The Intersection of Genes and Environment

Ayala, Estela; Kudelko, Kristina; Haddad, François; Zamanian, Roham T.; Perez, Vinicio de Jesus

doi:10.1378/chest.11-1402

Cited by 14 publications

(4 citation statements)

References 4 publications

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“…However, evidence provided in the present study is limited, and future studies on the gene silencing of MyD88 may be required to validate the involvement of TLR4 downstream signaling in the WD-induced lung pathology in the absence of ApoE more convincingly. Due to the complexity of the mechanism of the gene-environment interaction ( 26 ), the neuroendocrine system, the changes in the gene methylation pattern and the roles of other TLRs in the animal model used in the present study, further investigation is warranted.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E deficiency and high-fat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway

Ouyang

Huang

Lin

et al. 2015

Molecular Medicine Reports

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Apolipoprotein E deficiency (ApoE−/−) combined with a high-fat Western-type diet (WD) is known to activate the toll-like receptor (TLR4) pathway and promote atherosclerosis. However, to date, the pathogenic effects of these conditions on the lung have not been extensively studied. Therefore, the present study examined the effects of ApoE−/− and a WD on lung injury and investigated the underlying mechanisms. ApoE−/− and wild-type mice were fed a WD or normal chow diet for 4, 12 and 24 weeks. Lung inflammation, lung cholesterol content and cytokines profiles in bronchoalveolar lavage fluid (BALF) were determined. TLR4 and its main downstream molecules were analyzed with western blot analysis. In addition, the role of the TLR4 pathway was further validated using TLR4-targeted gene silencing. The results showed that ApoE−/− mice developed lung lipidosis following 12 weeks of receiving a WD, as evidenced by an increased lung cholesterol content. Moreover, dependent on the time period of receiving the diet, those mice exhibited pulmonary inflammation, which was manifested by initial leukocyte recruitment (at 4 weeks), by increased alveolar septal thickness and mean linear intercept as well as elevated production of inflammation mediators (at 12 weeks), and by granuloma formation (at 24 weeks). The expression levels of TLR4, myeloid differentiation primary response 88 (MyD88) and nuclear factor kappa B were markedly upregulated in ApoE−/− WD mice at week 12. However, these effects were ameliorated by shRNA-mediated knockdown of TLR4. By contrast, ApoE−/− ND or wild-type WD mice exhibited low-grade or no inflammation and mild lipidosis. The levels of TLR4 and MyD88 in those mice showed only minor changes. In conclusion, ApoE deficiency acts synergistically with a WD to trigger lung lipidosis and inflammation at least in part via TLR4 signaling.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E deficiency and high-fat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway

Ouyang

Huang

Lin

et al. 2015

Molecular Medicine Reports

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“… 4 , 71 , 72 Reports of HHT‐related PAH associated with ENG mutations have typically lacked patient‐specific data, including results from RHC studies, and have often involved other precipitating factors, such as the concomitant use of dexfenfluramine or extensive stimulant abuse. 73 , 74 Therefore, patients with HHT1 exhibiting precapillary PH should be thoroughly evaluated to exclude other etiologies (e.g., CTEPH and congenital heart disease). Rarely, PAH has been identified in patients with HHT and mutations in GDF2 and BMPR2 .…”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review

Mathavan,

Reddy

et al. 2023

Pulm. circ.

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Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high‐output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left‐sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

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“…One major feature of Meth-APAH is that only a subset of methamphetamine users develop PAH, which likely denotes that there is a genetic component involved in pathogenesis. Some authors have theorized that perhaps there is a “two-hit phenomenon” in the development of PAH, with the first hit being a genetic mutation which renders an individual susceptible to developing PAH and then a second environmental trigger, such as methamphetamine exposure, is required to produce phenotypic disease [37]. Recent studies have used whole exome sequencing to identify a gene that may play a role in Meth-APAH pathogenesis.…”

Section: Disease/proposed Mechanismsmentioning

confidence: 99%

Methamphetamine and the risk of pulmonary arterial hypertension

Ramírez¹,

Perez

Zamanian

2018

Current Opinion in Pulmonary Medicine

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PAH patients undergoing diagnostic evaluation should be screened for a history of current or past methamphetamine use. Pharmacovigilance should be implemented to monitor patients being treated with methamphetamine for neuropsychiatric disorders (e.g., attention-deficit hyperactivity disorder). More studies will be needed to identify which susceptibility factors increase risk of PAH in methamphetamine users.

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The Intersection of Genes and Environment

Cited by 14 publications

References 4 publications

Apolipoprotein E deficiency and high-fat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway

Apolipoprotein E deficiency and high-fat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review

Methamphetamine and the risk of pulmonary arterial hypertension

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