Loss of alveolar capillary membrane integrity leads to Activation of Th2 cells

During the tissue injury-mediated immune response, naïve CD4+ T helper (Th) cells differentiate into two major functional subsets: Th1 and Th2 type. Both Th1 and Th2 secrete distinct cytokines that promote proliferation and differentiation of their respective T cell population and inhibit proliferation and differentiation of the opposing subset. Th2 cytokines including pro-inflammatory and fibrotic mediators such as GATA binding protein 3 (GATA-3), Interleukin (IL)-13 and Arginase (Arg)-1 are increased in lung-irradiation induced fibrosis (Brush et al., 2007; Han et al., 2011; Wynn, 2004). Th2 immune response is implicated in allergen-mediated lung fibrosis. Meta-analysis of gene expression data collected from lungs of mice exposed to various fibrogenic substances including multi-walled carbon nanotubes (MWCNTs), showed that the expression and function of Th2 response associated genes and pathways are altered in fibrotic lungs (Nikota et al., 2016). Exposure of mice lacking Signal transducer and activator of transcription 6 (STAT6) to MWCNTs resulted in abrogated expression of Th2 genes and reduced lung fibrosis (Nikota et al., 2017). IL-4, the archetypal Th2 cytokine is a pro-fibrotic cytokine and is elevated in idiopathic pulmonary fibrosis (IPF) and lung fibrosis. Overexpression of pro-fibrotic Th2 cytokine IL-13 results in sub-epithelial fibrosis with eosinophilic inflammation (Wilson and Wynn, 2009). In silica-induced pulmonary fibrosis in mice, T regulatory lymphocytes are recruited to the lungs where they increase expression of Platelet-derived growth factor (PDGF) and Transforming growth factor beta (TGF-β) (Maggi et al., 2005). Chemokines associated with the Th2 response in airway epithelial cells include C-C motif chemokine ligand (CCL)1, CCL17, CCL20, and CCL22 (Lekkerkerker et al., 2012).