Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension

Abstract

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-β activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.

Switching-Off Adora2b in Vascular Smooth Muscle Cells Halts the Development of Pulmonary Hypertension

“…Despite the detrimental consequences of PH, there are very limited therapies available that can treat PH in IPF patients (Collum et al, 2017a ). Although anti-fibrotic agents have been shown to attenuate experimental fibrosis and PH (Hemnes et al, 2008 ; Schroll et al, 2010 , 2013 ; Van Rheen et al, 2011 ; Karmouty-Quintana et al, 2012 , 2015 ; Bei et al, 2013 ; Grasemann et al, 2015 ; Chen et al, 2016 ; Avouac et al, 2017 ), these therapies have not translated to the clinic. Moreover, standard therapies for PAH have failed to show a benefit in Group III PH and have been associated with worsening mortality (Ruggiero et al, 2012 ; Klinger, 2016 ).…”

HYAL1 Is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits HFL-1 Fibroblast Proliferation When Upregulated

“…BMPR2 is a key regulator of cell proliferation [59] and could reportedly inhibit TGFβ signaling. BMPR2 can bind BMP ligands by associating with BMPR1A, thereby leading to the phosphorylation of SMADs 1/5/9 that suppress TGFβ signaling [60]. Thus, these results suggest that overexpressing HYAL1 in lung fibroblasts could enhance the expression of BMPR2 and the subsequent downstream signaling mediators SMAD1/5/9, which in turn suppress TGFβ signaling, and inhibit fibroproliferation.…”

Pathology and Pathobiology of Pulmonary Hypertension

“…However, the sequence of events from inflammation initiation to pulmonary vascular disease development remains unknown in PAH. Recent discoveries are indeed highlighting the importance played by the altered BMP receptor signaling not only for DNA lesions and their reparation 183,184 as well as for the modulation of the cellular metabolism [185][186][187] but also for inflammation and its resolution. 163,[188][189][190][191] While this body of knowledge provides a preliminary understanding, it also highlights subtleties and complexities that require further investigation to determine whether anti-inflammatory strategies will be useful in PAH treatment in the future.…”