Cell competition in pulmonary fibrosis and ARDS

特发性肺纤维化(IPF)是间质性肺疾病(ILD)的一种常见形式，导致肺泡 肺功能重塑和进行性丧失，呼吸衰竭，通常在5年内死亡 诊断。遗传学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病的内在发病机制。从组织学上讲， 肺实质中的呼吸道上皮细胞被通常仅限于 进行航空运输。纤维性病变和蜂窝结构取代了肺泡，后者通常由 肺泡I型(AT1)和AT2细胞。由呼吸道病毒感染引起的急性加重是最具破坏性的 IPF并发症，住院病死率大于50%。以前冠状病毒的数据 严重急性呼吸综合征(SARS)和中东呼吸综合征(MERS)等流行病， 以及来自新冠肺炎大流行的新数据表明，可能存在实质性的纤维化 新冠肺炎的病原体SARS-CoV-2感染后的后果。有趣的是，主要风险 严重新冠肺炎的因素与特发性肺纤维化相同，即年龄增加，男性 性，以及高血压和糖尿病等合并症。尽管许多发展为急性胰腺炎的患者 呼吸窘迫综合征(ARDS)在疾病的急性期存活下来，相当大比例的人死于 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-Pod的积累，细胞向不受控制的增殖转变， 成纤维细胞和肌成纤维细胞。在这些患者中，也有过度的胶原沉积与其他 导致进行性肺纤维化的细胞外基质成分。不同的上皮细胞 干细胞/祖细胞池和/或其间充质壁龛根据损伤的程度重新填充组织 和损伤类型，严重的肺泡上皮损伤后再生或纤维化的结果是 在一定程度上取决于这些细胞群体之间的细胞竞争动态。在组织中含有一种 嵌合体cMyc或YAP蛋白水平失衡，cMyc或核YAP水平较高的细胞变得超级 竞争对手，通过淘汰较低水平的细胞来进行扩张。或者，如果确定 干细胞群因损伤类型而选择性地被消灭，其他逃脱的干细胞群 受伤的人可能不太擅长替换被破坏的组织，现在将有一个竞争性的 优势。例如，SARS-CoV-2通过其受体血管紧张素转换进入呼吸道上皮细胞 酶2(ACE2)，引起严重的呼吸道和肺泡上皮损伤。基于ACE2表达式，截然不同 干细胞/祖细胞池似乎对SARS-CoV-2感染具有不同的易感性。这项拨款建议 寻求操纵细胞竞争的潜在机制，以帮助预防和治疗IPF和ARDS。 还可以利用细胞竞争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.