Cell competition in pulmonary fibrosis and ARDS

肺纤维化和 ARDS 中的细胞竞争

• 批准号: 10686806
• 负责人: Stijn Piet Johan De Langhe
• 金额: $ 95.4万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2029-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686806
• 关键词: 2019-nCoV; ACE2; AGTR2 gene; Acute; Acute Respiratory Distress Syndrome; Age; Alveolar; Alveolus; Applications Grants; COVID-19; COVID-19 pandemic; COVID-19 susceptibility; Cell Proliferation; Cells; Cessation of life; Chronic; Collagen; Complication; Data; Deposition; Diabetes Mellitus; Diagnosis; Disease; Epithelial Cells; Extracellular Matrix; Failure; Fibroblasts; Fibrosis; Genetic; Histologic; Hospital Mortality; Hypertension; Individual; Injury; Interstitial Lung Diseases; Lesion; Mesenchymal; Middle East Respiratory Syndrome; Myofibroblast; Natural regeneration; Nuclear; Outcome; Pathogenesis; Patients; Phase; Population; Proteins; Pulmonary Fibrosis; Respiratory Failure; Risk Factors; SARS-CoV-2 infection; Severe Acute Respiratory Syndrome; Structure; Structure of parenchyma of lung; Syndrome; Tissues; Viral Respiratory Tract Infection; airway epithelium; alveolar epithelium; c-myc Genes; comorbidity; coronavirus pandemic; epithelial injury; epithelial stem cell; idiopathic pulmonary fibrosis; injured; male; mosaic; post SARS-CoV-2 infection; prevent; pulmonary function; receptor; repaired; replacement tissue; respiratory; response; severe COVID-19; sex; stem cell population; stem cells

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.

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。遗传和实验证据支持慢性肺泡上皮损伤和 无法正确修复呼吸道上皮是 IPF 疾病发病机制所固有的。组织学上， 肺实质中的呼吸道上皮细胞被通常仅限于的细胞所取代 传导气道。纤维化病变和蜂窝结构取代了肺泡，后者通常衬有 肺泡 1 型 (AT1) 和 AT2 细胞。呼吸道病毒感染引起的急性加重是最具破坏性的 IPF的并发症，院内死亡率超过50%。之前的冠状病毒数据 严重急性呼吸系统综合症（SARS）和中东呼吸系统综合症（MERS）等流行病， 以及来自 COVID-19 大流行的新数据表明，可能存在大量纤维化 SARS-CoV-2（COVID-19 的病原体）感染后的后果。有趣的是，主要风险 导致严重 COVID-19 的因素与特发性肺纤维化 (IPF) 相同，即年龄增长、男性 性别以及高血压和糖尿病等合并症。尽管许多患者出现急性 呼吸窘迫综合征 (ARDS) 在疾病的急性期存活下来，相当一部分人因呼吸困难而死亡 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 ARDS，而在其他情况下，随着 BC-pod 的积累，细胞增殖会发生转变， 成纤维细胞和肌成纤维细胞。在这些患者中，胶原蛋白与其他物质一起过度沉积。 细胞外基质的成分导致进行性肺纤维化。明显的上皮细胞 干细胞/祖细胞库和/或其间充质生态位根据损伤的程度重新填充受损组织 和损伤类型，以及响应严重肺泡上皮损伤的再生或纤维化的结果是 部分取决于这些细胞群之间的细胞竞争动态。在组织中含有 cMyc 或 Yap 蛋白水平镶嵌不平衡，具有较高 cMyc 或核 Yap 水平的细胞变得超级 竞争者并通过消除较低水平的细胞来扩大规模。或者，如果确定 由于损伤的类型，干细胞群被选择性消灭，其他干细胞群逃脱 损伤并且可能不那么擅长替换被破坏的组织现在将具有竞争力 优势。例如，SARS-CoV-2 通过其受体血管紧张素转换蛋白进入呼吸道上皮细胞 酶 2 (ACE2)，导致严重的气道和肺泡上皮损伤。基于 Ace2 表达，不同 干/祖细胞库似乎对 SARS-CoV-2 感染具有不同的易感性。本次拨款提案 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。