In ARDS, lung cells that should repair damaged tissue instead enter a state of premature aging, locking them into a cycle of inflammation that worsens the disease. This matters because acute respiratory distress syndrome kills 30–40% of patients who develop it, and no drug exists to treat the underlying cause. The researchers have identified a specific protein, p21, that drives this cellular aging in the lung’s air sacs. Their pilot data show that transferring mitochondria from stem cells can reverse the aging effect in lung cells grown in the lab. If the team confirms that blocking p21 or delivering mitochondria halts senescence in animal models and human lung tissue, it could open a new class of treatments for ARDS—and potentially for other inflammatory lung diseases such as COPD and pulmonary fibrosis. The work is primarily fundamental science, probing a mechanism never before linked to ARDS. A deeper understanding of how cellular aging spreads through the lung could eventually lead to therapies that prevent the cascade of tissue damage, reducing the need for prolonged intensive care and improving survival.
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Need for the research. Acute respiratory distress syndrome (ARDS) is a severe, life-threatening condition characterized by widespread inflammation in the lungs associated with impaired pulmonary endothelial-epithelial barriers, resulting in fluid accumulation in the distal airspaces, frequently accompanied by multi-system organ failure. ARDS continues to result in high mortality up to 30-40% and high costs related to prolonged hospital stays. The importance of ARDS has been emphasised by recent Covid-19 pandemic, where development of ARDS is one of the leading causes of mortality. ARDS pathogenesis has not been fully elucidated and there is no effective pharmacological treatment. Therefore, further research into the mechanisms of pathogenesis and novel therapies is needed. Summary of the proposed project. Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the senescence-associated secretory phenotype (SASP). SASP is characterized by an overproduction of pro-inflammatory cytokines and extracellular matrix remodelling enzymes. These secretory molecules can facilitate the development of premature senescence in neighbouring cells. The accumulation of senescent cells overtime disrupts tissue structure and function. Intriguingly, many of ARDS triggering events lead to activation of cell signalling cascades that are linked to the premature senescence. Senescent alveolar epithelium is unable to repair injured tissue, while spread of senescence to neighbouring cells through SASP would amplify the progression of the disease. Yet, little is known about senescence mechanisms in ARDS. Our pilot data show that inflammatory stimuli induce senescence in lung cells, while mitochondrial transfer mediated by extracellular vesicles derived from mesenchymal stromal cells (MSC) was able to reverse these effects. We also show that activation of p21 is critical for driving senescence phenotype both in vitro and in vivo. A clear knowledge gap exists regarding the link between premature epithelial cell senescence and regulation of lung recovery, immune response and maladaptive remodelling in ARDS. In this proposal we plan to address this gap by investigating the cross-talk between premature senescence and alveolar epithelial function in ARDS and test novel therapeutic strategies based on engineered MSC EVs and isolated MSC mitochondria. We hypothesize that during the course of ARDS pulmonary epithelial cells develop pre-mature senescence which contributes to exacerbation of inflammation and tissue damage through secretion of SASP and targeting senescence pathways may be a promising therapeutic strategy. To test this hypothesis we have formulated the following aims: Aim 1: To investigate the role of p21-driven epithelial senescence and SASP for severity of lung injury and modulation of immune response in vivo, using conditional KO mice where p21 is specifically deleted in alveolar epthelial cells (SPC-p21 KO mice). Aim2: To investigate and test pathways involved in epithelial senescence and SASP in ARDS using 2D and 3D primary human pulmonary cell models in vitro. Aim3: To test therapeutic strategies to alleviate senescence and reduce severity of lung injury. Value of the results. This research addresses an unmet clinical need by enhancing our understanding of ARDS and cellular aging, leading to innovative therapies. Beyond ARDS, the findings have broader implications for lung conditions like chronic obstractive pulmonary disease, idiopathic pulmonary fibrosis and sepsis as all these diseases are characterized by dysregulated inflammation. Ultimately, this project aims to benefit ARDS patients and ICU clinicians, improving patient outcomes and reducing the burden of this devastating condition.
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