Gut microbiota modification suppresses the development of pulmonary arterial hypertension in an SU5416/hypoxia rat model

Jujo, Takayuki; Hosomi, Koji; Shoji, Hiroki; Park, Jonguk; Naito, Akira; Ikubo, Yumiko; Yanagisawa, Akiko; Kobayashi, Takayuki; Miwa, Hideki; Suda, Rika; Sakao, Seiichiro; Mizuguchi, Kenji; Kunisawa, Jun; Tanabe, Nobuhiro

doi:10.1177/2045894020929147

Cited by 40 publications

(37 citation statements)

References 50 publications

(125 reference statements)

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“…This intravascular pathology would increase the dead space and hypoxemia in CARDS patients [ 2 , 10 ]. Besides, the widespread pulmonary vascular thrombosis could result in pulmonary hypertension (PH) and right ventricular dysfunction (RVD) [ 11 ]. Previous meta-analysis demonstrated that PH and RVD are prevalent in COVID-19 patients (19% and 22%, accordingly) and associated with higher mortality, severity, intensive care unit admission, and mechanical ventilation usage [ 12 ].…”

Section: Main Textmentioning

confidence: 99%

Inhaled prostacyclin analogues in COVID-19 associated acute respiratory distress syndrome: scientific rationale

Mulia

Luke

2021

Egypt Heart J

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Background COVID-19 associated acute respiratory distress syndrome (CARDS) is a severe form of SARS CoV-2 infection and affects about 15–30% of hospitalized patients with a high mortality rate. Growing research and data suggest several available drugs with appropriate pharmacological effects to treat COVID-19. Main body Prostacyclin analogues are regiments for pulmonary artery hypertension. Prostacyclin analogues are expected to be beneficial in treating CARDS based on at least four rationales: (1) inhaled prostacyclin analogues improve oxygenation, V/Q mismatch, and act as an ARDS therapy alternative; (2) it alleviates direct SARS-CoV-2-related coagulopathy; (3) increases nitric oxide production; and (4) possible anti-inflammatory effect. Prostacyclin analogues are available in oral, intravenous, and inhaled forms. The inhaled form has the advantage over other forms, such as parenteral administration risks. Previously, a meta-analysis demonstrated the beneficial effects of inhaled prostaglandins for ARDS treatment, such as improved PaO2/FiO2 and PaO2 along with reduced pulmonary artery pressure. Currently, two ongoing randomized controlled trials are evaluating inhaled epoprostenol (VPCOVID [NCT04452669]) and iloprost (ILOCOVID [NCT04445246]) for severe COVID-19 patients. Conclusions Inhaled prostacyclin could be considered in patients with refractory, life-threatening hypoxia despite standard management.

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Section: Main Textmentioning

confidence: 99%

Inhaled prostacyclin analogues in COVID-19 associated acute respiratory distress syndrome: scientific rationale

Mulia

Luke

2021

Egypt Heart J

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“…In kidney disease, immune deregulation and inflammation are both a cause and consequence of microbial dysbiosis 41 . Dysbiosis causes chronic inflammation and leads to renal disease, which ultimately modifies the GM, leading to dysbiosis 42 . Most medical conditions with a high mortality rate, caused due to SARS-CoV-2 infection, are related to increased intestinal dysbiosis, diabetes, obesity, lung inflammatory conditions, and cardiovascular disorders (CVDs) 43 .…”

Section: Gm Permeability and Dysbiosis In Covid-19 Patientsmentioning

confidence: 99%

Harmful Effects of COVID-19 on Major Human Body Organs: A Review

Chowdhury¹,

Mas-ud²,

Ali³

et al. 2021

J Pure Appl Microbiol

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The world experienced the outbreak of a new pandemic disease in 2019, known as coronavirus (CoV) disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome-CoV-2 (SARS-CoV-2). The respiratory system is the organ system most commonly affected by COVID-19; however, several other organ systems have been reported to be affected. The SARS-CoV-2 RNA found in infected stub samples can cause lung contagion by binding to the angiotensin-converting enzyme-2 (ACE-2) receptor of the alveolar epithelial cells. The gut microbiota (GM) promote immunity, indicating that the alignment of the microbiota and corresponding metabolic processes in COVID-19 can help to identify novel biomarkers and new therapeutic targets for this disease. The cause of kidney damage in COVID-19 patients is possibly multifactorial, involving a complex mechanism that involves complement dysregulation and thrombotic microangiopathy, as well as the occurrence of a “cytokine storm” syndrome, which are immune responses that are abandoned and dysfunctional with unfavorable prognosis in severe COVID-19 cases. Furthermore, COVID-19 involves a continuous proliferation and activation of macrophages and lymphocytes. SARS-CoV-2 can also bind to the ACE-2 receptor expressed in the cerebral capillary endothelial cells that can invade the blood-brain wall, to penetrate the brain parenchyma. However, in the ongoing pandemic, there has been a surge in studies on a wide range of topics, including causes of respiratory failure, asymptomatic patients, intensive care patients, and survivors. This review briefly describes the damaging effects of COVID-19 on vital human organs and the inhibitory function of the ACE-2 receptor on the GM, which causes gut dysbiosis, and thus, this review discusses topics that have an opportunity for further investigation.

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“…Inflammation in both the lung vascular and right ventricular (RV) compartments are major contributing factors to the pathology of PH [ 3 ]. In addition, studies from animal models and in patients with pulmonary arterial hypertension (PAH) have suggested a possible role of alterations in the gut microbiota in disease pathogenesis [ 4 , 5 , 6 ]. Emerging data provide a link between blood pressure regulation and microbiota-derived-metabolites, such as the short-chain fatty acid butyrate, which is also known to possess HDAC inhibitory activity [ 4 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

Karoor

Strassheim

Sullivan

et al. 2021

IJMS

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Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.

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Gut microbiota modification suppresses the development of pulmonary arterial hypertension in an SU5416/hypoxia rat model

Cited by 40 publications

References 50 publications

Inhaled prostacyclin analogues in COVID-19 associated acute respiratory distress syndrome: scientific rationale

Inhaled prostacyclin analogues in COVID-19 associated acute respiratory distress syndrome: scientific rationale

Harmful Effects of COVID-19 on Major Human Body Organs: A Review

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

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