Deciphering the interplay between endoplasmic reticulum stress and senescence in contributing to extracellular matrix remodeling in lung aging and COPD

Age-related lung diseases create a persistent burden for healthcare systems and this burden is expected to increase, as worldwide elderly populations are projected to continue to increase. Gaining knowledge of how aging contributes to the susceptibility of some individuals to develop lung diseases has become critical. Biological mechanisms including loss of proteostasis with increased endoplasmic reticulum (ER) stress, increased cellular senescence and remodeling of the extracellular matrix (ECM) were identified as features of lung aging. However, potential interaction between these features remains understudied. Thus, the first aim of this thesis was to characterize ER stress and senescence, and examine the crosstalk between these two processes and the relation with ECM changes in lung fibroblasts from young and old patients who had normal lung function and were without chronic lung diseases. Secondly, the ECM remodeling in the normal aging lung and the COPD lung was characterized. This thesis demonstrated the age-related increased levels of ER Stress, senescence and ECM protein changes in lung fibroblasts. Furthermore, the role of ER stress in the establishment and maintenance of a senescent profile in lung fibroblasts, and the possible impact of the crosstalk between ER stress and senescence on ECM remodeling were demonstrated. Additionally, age associated differences in human lung ECM and the alterations in the ECM landscape between non disease and COPD lung tissue were revealed. To conclude, these findings suggest that the ER stress response and senescence axis might play an important role in the age and COPD-related differences observed in the lung ECM profile