Basal cells in airway and alveolar remodeling

摘要 急性呼吸道病毒感染是一个巨大的社会和经济负担，有可能 恢复期患者的肺功能持续下降。严重感染会引发异常修复 导致小气道和肺泡重塑的过程和炎症，损害肺功能 以及在特别易感人群中的死亡。小鼠肺损伤、修复和重塑的这些特点 呼吸道和肺泡，在H1N1流感(PR8)病毒感染的小鼠模型中，其中肺泡 损伤导致呼吸道内基底细胞(BC)的扩张，并替换受损的肺泡上皮。在……里面 初步研究表明，新生BC来源于一种浆液性的呼吸道亚群 分泌细胞(叶内浆液质或IS)。我们已经在TAp63的规范中确定了一个意外的角色 新生BC和PR8感染肺AT2细胞表达Lcn2参与了BC的形成 向受伤的肺泡招募。最后，我们发现新生BC重新聚集到受损的牙槽区域 影响存活的肺泡2型(AT2)细胞的增殖活性和克隆行为。这项提议的目的 试图验证最重要的假设，即PR8诱导了新生的BC，最终定植于受损的肺泡 区域由IS细胞通过TAp63调控的命运转变而来。此外，我们 假设AT2来源的Lcn2介导BC募集到损伤的肺泡，在那里它们调节局部Wnt 信号转导和抑制AT2细胞增殖。目标1将研究TAp63及其下游靶标在 在PR8诱导的肺损伤后的IS&gT；BC规范。AIM 2将调查AT2衍生的Lcn2在 PR8诱导的BC向损伤的肺泡募集。Aim 3将测试新生的BC招募到站点的假设 实质损伤抑制存活的AT2细胞的再生能力，并将探索BC- 在这一过程中衍生出Wnt配体。这些目标的完成将为细胞和分子提供新的见解 急性肺损伤的修复机制以及这些修复途径的持续激活可能起到的作用 与肺部疾病的组织重塑有关。

Abstract Acute respiratory viral infections represent an enormous societal and economic burden with the potential for persistent declines in lung function among recovering patients. Severe infections trigger abnormal repair processes and inflammation leading to remodeling of small airways and alveoli, impaired pulmonary function and death in particularly susceptible individuals. These features of lung injury, repair and remodeling of small airways and alveoli, are recapitulated in mouse models of H1N1 influenza (PR8) virus infection, wherein alveolar injury leads to expansion of basal cells (BC) in airways and replacement of damaged alveolar epithelium. In preliminary studies we provide evidence that nascent BC are derived from a serous-like subset of airway secretory cells (intralobar serous or IS). We have identified an unexpected role for TAp63 in the specification of nascent BC and that Lcn2 expression by “activated” AT2 cells of the PR8-infected lung contributes to BC recruitment to injured alveoli. Finally, we show that recruitment of nascent BC to damaged alveolar regions impacts the proliferative activity and clonal behavior of surviving alveolar type 2 (AT2) cells. Aims of this proposal seek to test the overarching hypothesis that PR8-elicited nascent BC that ultimately colonize damaged alveolar regions are derived from IS cells through a fate transition that is regulated by TAp63. Furthermore, we hypothesize that AT2-derived Lcn2 mediates BC recruitment to injured alveoli where they regulate local Wnt signaling and inhibit AT2 cell proliferation. Aim 1 will examine the role of TAp63 and its downstream targets in IS>BC specification following PR8-induced lung injury. Aim 2 will investigate roles for AT2-derived Lcn2 in recruitment of PR8-elicited BC to injured alveoli. Aim 3 will test the hypothesis that nascent BC recruited to sites of parenchymal injury suppress the regenerative capacity of surviving AT2 cells and will explore roles for BC- derived Wnt ligands in this process. Completion of these aims will provide new insights into cellular and molecular mechanisms of repair in acute lung injury and how persistent activation of these repair pathways might contribute to tissue remodeling in lung disease.