Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury.

A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz were normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2-to-AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to an LPS injury prevented AT1 cell regeneration, led to intraalveolar collagen deposition, and resulted in persistent innate inflammation. These findings establish that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.

Elevated bone marrow sympathetic drive precedes systemic inflammation in angiotensin II hypertension.

Increased sympathetic nervous system activity is a hallmark of hypertension (HTN), and it is implicated in altered immune system responses in its pathophysiology. However, the precise mechanisms of neural-immune interaction in HTN remain elusive. We have previously shown an association between elevated sympathetic drive to the bone marrow (BM) and activated BM immune cells in rodent models of HTN. Moreover, microglial-dependent neuroinflammation is also seen in rodent models of HTN. However, the cause-effect relationship between central and systemic inflammatory responses and the sympathetic drive remains unknown. These observations led us to hypothesize that increase in the femoral BM sympathetic nerve activity (fSNA) initiates a cascade of events leading to increase in blood pressure (BP). Here, we investigated the temporal relationship between the BM sympathetic drive, activation of the central and peripheral immune system, and increase in BP in the events leading to established HTN. The present study demonstrates that central infusion of angiotensin II (ANG II) induces early microglial activation in the paraventricular nucleus of hypothalamus, which preceded increase in the fSNA. In turn, activation of fSNA correlated with the timing of increased production and release of CD4+.IL17+ T cells and other proinflammatory cells into circulation and elevation in BP, whereas infiltration of CD4+ cells to the paraventricular nucleus marked establishment of ANG II HTN. This study identifies cellular and molecular mechanisms involved in neural-immune interactions in early and established stages of rodent ANG II HTN. NEW & NOTEWORTHY Early microglia activation in paraventricular nucleus precedes sympathetic activation of the bone marrow. This leads to increased bone marrow immune cells and their release into circulation and an increase in blood pressure. Infiltration of CD4+ T cells into paraventricular nucleus paraventricular nucleus marks late hypertension.