Abstract
Lung aging is characterized by lung function impairment, ECM remodeling and airspace enlargement. Tenascin-C (TNC) is a large extracellular matrix (ECM) protein with paracrine and autocrine regulatory functions on cell migration, proliferation and differentiation. This matricellular protein is highly expressed during organogenesis and morphogenetic events like injury repair, inflammation or cancer. We previously showed that TNC deficiency affected lung development and pulmonary function, but little is known about its role during pulmonary aging. In order to answer this question, we characterized lung structure and physiology in 18 months old TNC-deficient and wild-type (WT) mice. Mice were mechanically ventilated with a basal and high tidal volume (HTV) ventilation protocol for functional analyses. Additional animals were used for histological, stereological and molecular biological analyses. We observed that old TNC-deficient mice exhibited larger lung volume, parenchymal volume, total airspace volume and septal surface area than WT, but similar mean linear intercept. This was accompanied by an increase in proliferation, but not apoptosis or autophagy markers expression throughout the lung parenchyma. Senescent cells were observed in epithelial cells of the conducting airways and in alveolar macrophages, but equally in both genotypes. Total collagen content was doubled in TNC KO lungs. However, basal and HTV ventilation revealed similar respiratory physiological parameters in both genotypes. Smooth muscle actin (α-SMA) analysis showed a faint increase in α-SMA positive cells in TNC-deficient lungs, but a marked increase in non-proliferative α-SMA + desmin + cells. Major TNC-related molecular pathways were not up- or down-regulated in TNC-deficient lungs as compared to WT; only minor changes in TLR4 and TGFβR3 mRNA expression were observed. In conclusion, TNC-deficient lungs at 18 months of age showed exaggerated features of the normal structural lung aging described to occur in mice between 12 and 18 months of age. Correlated to the increased pulmonary function parameters previously observed in young adult TNC-deficient lungs and described to occur in normal lung aging between 3 and 6 months of age, TNC might be an advantage in lung aging.
Highlights
In human, lung aging is characterized by a progressive lung function decline, with decreased forced expiratory volume over forced vital capacity ratio (FEV1/FVC), decreased elastic recoil and a “senile emphysema” comparable to chronic obstructive pulmonary disease (COPD) emphysema, but devoid of inflammation and alveolar septa destruction (Brandsma et al, 2017; Navarro and Driscoll, 2017; Bowdish, 2019)
As changes in pulmonary function related to age could go unseen in basal conditions, we evaluated the pulmonary function of old TNC knockout (TNC KO) and WT male and female mice under a mechanical stress induced by 1 h of a high tidal volume (HTV) profile
Human lung aging is described as a functional decline, with increased residual volume (RV) and functional residual capacity (FRC), reduced regeneration capacity and structurally, airspace enlargement, defined as “senile emphysema” in opposition to the COPD-related inflammatory emphysema
Summary
Lung aging is characterized by a progressive lung function decline, with decreased forced expiratory volume over forced vital capacity ratio (FEV1/FVC), decreased elastic recoil and a “senile emphysema” comparable to chronic obstructive pulmonary disease (COPD) emphysema, but devoid of inflammation and alveolar septa destruction (Brandsma et al, 2017; Navarro and Driscoll, 2017; Bowdish, 2019). Human studies being hard to realize and standardize, more complete studies on lung aging were undertaken in rodents They ended up with similar findings, especially an increase in static compliance and total inspiratory capacity as well as an increase in lung volume and airspace volume in old mice. They allowed a more precise description of structural/microstructural evolution of the lung with age (Yamamoto et al, 2003; Huang et al, 2007; Elliott et al, 2016; Kling et al, 2017; Schulte et al, 2019; Veldhuizen et al, 2019)
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