Effects of N-Acetylcysteine and Ambroxol on the Production of IL-12 and IL-10 in Human Alveolar Macrophages

Aihara, Masayuki; Dobashi, Kunio; Akiyama, Masato; Nakazawa, Takahiro; Mori, Masatomo

doi:10.1159/000056297

Cited by 22 publications

(13 citation statements)

References 51 publications

(57 reference statements)

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“…Studies of the IPA murine model have demonstrated that resistance to infection is associated with the production of Th1 cytokines, whereas Th2-cytokine release was correlated with disease progression [32,38,39] . Aihara et al previously reported that NAC could increase Th1/Th2 cytokine levels in vitro [40] . TNF-α is a pro-inflammatory Th1 cytokine that is important to the host response to infectious agents, including fungal pathogens [41] .…”

Section: Discussionmentioning

confidence: 95%

NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model

Jian

et al. 2009

Acta Pharmacol Sin

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Aim: Neutropenic individuals are at high risk for invasive pulmonary aspergillosis (IPA), a life-threatening infection. To evaluate the therapeutic potential of antioxidants, IPA was induced in neutropenic mice and the effect of N-acetyl-l-cysteine (NAC) on oxidative stress levels and lung injury was analyzed. Methods: Mice were pretreated with three daily intraperitoneal injections of 150 mg/kg cyclophosphamide, followed by intratracheal inoculation with 4.5×10 6 conidia of Aspergillus fumigatus. The infected mice were then randomly assigned to an amphotericin B (AMB) group, an AMB plus NAC group, or an untreated control (C) group. In each group, the duration of treatment was 24, 48, or 72 h, and activities such as appearance, feeding, and dermal temperature were observed throughout the experiment. Sera and lung tissues were collected and analyzed by quantitative enzyme-linked immunosorbent assay (ELISA) for total protein, superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) levels. The wet/dry weight ratio of the lung was also calculated and lung sections were stained with hematoxylin-eosin for pathological examination and with methenamine silver stain for fungus detection. Results: Compared with the mice untreated with NAC, mice in the AMB plus NAC group had increased SOD and reduced MDA levels both systemically and locally at 24, 48, and 72 h after inoculation with conidia. NAC treatment also decreased the pulmonary protein content at 48 and 72 h and the lung wet/dry weight ratio at 24 and 48 h. Additionally, NAC enhanced pulmonary production of TNF-α and IL-10 at 24 h and 48 h. Conclusion: In combination with antifungal therapy, NAC treatment can alleviate oxidative stress and lung injury associated with IPA in neutropenic mice.

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Section: Discussionmentioning

confidence: 95%

NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model

Jian

et al. 2009

Acta Pharmacol Sin

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“…The effects of NAC on IL-12 secretion have been shown to be stimulus-and concentration dependent (17,42), and exactly how Nrf2 deficiency modulates the actions of NAC requires further study. Other products produced by DCs that affect Th2 differentiation include VEGF and IL-18, and we found that secretion of both of these was affected by RWE.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Erythroid 2 p45-Related Factor 2 Inhibits the Maturation of Murine Dendritic Cells by Ragweed Extract

