Gene expression changes in human small airway epithelial cells exposed to Δ9-tetrahydrocannabinol

Sarafian, Theodore A.; Habib, Nancy; Mao, Jenny T.; Tsu, I-Hsien; Yamamoto, Mitsuko L.; Hsu, Erin L.; Tashkin, Donald P.; Roth, Michael D.

doi:10.1016/j.toxlet.2005.03.008

Cited by 22 publications

(24 citation statements)

References 37 publications

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“…We demonstrated that Ni exacerbated acute lung injury in MT null mice (20), acknowledging its protective function in the lung. MT is basally expressed in the airway epithelium (38) and inducible by exogenous chemicals (39,40). Our data in Figure 1A corroborate previous findings that Ni induces MT2A mRNA (13,33).…”

Section: Discussionsupporting

confidence: 90%

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

Nemec

Leikauf²,

Pitt³

et al. 2009

Am J Respir Cell Mol Biol

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We recently reported that induction of metallothionein (MT) was critical in limiting nickel (Ni)-induced lung injury in intact mice. Nonetheless, the mechanism by which Ni induces MT expression is unclear. We hypothesized that the ability of Ni to mobilize zinc (Zn) may contribute to such regulation and therefore, we examined the mechanism for Ni-induced MT2A expression in human airway epithelial (BEAS-2B) cells. Ni induced MT2A transcript levels and protein expression by 4 hours. Ni also increased the activity of a metal response element (MRE) promoter luciferase reporter construct, suggesting that Ni induces MRE binding of the metal transcription factor (MTF-1). Exposure to Ni resulted in the nuclear translocation of MTF-1, and Ni failed to induce MT in mouse embryonic fibroblasts lacking MTF-1. As Zn is the only metal known to directly bind MTF-1, we then showed that Ni increased a labile pool of intracellular Zn in cells as revealed by fluorescence-activated cell sorter using the Zn-sensitive fluorophore, FluoZin-3. Ni-induced increases in MT2A mRNA and MRE-luciferase activity were sensitive to the Zn chelator, TPEN, supporting an important role for Zn in mediating the effect of Ni. Although neither the source of labile Zn nor the mechanism by which Ni liberates labile Zn was apparent, it was noteworthy that Ni increased intracellular reactive oxygen species (ROS). Although both N-acetyl cysteine (NAC) and ascorbic acid (AA) decreased Ni-induced increases in ROS, only NAC prevented Ni-induced increases in MT2A mRNA, suggesting a special role for interactions of Ni, thiols, and Zn release.

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Section: Discussionsupporting

confidence: 90%

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

Nemec

Leikauf²,

Pitt³

et al. 2009

Am J Respir Cell Mol Biol

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“…In previous studies using lung epithelial cells we observed that THC disrupted mitochondrial membrane potential and lowered ATP levels, an effect also observed with marijuana smoke extract but not with tobacco or placebo marijuana smoke extract (Sarafian et al, 2003;Sarafian et al, 2005). Among the questions raised in these studies was the role of cannabinoid receptors in mediating the effects on cell energetics.…”

Section: Resultsmentioning

confidence: 94%

“…We have previously shown that THC, alone and in the presence of other smoke components, can regulate gene expression in human lung epithelial cells (Sarafian et al, 2005), disrupt mitochondrial function and cellular energetics (Sarafian et al, 2003) modulate cytokine and immune function (Baldwin et al, 1997;Yuan et al, 2002), and regulate the balance between an apoptotic and necrotic response to injury (Sarafian et al, 2001). The chemotactic activity of lung epithelial cells, the primary focus of this report, is felt to play an important role in lung remodeling, host protection and lung repair (Rennard et al, 2006;Shahabuddin et al, 2006).…”

Section: Discussionmentioning

confidence: 93%

“…We have shown previously that THC and marijuana smoke extract compromise cell energetics in lung epithelial cells in vitro (Sarafian et al, 2003;Sarafian et al, 2005). In both primary human lung epithelial cells and the lung tumor cell line, A549, mitochondrial membrane potential (Ψ m ) is diminished along with cellular ATP level.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies revealed that Δ 9 -tetrahydrocannabinol (THC) caused mitochondrial injury in primary lung epithelial cells and in the cell line, A549 (Sarafian et al, 2003;Sarafian et al, 2005). The role of cannabinoid receptors in this injury was unclear, as was the potential impact on cell function.…”

mentioning

confidence: 99%

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Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Sarafian

Montes

Harui

et al. 2008

Toxicology and Applied Pharmacology

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Marijuana smoking is associated with a number of abnormal findings in the lungs of habitual smokers. Previous studies revealed that Δ 9 -tetrahydrocannabinol (THC) caused mitochondrial injury in primary lung epithelial cells and in the cell line, A549 (Sarafian et al., 2003;Sarafian et al., 2005). The role of cannabinoid receptors in this injury was unclear, as was the potential impact on cell function. In order to investigate these questions, A549 cells were engineered to over-express the type 2 cannabinoid receptor (CB2R) using a self-inactivating lentiviral vector. This transduction resulted in a 60-fold increase in CB2R mRNA relative to cells transduced with a control vector. Transduced cell lines were used to study the effects of THC on chemotactic activity and mitochondrial function. Chemotaxis in response to a 10 % serum gradient was suppressed in a concentration-dependent manner by exposure to THC. CB2R-transduced cells exhibited less intrinsic chemotactic activity (p < 0.05) and were 80-to 100-fold more sensitive to the inhibitory effects of THC. Studies using SR144528, a selective CB2R antagonist, verified that these effects were mediated by the CB2R. Marijuana smoke extract, but not smoke extracts from tobacco or placebo marijuana cigarettes, reproduced these effects (p < 0.05). THC decreased ATP level and mitochondrial membrane potential (Ψ m ) in both control and CB2R-transduced cells. However, these decreases did not play a significant role in chemotaxis inhibition since cyclosporine A, which protected against ATP loss, did not increase cell migration. Moreover, CB2R-transduced cells displayed higher Ψ m than did control cells. Since both Ψ m and chemotaxis are regulated by intracellular signaling, we investigated the effects of THC on the activation of multiple signaling pathways. Serum exposure activated several signaling events of which phosphorylation of IκB-α and JNK were regulated in a CB2R-and THC-dependent manner. We conclude that airway epithelial cells are sensitive to both CB2R-dependent and independent effects mediated by THC.

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Role of the Endocannabinoid System in Systems Toxicity

Pistos

Theocharis

2009

General, Applied and Systems Toxicology

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The scientific knowledge regarding the modulation of the endogenous cannabinoid system and its effect on disease pathophysiology has been significantly improved in the last 20 years. Alterations in the expression of cannabinoid receptors, their main endogenous ligands (arachidonoylethanolamide and 2‐arachidonoylglycerol), and related enzyme levels have been reported in different disease states, suggesting their important regulatory role. The pharmacological effects of synthetic compounds that selectively target the endocannabinoid system, established cause‐effect relationships between endocannabinoids and the progress of several disorders. In this review, the importance of endocannabinoid system modulation and also the aspects of the underlying pathways leading to disease or target organ toxicity are reported.

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Gene expression changes in human small airway epithelial cells exposed to Δ9-tetrahydrocannabinol

Cited by 22 publications

References 37 publications

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Role of the Endocannabinoid System in Systems Toxicity

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