Cell competition in pulmonary fibrosis and ARDS

特发性肺纤维化（IPF）是间质性肺疾病（ILD）的常见形式，导致肺泡炎。 肺功能重塑和进行性丧失、呼吸衰竭和死亡，通常在5年内发生 诊断.遗传和实验证据支持慢性肺泡上皮损伤和 不能正确修复呼吸道上皮是IPF疾病发病机制的内在原因。组织学上， 肺实质中的呼吸上皮细胞被通常限于 导气管纤维化病变和蜂窝状结构取代肺泡，后者通常由 肺泡1型（AT 1）和AT 2细胞。呼吸道病毒感染的急性加重是最具破坏性的 IPF并发症，住院死亡率超过50%。以前冠状病毒的数据 严重急性呼吸系统综合征（SARS）和中东呼吸系统综合征（MERS）等大流行病， 以及COVID-19大流行的新数据表明， SARS-CoV-2感染后的后果，COVID-19的病原体。有趣的是， 严重COVID-19的因素与特发性肺纤维化（IPF）相同，即年龄增加，男性 性和合并症如高血压和糖尿病。虽然许多急性发作的患者 呼吸窘迫综合征（ARDS）存活于疾病的急性期，相当大比例的患者死于急性呼吸窘迫综合征。 进行性肺纤维化的结果。目前尚不清楚为什么某些人能够从 而在其他情况下，随着BC-荚的积累，细胞增殖转变为不受抑制的细胞增殖， 成纤维细胞和肌成纤维细胞。在这些患者中，也有过度沉积的胶原蛋白与其他 细胞外基质的组分导致进行性肺纤维化。不同上皮 干/祖细胞池和/或它们的间充质小生境重新填充损伤的组织 和损伤类型，以及严重肺泡上皮损伤后再生或纤维化的结果， 这部分取决于这些细胞群之间的细胞竞争动力学。在含有a cMyc或雅普蛋白水平的嵌合失衡，具有较高cMyc或核雅普水平的细胞变得超 竞争对手，并扩大以牺牲细胞水平较低，通过消除他们。或者，如果某些 由于损伤类型的不同，干细胞群体被选择性地消灭，其他干细胞群体逃脱 受伤的组织可能不太擅长替换被破坏的组织， 优势例如，SARS-CoV-2通过其受体血管紧张素转换酶进入呼吸道上皮细胞， 酶2（ACE 2），导致严重的气道和肺泡上皮损伤。基于Ace2表达， 干/祖细胞库似乎对SARS-CoV-2感染的敏感性不同。这份拨款申请 旨在操纵细胞竞争的潜在机制，以帮助预防和治疗IPF和ARDS。 细胞竞争也可能被用来最大限度地发挥健康组织替代的潜力。

Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD), resulting in alveolar remodeling and progressive loss of pulmonary function, respiratory failure, and death often within 5 years of diagnosis. Genetic and experimental evidence support the concept that chronic alveolar epithelial injury and failure to properly repair the respiratory epithelium are intrinsic to IPF disease pathogenesis. Histologically, respiratory epithelial cells in the lung parenchyma are replaced by cells which are normally restricted to conducting airways. Fibrotic lesions and honeycomb structures replace alveoli, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Acute exacerbations by respiratory viral infections are the most devastating complication of IPF, having an in-hospital mortality rate of greater than 50%. Data from previous coronavirus pandemics such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection, the causative agent of COVID-19. Interestingly, the major risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male sex, and comorbidities such as hypertension and diabetes. Although many patients who develop acute respiratory distress syndrome (ARDS) survive the acute phase of the illness, a substantial proportion die as a result of progressive pulmonary fibrosis. It remains unclear why certain individuals are able to recover from ARDS, whereas in others there is a shift to unchecked cellular proliferation with the accumulation of BC-pods, fibroblasts and myofibroblasts. In these patients, there is also excessive deposition of collagen alongside other components of the extracellular matrix resulting in progressive pulmonary fibrosis. Distinct epithelial stem/progenitor cell pools and/or their mesenchymal niches repopulate injured tissue depending on the extent and type of injury, and the outcomes of regeneration or fibrosis in response to severe alveolar epithelial injury is dependent in part on the dynamics of cell competition between these cell populations. In tissues harboring a mosaic imbalance in cMyc or Yap protein levels, cells with higher cMyc or nuclear Yap levels become super- competitors and expand at the expense of cells with lower levels, by eliminating them. Alternatively, if certain stem cell populations are selectively wiped out due to the type of injury, other stem cell populations that escape the injury and which may not be so adept at replacing the destroyed tissue will now have a competitive advantage. For example, SARS-CoV-2 enters respiratory epithelial cells via its receptor, angiotensin-converting enzyme 2 (ACE2), causing severe airway and alveolar epithelial injury. Based on Ace2 expression, distinct stem/progenitor cell pools appear to be differentially susceptible to SARS-CoV-2 infection. This grant proposal seeks to manipulate the underlying mechanisms of cell competition to help prevent and treat IPF and ARDS. Cell competition might also be exploited to maximize the potential of healthy tissue replacement.