Lung transplantation for pulmonary hypertension
Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell in LUNG Transplantation, 2016
PAH probably develops because of a combination of environmental factors and genetic predisposition to pulmonary vascular disease. Environmental factors may include additional acquired genetic mutation, viral infection (including HIV), a chronic inflammatory condition (connective tissue disease), drugs (appetite suppressants), and variations in the hemodynamics of the pulmonary circulation (congenital systemic-to-pulmonary shunts). Mutations with a role in PAH have been found in genes encoding for bone morphogenetic protein receptor type II (BMPR2), activin receptor–like kinase 1 (ALK1), 5-hydroxytryptamine transporter (5HTT), endoglin (ENG), mothers against decapentaplegic homolog 9 (SMAD9), caveolin-1 (CAV1), and potassium channel subfamily K member 3 (KCNK3).8–14 Genetic predisposition and exposure to environmental factors probably lead to dysregulation of the microenvironment of the lung, which in turn results in an imbalance between agents with promitotic or vasoconstrictive (endothelin) and antimitotic or vasodilatative (nitric oxide, prostacyclin) effects.15 Indeed, an increase in the production of endothelin, as well as a lack of nitric oxide and prostacyclin production, has been suggested in different studies.16–21 Consequently, vasoconstriction and vascular remodeling occur, which in turn leads to increased pulmonary vascular resistance (PVR) and PH.
Pulmonary vascular diseases
Louis-Philippe Boulet in Applied Respiratory Pathophysiology, 2017
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in resistance to blood flow engendered by the conjugated effects of vasoconstriction, pulmonary blood vessels remodeling, and in situ thrombosis (Figure 7.7) [30]. The underlying physiopathology of the disease remains poorly understood. This group of PH includes different entities such as idiopathic pulmonary hypertension (IPAH), hereditary PAH (HPAH), PAH associated with drugs and toxins, as well as associated pulmonary arterial hypertension (APAH) including connective tissue disease, congenital heart diseases, HIV, portopulmonary hypertension, and others. A germline mutation in the gene encoding a type II receptor of the TGF-β superfamily (Bone Morphogenic Protein Receptor II or BMPR2) is identified in 75% of familial PAH and 10%–30% of “sporadic” PAH [31–34]. These mutations are rarely observed in other forms of PAH. However, BMPR2 expression is reduced even in the absence of mutations [35]. More recently, other mutations associated with HPAH were identified, including activin-like receptor kinase-1 (ALK1), endoglin (ENG), mothers against decapentaplegic 9 (Smad 9), and the potassium channel subfamily K member 3 (KCNK3) [34,36]. Nevertheless, other genes could be involved, possibly from the BMP/TGF-β pathway, which plays an important role in regulating pulmonary vasculature. Since the penetrance of the mutations remains low (10%–30%), the development of PAH probably requires a genetic predisposition coupled with certain risk factors. Nongenetic abnormalities are also involved in the progression of disease (Table 7.2) [30].
Therapeutics in pulmonary hypertension
Anthony J. Hickey, Heidi M. Mansour in Inhalation Aerosols, 2019
Mutations in genes that encode proteins involved in the Tumor necrosis factor β (TNF-β) signaling pathway are implicated in the development of PH. These mutations include Bone morphogenetic protein receptor type 2 (BMPR2), Activin A receptor like type 1 (ACVRL1), Endoglin (ENG), Smad8, Smad1, Smad5, and Caveolin-1. TNF-β signaling pathway controls growth, differentiation, and apoptosis of various cell types including pulmonary vascular (ECs) and SMCs (12). Thus, mutations in genes involved in the TGF-β signaling pathway may be responsible for the abnormal proliferation of pulmonary vascular SMCs and may promote ECs apoptosis (12).
An update on the diagnosis and treatment of pediatric pulmonary hypertension
Published in Expert Opinion on Pharmacotherapy, 2020
Further evaluation of various genes such as NOTCH3, SMAD9, GDF2, AQP1, SMAD8, SOX17, and ATP13A3 genes may also be done in children with PAH [30]. Most prevalent mutation is bone morphogenetic protein receptor2 (BMPR2) mutation. Approximately 80% of familial and 20% of IPAH patients carry a heterozygous (BMPR2) mutation. Lower levels of BMPR2 signaling and expression have also been reported in patients with PAH-CHD, PAH-CTD, drug-induced PAH, and interstitial lung disease [48,49]. Patients with BMPR2 mutations, exhibit more severe disease symptoms at a young age and are nonresponsive to AVT, they require more aggressive therapy and have a high risk of mortality. BMPR2 mutation is a strong high-risk criterion even in the absence of other criteria [50–52]. Asymptomatic mutation carriers and family members of the patients should be followed-up using echocardiograms and must be provided with genetic counseling. Genetic testing should be routinely performed in all pediatric PH patients.
Is sotatercept, which traps activins and growth differentiation factors, a new dawn in treating pulmonary arterial hypertension (PAH)?
Published in Expert Opinion on Biological Therapy, 2023
Sotatercept is an activin receptor type IIA fusion protein (ActRIIA-Fc) [1]. In heritable PAH, several mutations in the genes have been demonstrated including those encoding bone morphogenetic protein receptor type 2 (BMPR2), which is a member of the transforming growth factor-β superfamily of signaling molecules [5]. Normally, in pulmonary circulation, there is a balance between proliferative and antiproliferative factors, which include BMP. In PAH, it is proposed that there is a downregulation of the BMPR2 pathway leading to a prominence of the upregulation pathway that is mediated by activins growth differentiation factors acting at the ActRIIA. As an ActRIIA-Fc, sotatercept removes these proliferative factors to correct the imbalance in PAH [2].
The Relationship between Extracellular/intracellular microRNAs and TLRs May Be Used as a Diagnostic and Therapeutic Approach in Sepsis
Published in Immunological Investigations, 2022
Navid Shomali, Ata Mahmoodpoor, Ali Namvaran Abbas Abad, Faroogh Marofi, Morteza Akbari, Huaxi Xu, Siamak Sandoghchian Shotorbani
miR-342-5p regulates miR-155 positively with suppressing the expression of Akt1 in APC cells such as macrophages. Also, Bone morphogenetic protein receptor type-2 (Bmpr2) avoids targeting of Akt1 by miR-342-5p. In addition, the suppression of Bmpr2 increases the ability of miR-342-5p, therefore, increase the targeting of Akt1. These activities cause activation of miR-342. Moreover, the up-regulation of miR-155 in activated APC cells promote inflammation. However, this will not happen if TLR4 is not activated via LPS (Vasilescu et al. 2009b). miR-342 has been found to be down-regulated in sepsis patients (Vasilescu et al. 2009b).
Related Knowledge Centers
- Bone Morphogenetic Protein
- Cell Growth
- Ligand
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- Transforming Growth Factor Beta
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- Osteoblast
- Serine/Threonine-Specific Protein Kinase
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- Bone Morphogenetic Protein Receptor, Type 1