ABSTRACT
Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). Dpp4 knockout (Dpp4KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in Dpp4KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in Dpp4KO mice was milder than that in WT mice. The viability of TGFß-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the DPP4 knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFß treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, DPP4 knockdown in hPASMCs inhibited the pathways upregulated by TGFß treatment. These results suggest that genetic deficiency of Dpp4 protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFß-related pathways in PASMCs.
Subject(s)
Hypertension, Pulmonary , Lung Diseases, Interstitial , Osteochondrodysplasias , Humans , Animals , Mice , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/genetics , Dipeptidyl Peptidase 4/genetics , Phosphatidylinositol 3-Kinases , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/genetics , Bleomycin/toxicity , Mice, Knockout , Transforming Growth Factor beta/geneticsABSTRACT
RNF213 p.Arg4810Lys is linked to various vascular diseases, including pulmonary arterial hypertension (PAH); however, its pathogenesis remains unclear. Here, we report the unique features of two cases of severe PAH with this variant: one is the first reported case with stenosis of the thoracic and abdominal aorta, femoral arteries, and subclavian veins. Coexistence of severe and continuous eosinophilic inflammation, which has been suspected to be implicated in the pathogenesis of PAH in previous fundamental studies, was also present in both cases. Further studies are needed to clarify the pathogenetic mechanisms in vascular lesions with this variant.
ABSTRACT
Pulmonary hypertension (PH) is a life-threatening disorder, which originates from various aetiologies. Ventilation-perfusion (V/Q) scanning is commonly used to evaluate the differential diagnosis of PH. Meanwhile, previous studies have shown that single-photon emission computed tomography (SPECT)/CT imaging can provide a more detailed analysis for the assessment of pulmonary blood flow. However, there is insufficient evidence supporting the merits of V/Q SPECT/CT image data in detecting pulmonary vascular disease. Here, we report a case of pulmonary arterial hypertension with localized accumulation and peculiar distribution just below the pleura on V/Q SPECT/CT. Our finding is unique, and it suggests that V/Q SPECT/CT image data might be useful to detect blood flow not only in cases of pulmonary embolism, but also in the more commonly encountered PH.
