Additive counteraction by α7 and α4β2-nAChRs of the hypotension and cardiac sympathovagal imbalance evoked by endotoxemia in male rats

Sallam, Marwa Y.; El‐Gowilly, Sahar M.; El‐Gowelli, Hanan M.; El-Lakany, Mohammed A.; El‐Mas, Mahmoud M.

doi:10.1016/j.ejphar.2018.07.008

Cited by 35 publications

(33 citation statements)

References 56 publications

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“…Actually, elevated HO-1 expression can increase the expression of tight junction proteins to preserve the intestinal barrier integrity in mice with cholestatic liver injury and CCl4 injected mice [26,52]. We found that α7nAChR activation up-regulated HO-1 expression in intestinal tissues in BDL mice and epithelial cells co-cultured with macrophages, consistent with previous observations [54]. Moreover, α7nAChR activation increased IL-10 expression in macrophages, independent of HO-1 expression.…”

Section: Discussionsupporting

confidence: 91%

Activation of α7nAChR Preserves Intestinal Barrier Integrity and Ameliorates Cholestasis Liver Fibrosis in Mice by Enhancing the HO-1 / STAT3 Signaling to Inhibit NF-κB Activation

Lei

Zhao

Sun

et al. 2021

Preprint

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Background: Activation of alpha-7 nicotinic acetylcholine receptor (α7nAChR) can inhibit the systemic inflammatory response and preserve intestinal barrier integrity. This study aimed at elucidating the molecular mechanisms by which α7nAChR activation could inhibit intestinal barrier injury and cholestatic liver fibrosis in mice induced by bile duct ligation (BDL).Methods: The intestine-specific HO-1 knockout VillinCreHmox1-/- and control Hmox1floxp/floxp C57BL/6 mice were subjected to BDL. The therapeutic effects of GST-21, a specific ligand for α7nAChR, on systemic and intestinal inflammation, intestinal barrier integrity, liver fibrosis and injury, HO-1 expression, STAT3, AKT and NF-kBp65 activation were examined in these mice and intestinal epithelial cells co-cultured with macrophages. Results: Compared with BDL mice, α7nAChR activation by GST-21 decreased intestinal and liver injury and fibrosis in BDL mice, accompanied by reducing serum cytokine responses. In addition, activation of α7nAChR preserved the tight junction protein expression and intestinal epithelial cell barrier integrity in BDL mice and epithelial cells co-cultured with macrophages. The therapeutic effects of α7nAChR activation were mediated by enhancing HO-1 expression, STAT3 phosphorylation, and reducing the NF-kBp65 activation in intestinal tissues and epithelial cells co-cultured with macrophages. Finally, activation of α7nAChR induced HO-1 expression and STAT3 phosphorylation in an interdependent manner, independent of the PI3K/AKT signaling. Conclusion: Activation of α7nAChR enhanced HO-1 expression and STAT3 signaling to inhibit NF-κB activation, preserving the intestinal barrier integrity, and reducing inflammation and liver fibrosis in cholestasis mice. Therefore, targeting α7nAChR may be a promising interventional strategy for primary biliary cholangitis.

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Section: Discussionsupporting

confidence: 91%

Activation of α7nAChR Preserves Intestinal Barrier Integrity and Ameliorates Cholestasis Liver Fibrosis in Mice by Enhancing the HO-1 / STAT3 Signaling to Inhibit NF-κB Activation

Lei

Zhao

Sun

et al. 2021

Preprint

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“…1-2 A-F, available at https://doi.org/10.1523/JNEUROSCI.2324-19.2020.f1-2), indicating that neuronal Mfn2-regulated cardiac function, potentially through autonomic regulation, is likely an important mechanism for the suppression of lethality associated with septic shock in TMFN mice. In support of this notion, previous studies have identified autonomic control of myocardial dysfunction in LPS rodent models, particularly through cholinergic neurons of the sympathovagal system (Plaschke et al, 2018;Sallam et al, 2018;Ndongson-Dongmo et al, 2019). Nevertheless, additional work is still needed to clarify whether autonomic neurotransmission is altered by Mfn2 overexpression in neurons.…”

