Resistin-like molecule alpha (RELMα) is a secreted protein implicated in murine models of allergen-induced asthma, bleomycin-induced pulmonary fibrosis, and helminth infection. Transient pulmonary overexpression of Oncostatin M by Adenovirus vector (AdOSM) induces lung inflammation biased toward Th2 cytokines, eosinophil and alternatively activated (AA/M2) macrophage accumulation. In AdOSM-treated C57Bl/6 and BALB/c mice, we observed RELMα mRNA and protein markedly induced. RELMα is recognized as a marker of AA/M2 macrophages, and we observed by chromogenic in situ hybridization that RELMα mRNA co-expresses with the macrophage marker CD68, and RELMα mRNA was also highly induced in columnar airway epithelial cells upon AdOSM treatment. Assessing IL-6 as a comparator gp130 cytokine, AdIL-6 induced RELMα at significantly lower levels, however maximal induction of RELMα by AdOSM in C57Bl/6 mice required IL-6, assessed in IL-6–/– mice. Maximal induction of RELMα by AdOSM also required IL-33 in C57Bl/6 mice but not in BALB/c mice, assessed in IL-33–/– mice. We investigated functions of RELMα in response to OSM, in RELMα–/– mice. Inflammatory cell infiltration and Th2-associated cytokine responses were not altered in RELMα–/– in comparison to wildtype mice. However, RELMα-deficiency resulted in less accumulation of CD206+ AA/M2 macrophages, IFNγ+ Th1 cells in the lung, reduced induction of extracellular matrix gene mRNAs for COL1A1, COL3A1, MMP13, TIMP1, and reduced parenchymal alpha smooth muscle actin. RELMα–/– mice also showed less airway epithelial hyperplasia, increased epithelial cell damage/death (assessed morphologically) and increased LDH and soluble CK18 in response to AdOSM. Our findings suggest that RELMα does not modulate Th2 cytokines, but does participate in matrix deposition, airway remodelling mechanisms, and protection from inflammation-induced damage due to OSM-overexpression in lungs of C57Bl/6 mice. / Dissertation / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24875 |
| Date | January 2019 |
| Creators | Ho, Lilian |
| Contributors | Richards, Carl, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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