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， 恢复期患者的肺功能持续下降。严重感染引发异常修复 过程和炎症导致小气道和肺泡重塑，肺功能受损 尤其是易感人群的死亡。这些肺损伤的特点，修复和重塑小 在H1N1流感（PR 8）病毒感染的小鼠模型中重现，其中肺泡 损伤导致气道中基底细胞（BC）的扩张和受损肺泡上皮的替换。在 我们的初步研究提供了证据表明，新生BC来源于气道的浆液样亚群， 分泌细胞（叶内浆液性或IS）。我们在规范中发现了TAp 63的意想不到的作用 PR 8感染肺的“活化的”AT 2细胞表达Lcn 2有助于BC 恢复到受伤的肺泡。最后，我们发现新生BC向受损肺泡区域的募集 影响存活的肺泡2型（AT 2）细胞的增殖活性和克隆行为。本提案的目的 试图检验PR 8引起新生BC最终定殖于受损肺泡的总体假设， 区域通过由TAp 63调节的命运转变源自IS细胞。而且我们 假设AT 2衍生的Lcn 2介导BC募集到损伤的肺泡，在那里它们调节局部Wnt 信号传导并抑制AT 2细胞增殖。目标1将研究TAp 63及其下游靶点在以下方面的作用： PR 8诱导的肺损伤后IS>BC规格。目的2将研究AT 2衍生的Lcn 2在 PR 8的募集引发BC到达受伤的肺泡。目标3将检验新生BC招募到研究中心的假设 实质损伤抑制存活的AT 2细胞的再生能力，并将探讨BC- 在这个过程中衍生的Wnt配体。这些目标的完成将为细胞和分子生物学提供新的见解。 急性肺损伤的修复机制，以及这些修复途径的持续激活如何有助于 肺部疾病的组织重塑

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.