Peroxisomal functions in the lung and their role in the pathogenesis of lung diseases

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KarnatiSrikanth_2019_07_01.pdf (6.3 MB)

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2018

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DOI:
http://dx.doi.org/10.22029/jlupub-14984

Abstract

The well-studied pulmonary cell types of the lung are club cells, AECII, fibroblasts, and alveolar macrophages. Therefore, in this study, peroxisomal functions were mainly investigated in these cell types, and their possible functional roles in chronic lung diseases were summarized.The morphological and functional postnatal differentiation of club cells in the mouse postnatal developmental stages (newborn, P15, and adult lung) by quantitative stereological analyses showed that 64% of the volume of bronchiolar epithelial cells from adult mice of C57BL/6J strain lining the distal airways were club cells (Karnati et al., 2016a). Furthermore, morphometric analysis demonstrated a significant increase in the number of club cells and volume of secretory granules within 15 days after birth, suggesting that the club cell is not a matured, rather fully differentiated cell, at birth, and maturation occurs postnatally (Karnati et al., 2016a). This investigation suggests that mice are excellent animal models to study the factors controlling club cell differentiation and the role of peroxisomes in the pathogenesis of pulmonary diseases (Karnati et al., 2016a).The distribution and enzymatic composition of peroxisomal proteins in epithelial cells of the distinct lung developmental stages suggested that peroxisomal antioxidative enzymes might protect the pulmonary epithelium since higher abundance of peroxisomal proteins was detected in bronchiolar (ciliated cells, club cells), alveolar (AECII), and macrophages of the lung (Karnati and Baumgart-Vogt., 2008, 2009). Since peroxisomes harbor several antioxidative enzymes, therefore SOD2 was also considered to be a peroxisomal protein in addition to mitochondria (Singh et al., 1999). However, we showed that SOD2 was never present in peroxisomes and SOD2 is a pure mitochondrial protein (Karnati et al., 2013).Indeed, club and AECII cells are very difficult to maintain in primary culture. Therefore, C22-club and T7-AECII cell cultures were established and we characterized the peroxisomal compartment and its associated metabolic signaling pathways therein (Karnati et al., 2016b). Peroxisomes in club cells and AECII play an important role in the regulation of ROS levels and nuclear receptors, suggesting that the C22- and T7-cell lines of the immortomouse lung are useful models to study the regulation and metabolic function of the peroxisomal compartment and its alterations by paracrine factors in club cells and AECII (Karnati et al., 2016b).IPF is a chronic, devastating disease, and its pathogenic mechanisms remain incompletely understood. By using human IPF and control fibroblast cultures as well as the bleomycininduced mouse lung fibrosis model, we showed that the peroxisomal compartment is severely affected and compromised in IPF, mediated by TGFbeta1 and AP1 signaling and the action of pro-inflammatory cytokines (TNFalpha and IL-6) (Oruqaj et al., 2015). Further, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-alpha activators, induced peroxisome proliferation and reduced the TGFbeta-induced myofibroblast differentiation in IPF (Oruqaj et al., 2015). Furthermore, new experimental strategies were discussed to the role of PPARgamma ligands as novel therapeutic agents for the treatment of fibrotic lung diseases (Boateng et al., 2016).We identified a new role of PPAR-independent signaling on peroxisomes in regulating the macrophage inflammatory response activated by the TLR-4 ligand LPS (Vijayan et al., 2017). 4-PBA, a PPAR-independent peroxisome proliferator, induced peroxisome proliferation in murine alveolar macrophages and suppressed pro-inflammatory cytokine release after stimulation by LPS, suggesting that peroxisomes in alveolar macrophages play an important role in the inhibition of LPS-induced pro-inflammatory response. Therefore, 4-PBA-mediated peroxisome proliferation might be a beneficial therapeutic intervention in chronic inflammatory disorders (Vijayan et al., 2017). In summary, this habilitation thesis suggests an important role of peroxisomes 1) in the differentiation process of the lung (Karnati and Baumgart-Vogt., 2009), (2) in the protective role against high oxygen concentration and oxidative stress by metabolizing ROS, and (3) in the pulmonary lipid metabolism with induction of the peroxisomal beta-oxidation of eicosanoids and thus inhibition of the inflammatory cascade (Vijayan et al., 2017). Finally, the modulation of the peroxisome compartment might be a good future treatment option for patients with IPF or chronic inflammatory diseases.

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