Rangasamy¹,

Williams²,

Bauer³

et al. 2010

Am J Respir Cell Mol Biol

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Oxidative stress plays an important role in immune regulation and dendritic cell (DC) maturation. Recent studies indicate that allergens, including ragweed extract (RWE), possess prooxidant activities, but how RWE interacts with DCs is not well understood. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a key transcription factor that regulates constitutive and coordinated induction of a battery of antioxidant genes. We hypothesized that RWE would activate DCs and that this response would be augmented in the absence of Nrf2. We generated bone marrow-derived DCs (BM-DCs) and isolated lung DCs from Nrf2 1/1 and Nrf2 2/2 mice and studied the effects of RWE on DCs in vitro. Under resting conditions, Nrf2 2/2 BM-DCs exhibited constitutively greater levels of inflammatory cytokines and costimulatory molecules than Nrf2 1/1 BM-DCs. Exposure to RWE impaired endocytic activity, significantly induced oxidative stress, and enhanced the expression of CD80, CD86, and MHCII in Nrf2 2/2 BM-DCs when compared with Nrf2 1/1 BM-DC, in association with reduced expression of Nrf2-regulated antioxidant genes. RWE significantly induced the secretion of inflammatory cytokines IL-6 and TNF-a in BM-DCs and lung DCs from Nrf2 2/2 mice than Nrf2 1/1 mice and significantly inhibited the secretion of IL-12 in Nrf2 1/1 BM-DCs and IL-18 in Nrf2 1/1 and Nrf2 2/2 BM-DCs. The stimulatory effects of RWE on DC activation were inhibited to varying degrees by the antioxidant N-acetyl cysteine. Our findings indicate that a defect in Nrf2-mediated signaling mechanisms alters the response of DCs to a common environmental allergen, which may contribute to the susceptibility to allergic diseases.

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“…Amb significantly reduced the lung hemorrhage, edema, exudation, neutrophil infiltration, the histological score of lung injury and the cytokine levels in a murine model of lipopolysaccharide-induced lung injury [17]. In another study, Amb enhanced LPS-induced secretion of IL-12 and the ratio of IL-12/IL-10, which suggests that Amb appears to strengthen innate immune response and cell-mediated immunity, and facilitate the development of Th-1 cells [28]. The effects of Amb on the release of histamine, leukotrienes, cytokines and superoxide anions from a variety of cells involved in the pathogenesis of allergic reaction and inflammation [14].…”

Section: Introductionmentioning

confidence: 90%

Inhalation of ambroxol inhibits cigarette smoke-induced acute lung injury in a mouse model by inhibiting the Erk pathway

Liu

Lin

et al. 2016

International Immunopharmacology

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Oral and injection administration of ambroxol has been clinically used to treat airway disease. However, little is known about its potentials in inhalation therapy. In present studies, we tested the effects of ambroxol by inhalation with intravenous administration, and explored the underlying working mechanism. The mice received 10 cigarettes exposure every day for 4 days. Inhaled solution of ambroxol was aerosolized 20 min before the exposure of cigarette smoke (CS). The effect of ambroxol on the expression of mucoprotein 5 AC (MUC5AC) and proinflammatory cytokines in NCI-H292 cells stimulated with cigarette smoke extract (CSE). Four days of daily inhalation of ambroxol at 3.75 or 7.5mg/ml for 20 min suppressed the accumulation of neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) and lung tissues, and inhibited increases in the mRNA and protein levels of tumor necrosis factor (TNF)-α, CCL-2 and KC, but not interleukin (IL)-1β in the CS-exposed mice. Moreover, ambroxol at 3.75 or 7.5mg/ml facilitated airway mucosa cilia clearance, reduced glycosaminoglycans level in BALF and MUC5AC mRNA levels in lung tissues. The effects of ambroxol by inhalation at 7.5mg/ml was comparable to that of ambroxol at 20mg/kg i.v. and dexamethasone at 0.5mg/kg i.p. Using cultured lung epithelial cells, we demonstrated that pretreatment with ambroxol at 2 or 20 μM inhibited the CSE-induced up-regulation of MUC5AC, TNF-α, IL-1β mRNA levels, which was through inhibiting Erk signaling pathway. Our results demonstrate the beneficial effects of ambroxol as an inhalation replace systemic administration for COPD therapy.

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Effects of N-Acetylcysteine and Ambroxol on the Production of IL-12 and IL-10 in Human Alveolar Macrophages

Cited by 22 publications

References 51 publications

NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model

NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model

Nuclear Erythroid 2 p45-Related Factor 2 Inhibits the Maturation of Murine Dendritic Cells by Ragweed Extract

Inhalation of ambroxol inhibits cigarette smoke-induced acute lung injury in a mouse model by inhibiting the Erk pathway

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