Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

Abstract

Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

“…Primarily defined as paracrine-acting soluble growth factors, angiocrine factors are now more broadly recognized to comprise organ-specific signaling programs including extracellular matrix (ECM) molecules and cell surface proteins (7). These angiocrine factors control organogenesis during development as well as organ function during health and disease (8)(9)(10)(11)(12).…”

Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension

“…The most striking examples include the important impact of PVD after premature birth, the contribution of PVD to poor outcomes in many developmental lung diseases, the association of PVD with genetic syndromes (especially Down syndrome), and other factors that reflect both prenatal and postnatal influences that may act through epigenetic mechanisms (7,8). Along with hemodynamic changes during the transition at birth, normal maturation of the lung circulation also plays a critical role during lung organogenesis and formation of the distal airspace through angiocrine signaling, and disruption of endothelial function can impair lung structure in diverse neonatal diseases (9,10). In addition, perinatal factors may increase the risk for the late development of PH in adulthood, suggesting that an important maturational window may exist during which early identification of susceptibility factors may permit interventions that can reduce the incidence or severity of PAH (11).…”

HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver

“…Considering that liver is the major metabolic organ that synthesizes HDL, it is likely that HDL produced by expanding hepatocytes stimulates regeneration via activation of S1P 1 on sinusoidal vessels (63,64). This finding might advance our understanding of hepatocyte-LSEC signaling crosstalk (24,25,65) that promotes regeneration and prevents fibrosis, and targeting of maladapted vascular system might spur regeneration and prevent fibrosis (31,(66)(67)(68)(69).…”

“…Liver fibrosis was assessed after CCl 4 injection and BDL. Collagen deposition was determined by Sirius red staining, and hepatic hydroxyproline level was measured (31,66). Liver lobes were weighed, homogenized, and baked in 12 N hydrochloric acid.…”