Tenascin-C: Friend or Foe in Lung Aging?

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.

The Stress of Lung Aging: Endoplasmic Reticulum and Senescence Tête-à-Tête

Beyond the structural changes, features including the dysregulation of endoplasmic reticulum (ER) stress response and increased senescence characterize the lung aging. ER stress response and senescence have been reported to be induced by factors like cigarette smoke. Therefore, deciphering the mechanisms underlying ER and senescent pathways interaction has become a challenge. In this review we highlight the known and unknown regarding ER stress response and senescence and their cross talk in aged lung.

Risk factors associated with the development of interstitial lung abnormalities

BackgroundAround 8–10% of individuals over 50 years, present interstitial lung abnormalities (ILA), but their risk factors are uncertain.MethodsFrom 817 individuals recruited in our “Lung Aging Program”, 80 (9.7%) showed ILA and were compared with 564 individuals of the same cohort with normal HRCT to evaluate demographic and functional differences, and with 80 individuals, randomly selected from the same cohort for biomarkers. We evaluated MUC5B (rs35705950) variant, telomere length, and serum levels of matrix metalloproteinases (MMP)-1, -2, -3, -7, -8, -9, -12, -13, interleukin (IL)-6, surfactant protein (SP)-D, alpha-Klotho and resistin.ResultsIndividuals with ILA were usually males (p<0.005), older than controls (<0.0001), smokers (p=0.01), with greater frequency of MUC5B rs35705950 (OR 3.5; CI 95% 1.29–9.44, p=0.01), and reduced DLCO and oxygen saturation. Resistin, IL-6, SP-D, MMP-1, MMP-7, and MMP-13 were significantly increased in individuals with ILA. Resistin (12±5 ng mL−1versus 9±4 ng·mL−1; p=0.0005) and MMP-13 (357±143 versus 298±116, p=0.004 pg·mL−1), were the most increased biomarkers. On follow-up (24±18 months), 18 individuals showed progression which was associated with gastroesophageal reflux disease (OR 4.1 CI 95% 1.2–12.9, p=0.02), and in females with diabetes mellitus (OR 5.3, CI 95% 1.03–27.4, p=0.01).ConclusionsAround 10% of asymptomatic respiratory individuals enrolled in our lung aging program show interstitial lung abnormalities. Increased serum concentrations of pro-inflammatory molecules and MMPs are associated with ILA.