Characterisation of Cadmium Chloride Induced Molecular and Functional Alterations in Airway Epithelial Cells

Abstract

Epidemiological studies show that cadmium (Cd) exposure causes pulmonary damage, such as emphysema, pneumonitis, and lung cancer. However, the mechanisms leading to pulmonary toxicity are not yet fully elucidated. The aim of this study was to further investigate cadmium chloride (CdCl₂) induced toxicity using Calu-3 cells as an in vitro model of human bronchial epithelial cells. CdCl₂ induced effects following either apical or basolateral exposure were evaluated by Neutral Red Uptake (NRU), Trans-Epithelial Electrical Resistance (TEER), and alteration in Metallothionein 1X (MT1X), Heat shock protein 70 (HSP70), and Heme oxygenase 1 (HMOX-1) genes. CdCl₂ exposure resulted in a collapse of barrier function and the induction of MT1X, HMOX-1 and HSP70 genes, prior to alterations in cell viability. These effects were more pronounced when the exposure was from the basolateral side. Co-administration of N-Acetylcysteine (NAC) exerted a strong protective effect against CdCl₂ induced barrier damage and stress related genes, while other antioxidants only attenuated CdCl₂ induced HSP70 and HMOX-1 and showed no protective effect on the barrier collapse. These findings indicate that CdCl₂ exposure is likely to impair Calu-3 barrier function at non cytotoxic concentrations by a direct effect on adherens junction proteins. The protective effect of NAC against CdCl₂ induced MT1X, HSP70 and HMOX-1 genes, demonstrates an anti-oxidant effect of NAC in addition to Cd chelation.

Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

“…MT expression is frequently observed in lung carcinoma tissue samples from human patients (Eckschlager et al, 2009). It has previously been shown that epithelial barrier disruption following low-dose exposure to cadmium in airway epithelia results in elevated MT expression (Forti et al, 2010). Elevated MT levels are observed in the present study in CCT-LC cells when they acquired cancer cell characteristics with chronic cadmium exposure, supporting the association between MT and malignant lung phenotype.…”

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…While 16HBE 14o-cells have been reported to exhibit morphological features including apical microvilli and cilia (Cozens et al, 1994), in our experience cilia are absent from polarized 16HBE 14o-cultures. In addition to their use for toxicology (Forti et al, 2010(Forti et al, , 2011 and drug transport studies, 16HBE 14o-and Calu-3 cell lines are frequently used for analysis of pathways involved in barrier function in response to environmental agents including allergens (Vinhas et al, 2011;Wan et al, 2001), particulates (Banga et al, 2012), cigarette smoke (Heijink et al, 2012) or viral infections (Harcourt et al, 2011;Rezaee et al, 2011). The other frequently used bronchial epithelial cell line, BEAS2B (Reddel et al, 1988), is not of value for transport studies as it fails to form an appreciable barrier (Forbes and Ehrhardt, 2005).…”

Cadmium in human and animal organism. ІІ. Effect on functional activity of organs and systems

“…Хоча активація лейкоцитів відіграє важливу роль у хворобах органів дихання під час надходження Кадмію, цей елемент і безпосередньо впливає на клітини епі-телію альвеол і бронхів, стимулюючи утворення в них активних форм Оксигену, по-рушення бар'єрної функції та загибель за участю апоптозу [30,68]. У дослідженнях in vitro показано, що після культивування зрізів легень упродовж 7 діб за наявності в середовищі 5,0 і 10,0 мкмоль CdCl 2 рівень виживання клітин становить, відповід-но, 40 і 6% [57].…”