Altered Th1/Th2 commitment contributes to lung senescence in CXCR3-deficient mice

Abstract

Aging is an inevitable process associated with immune imbalance, which is characterized by a progressive functional decline in major organs, including lung. However, effects of altered Th1/Th2 commitment on lung senescence are largely unknown. To examine effects of altered Th1/Th2 balance on lung aging, we measured proportions of Th1 and Th2 cells and expression of cytokines, chemokines, collagen deposition and other relevant physiological and pathological parameters in 2- and 20-months-old (mo) CXCR3-deficient (CXCR3(-/-)) C57BL/6J mice compared with wild-type (WT) mice. There was a significant weight-loss observed in 20-mo CXCR3(-/-) mice compared with the same aged WT group. Although lung function and structure changed with age in both groups, central airway resistance (Rn), tissue elastance (H) and damping (G) were significantly lower in 20-mo CXCR3(-/-) mice than those of WT mice. In contrast, the whole lung volume (V(L)), the mean linear intercept length of alveolar (L(m)), and the total lung collagen content were significantly elevated in 20-mo CXCR3(-/-) mice. With aging, the lungs of WT mice had typical Th1-type status (increased population of Th1 cells and concentrations of cytokine IFN-γ and CXCR3 ligands) while CXCR3(-/-) mice showed Th2-type polarization (decreased proportion of Th1 cells and concentrations of CXCR3 ligands but increased level of IL-4). Our data suggest that Immunosenescence is associated with lung aging, and that altered Th1/Th2 imbalance favors Th2 predominance in CXCR3(-/-) mice, which contributes to the process of accelerated lung aging in this model.

Keywords: B6; BALF; C57BL/6J inbred mouse strain; CCR; CXCL; CXCR; CXCR3; C–C chemokine receptor; D2; DBA/2J inbred mouse strain; ELISA; Enzyme-linked immunosorbent assay; FEV(1); FRC; FVC; G; H; H & E; I(a); I-TAC; IFN; IFN-inducible T cell α chemoattractant; IFN-γ-induced protein 10-kDa; IL; IP-10; Immunosenescence; KO; L(m); Lung aging; Lung mechanics; MIG; P(airspaces); PEEP; Rn; Sa; Th1/Th2 imbalance; V(L); WT; airway resistance; bronchoalveolar lavage fluid; chemokine (C–X–C motif) ligand; chemokine (C–X–C motif) receptor; d; forced expiratory volume in one second; forced vital capacity; functional residual capacity; hematoxylin and eosin stain; interferon; interleukin; intersections of a test line system with interalveolar septal surface; knockout; mean linear intercept length of alveolar; mo; monokine induced by IFN-γ; months old; points hitting airspaces in parenchymal volume; positive end-expiratory pressures; surface area of the alveolar; tissue damping; tissue elastance; unit length; whole lung volume; wild-type.