combination of immunosuppressive agents.
B cells were depleted post-rituximab therapy and clinical improvement was observed in 4 out of 5 PAP patients, completing six months post-rituximab treatment as measured by PaO2 improvement. B cell depletion with rituximab in PAP also had an effect on the T cells with decrease in activated T cells, but concomitant increases in FOXP3 expression, suggesting an increase in T regulatory cells. These results indicated that patients with PAP have a defective T regulatory cell compartment that can be modulated by a B cell targeted therapy. This study is the first to provide preliminary evidence on the efficacy of rituximab in PAP.
In summary, part one is the first to implicate the ERK and NF-κB pathways in GM-CSF-induced activin A expression and part two demonstrates the potential alternative therapeutic application of Rituximab in PAP patients. Overall, these studies demonstrate the important role of MAPK and NF-κB pathways in maintaining lung homeostasis, give a greater understanding of the mechanistic regulation of activin A in the lung environment and propose an alternative therapeutic approach with regard to the management of Pulmonary Alveolar Proteinosis.
|Adviser||Mary Jane Thomassen|
|School||EAST CAROLINA UNIVERSITY|
|Subjects||Cellular biology; Immunology|
About ProQuest Dissertations & Theses
With nearly 4 million records, the ProQuest Dissertations & Theses (PQDT) Global database is the most comprehensive collection of dissertations and theses in the world. It is the database of record for graduate research.
PQDT Global combines content from a range of the world's premier universities - from the Ivy League to the Russell Group. Of the nearly 4 million graduate works included in the database, ProQuest offers more than 2.5 million in full text formats. Of those, over 1.7 million are available in PDF format. More than 90,000 dissertations and theses are added to the database each year.