Role of Novel Cytokine-like Molecule Secretoglobin (SCGB) 3A2 in Lung

Division Of Basic Sciences - Nci

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Abstract

In aim to identify additional role for SCGB3A2, we focused on aging process using Scgb3a2-knockout (KO) and wild-type (WT) littermate mice. Lungs of both genotyped mice from birth to 8 weeks (postnatal period) and from 8 weeks to 2 years (aging period) were subjected to histological analysis, Victoria blue staining to evaluate elastic fibers, and lung morphometric analysis as a parameter for assessing lung function. The analyses demonstrated that the alveolar space of KO mice continuously expanded between 0.5 and 2 years of age, accompanied by increases of the mean linear intercept and destructive index, a sign of emphysema. Further, KO mouse lungs displayed inflammation associated with lymphocyte aggregate starting at 1 year of age, and the inflammation was worse than that of WT mouse lungs. A high number of lymphoma-like cells were presented in 2-year-old KO mouse lungs. Since spleen is the site of lymphocyte maturation, their spleens were histologically examined. The analysis demonstrated white pulp fusions present in both WT and KO mice older than 0.5 years, and the fusion was more severe in KO mice than in WT mice. It is to note that SCGB3A2 is not normally expressed in the spleen. Further, lymphocytes and macrophages mature in the spleen and migrate throughout the body, including the lung. In fact, we detected SCGB3A2 in serum. Therefore, it seems that numerous lymphocyte aggregation sites in the lungs of aging KO mice may have been caused by splenic abnormalities. However, the exact mechanism on how the lack of SCGB3A2 expression in lung relates to the development of splenic abnormalities remains to be understood. The expression of surfactant protein (SP)-A, SP-B, SP-C, and SP-D mRNAs in KO mouse lungs decreased with age, and after 1 year of age, the expression of most SPs was significantly lower in KO mice than in WT mice. SPs are known to participate in the homeostatic maintenance and immunity of lungs. Our findings suggest that SCGB3A2 deficiency accompanied by age-related decreases of SP levels increases the risk of emphysema in aging mice. RNAseq analysis carried out using KO vs WT mouse lungs demonstrated that KO mouse lungs have more severe inflammation and the expression of immune system-related genes was highly altered in KO mouse lungs. All these results suggest that SCGB3A2 may be required for maintaining homeostasis and immune activity in the lungs during aging, and SCGB3A2 deficiency might increase the risk of emphysema of the lung.