Section: Discussionmentioning

confidence: 87%

Neuronal Mitochondria Modulation of LPS-Induced Neuroinflammation

Harland¹,

Torres²,

Liu³

et al. 2020

J. Neurosci.

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Neuronal mitochondria dysfunction and neuroinflammation are two prominent pathological features increasingly realized as important pathogenic mechanisms for neurodegenerative diseases. However, little attempt has been taken to investigate the likely interactions between them. Mitofusin2 (Mfn2) is a mitochondrial outer membrane protein regulating mitochondrial fusion, a dynamic process essential for mitochondrial function. To explore the significance of neuronal mitochondria in the regulation of neuroinflammation, male and female transgenic mice with forced overexpression of Mfn2 specifically in neurons were intraperitoneally injected with lipopolysaccharide (LPS), a widely used approach to model neurodegeneration-associated neuroinflammation. Remarkably, LPS-induced lethality was almost completely abrogated in neuronal Mfn2 overexpression mice. Compared with nontransgenic wild-type mice, mice with neuronal Mfn2 overexpression also exhibited alleviated bodyweight loss, behavioral sickness, and myocardial dysfunction. LPS-induced release of IL-1␤ but not TNF-␣ was further found greatly inhibited in the CNS of mice with neuronal Mfn2 overexpression, whereas peripheral inflammatory responses in the blood, heart, lung, and spleen remained unchanged. At the cellular and molecular levels, neuronal Mfn2 suppressed the activation of microglia, prevented LPS-induced mitochondrial fragmentation in neurons, and importantly, upregulated the expression of CX3CL1, a unique chemokine constitutively produced by neurons to suppress microglial activation. Together, these results reveal an unrecognized possible role of neuronal mitochondria in the regulation of microglial activation, and propose neuronal Mfn2 as a likely mechanistic linker between neuronal mitochondria dysfunction and neuroinflammation in neurodegeneration.

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“…Mehanna and coworkers (Mehanna et al, 2007) described three phases for the arterial pressure response within the first hour after LPS (5 mg/kg) which consisted of an initial decrease (phase 1), rebound recovery (phase 2), and a long-lasting decrease (phase 3). Other studies also showed that the dose of 10 mg/kg promoted a reduction in arterial pressure over time (i.e., up to 180 min) (Sallam et al, 2017, 2018). Nevertheless, Lee et al (2005) in an extended analysis (i.e., up to 24 h after LPS administration), observed that the arterial pressure changes consisted of an initial hypotensive response (i.e., at 30–60 min), followed by a hypertensive response (i.e., from 1 to 9 h), and finally by a second hypotensive response (i.e., from 9 to 24 h) after the administration of 5 mg/kg of LPS in unanesthetized rats.…”

Section: Discussionmentioning

confidence: 90%

Time Course of Hemodynamic Responses to Different Doses of Lipopolysaccharide in Unanesthetized Male Rats

et al. 2019

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Lipopolysaccharide (LPS) administration is a well-known method to induce systemic inflammation widely used for investigating new therapeutic strategies for sepsis treatment, which is characterized by clinical manifestations such as tachycardia and hypotension. However, there are different doses of LPS used in several studies, and the hemodynamic responses were not always well characterized. Thus, the present study aimed to evaluate the arterial pressure, heart rate, heart rate variability, and baroreflex function from rats, over time, to different doses of LPS. Femoral artery and vein catheters were inserted into anesthetized Wistar-Hannover male rats for arterial pressure recording and LPS administration, respectively. On the next day, the arterial pressure was recorded before and after (90, 180, and 360 min) LPS injection (0.06, 20, 30, and 40 mg/kg). All doses of LPS tested increased the heart rate and decreased baroreflex sensitivity over time. In addition, while LPS administration of 20, 30, and 40 mg/kg increased the mean arterial pressure over time, 0.06 mg/kg decreased the mean arterial pressure at 360 min, as compared to baseline values. Furthermore, high doses of LPS decreased the power of the HF band of the cardiac interval spectrum over time, and the higher dose increased the power of the LF band. Our data indicate that high doses of LPS promote hypertensive response over time, while a low dose decreases arterial pressure. Moreover, the changes in heart rate variability and baroreflex function elicited by LPS may be not associated with arterial pressure response produced by the endotoxemia.

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Additive counteraction by α7 and α4β2-nAChRs of the hypotension and cardiac sympathovagal imbalance evoked by endotoxemia in male rats

Cited by 35 publications

References 56 publications

Activation of α7nAChR Preserves Intestinal Barrier Integrity and Ameliorates Cholestasis Liver Fibrosis in Mice by Enhancing the HO-1 / STAT3 Signaling to Inhibit NF-κB Activation

Activation of α7nAChR Preserves Intestinal Barrier Integrity and Ameliorates Cholestasis Liver Fibrosis in Mice by Enhancing the HO-1 / STAT3 Signaling to Inhibit NF-κB Activation

Neuronal Mitochondria Modulation of LPS-Induced Neuroinflammation

Time Course of Hemodynamic Responses to Different Doses of Lipopolysaccharide in Unanesthetized Male Rats

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