Synergistic and feedback signaling mechanisms in the regulation of inflammation in respiratory infections

Wang, Wenzhuo Y.; Lim, Jae Hyang; Li, Jian Dong

doi:10.1038/cmi.2011.65

Cited by 27 publications

(25 citation statements)

References 57 publications

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“…1B). These observations agreed with previous reports showing that NTHi infection is an inflammatory process to be induced in a TRAF6/IKK/NF-B-dependent manner (19). To determine whether NF-B plays a role in NTHi location upon epithelial infection, we tested the effect of the NF-B inhibitors CAPE and BAY11-7083 on bacterial cell invasion.…”

Section: Resultssupporting

confidence: 76%

“…This observation, in agreement with previous studies (19), attracted our interest because (i) persistent NTHi respiratory infection is linked to COPD exacerbation and irreversible progression, (ii) inflammation is a hallmark of COPD, and (iii) COPD patients are administered anti-inflammatory drugs. Moreover, glucocorticoids modulate NTHi-triggered inflammation signaling (21,24).…”

Section: Discussionsupporting

confidence: 69%

“…3A). BAY11-7083 is an irreversible inhibitor Given that NTHi-triggered inflammation seems to be mediated by TLR2-dependent and epidermal growth factor receptor (EGFR)-dependent signaling (19,42), we also sought to determine whether these molecules play a role in NTHi epithelial infection. NTHi375 invasion of cells transfected with two siRNAs (a and b) to TLR2 and two siRNAs (a and b) to EGFR (see Fig.…”

Section: Resultsmentioning

confidence: 99%

“…NTHi infection is also an inflammatory process (19). Chronic respiratory patients are prescribed anti-inflammatory therapies, which may influence NTHi infection.…”

mentioning

confidence: 99%

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Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Euba

Moleres

Segura

et al. 2015

Antimicrob Agents Chemother

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Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.

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Section: Resultssupporting

confidence: 76%

Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

“…NTHi infection is also an inflammatory process (19). Chronic respiratory patients are prescribed anti-inflammatory therapies, which may influence NTHi infection.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Euba

Moleres

Segura

et al. 2015

Antimicrob Agents Chemother

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“…4,9 The overwhelming expression of proinflammatory cytokines can lead to various severe diseases such as sepsis, multiple organ failure or even death. 16,17 In contrast, the anti-inflammatory cytokine IL-10 plays an indispensable role in maintaining homeostasis to avoid host damage. 12 When faced with an acute, life-threatening infection, it is essential to maintain a moderate equilibrium between pro-and anti-inflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway

Zheng

Yang

et al. 2013

Cell Mol Immunol

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Approaches for controlling inflammatory responses and reducing the mortality rate of septic patients remain clinically ineffective; new drugs need to be identified that can induce anti-inflammatory responses. Ephedrine hydrochloride (EH) is a compound that is widely used in cardiovascular diseases, especially to treat hypotension caused by either anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of the inflammatory response. EH increased IL-10 and decreased proinflammatory cytokine (IL-6, tumor-necrosis factor (TNF)-a, IL-12 and IL-1b) expression in primary peritoneal macrophages and Raw264.7 cells treated with peptidoglycan (PGN), a Gram-positive cell wall component. The anti-inflammatory role of EH was also demonstrated in an experimental mouse model of peritonitis induced by intraperitoneal PGN injection. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for the EH-mediated increase in IL-10 production and decrease in IL-6 expression. Therefore, our results illustrated that EH can help maintain immune equilibrium and diminish host damage by balancing the production of pro-and anti-inflammatory cytokines after PGN challenge. EH may be a new potential anti-inflammatory drug that can be useful for treating severe invasive Gram-positive bacterial infection.

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Pathogenesis of Haemophilus influenzae in Humans

Harrison

Mason

2015

Human Emerging and Re‐emerging Infections

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Synergistic and feedback signaling mechanisms in the regulation of inflammation in respiratory infections

Cited by 27 publications

References 57 publications

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway

Pathogenesis of Haemophilus influenzae in Humans

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