Cadmium induces lung inflammation independent of lung cell proliferation: a molecular approach
© Kundu et al; licensee BioMed Central Ltd. 2009
Received: 31 August 2008
Accepted: 12 June 2009
Published: 12 June 2009
Cadmium is one of the inflammation-related xenobiotics and has been regarded as a potent carcinogen. The relationship between inflammation and cell proliferation due to chronic infection has been studied, but the mechanism is not fully clear. Though the mode of cadmium toxicity is well characterized in animal cells, still it requires some further investigations. Previously we reported that cadmium induces immune cell death in Swiss albino mice. In the present study we showed that instead of inducing cell death mechanism, cadmium in low concentration triggers proliferation in mice lung cell and our results reveals that prior to the induction of proliferation it causes severe inflammation.
Swiss albino mice were treated with different concentrations of cadmium to determine the LD50. Mice were subdivided (5 mice each) according to the exposure period (15, 30, 45, 60 days) and were given sub lethal dose (5 mg/Kg body weight) of cadmium chloride and ibuprofen (50 mg/Kg body weight, recommended dose) once in a week. SEM and histology were performed as evidence of changes in cellular morphology. Inflammation was measured by the expression of Cox-2 and MMPs. Expression of proinflammatory cytokines (Cox-2, IL-6), signaling and cell cycle regulatory molecules (STAT3, Akt, CyclinD1) were measured by western blot, ELISA and immunoprecipitation. Mutagenecity was evidenced by comet assay. Cell proliferation was determined by cell count, cell cycle and DNA analysis.
Prolonged exposure of low concentration of cadmium resulted in up regulation of proinflammatory cytokines and cell cycle regulatory molecules. Though NSAIDs like Ibuprofen reduces the expression of inflammatory cytokines, but it did not show any inhibitory effect on cadmium adopted lung cell proliferation.
Our results prove that cadmium causes both inflammation and cell proliferation when applied in a low dose but proliferative changes occur independent of inflammation.
Cadmium has been shown to have various detrimental effects on health . Upon absorption, Cadmium is rapidly transported by blood to different organs in the body where its estimated half-life in humans is 15–20 years . Additionally chronic exposure to Cadmium has been associated with a number of physiological consequences such as renal failure and immunosuppression as well as various types of cancers in mammals. Several toxicities such as hepatoxicity, neurotoxicity and cardiotoxicity are also documented under high Cadmium exposure [3, 4]. In recent years progress has been made in dissecting apart the molecular mechanisms underlying the effects of exposure to this toxic metal.
The amount of Cadmium absorbed in the body following its exposure varies depending on the route of entry. Though the primary routes of cadmium exposure in humans are via inhalation from such sources as cigarette smoking , food is also reported as source for human exposure to Cadmium. Cadmium is selectively taken up by certain edible plants and certain food items, such as crab contains Cadmium as high as 30–50 ppm . In general, exposure of cells to low, micromolar concentrations of Cadmium results significant toxicity [7, 8]. Strong evidence, based on experimental studies exists to support the carcinogenic potential of Cadmium. Following various routes of exposure to Cadmium, experimental animals produce tumors of multiple organs [9, 10]. Only about 5% of a given dosage of cadmium is absorbed from the gastrointestinal tract, while lung absorption is as much as 90% of a dose inhaled into the lungs. Despite being one of the major routes for cadmium absorption, the toxic mechanism of cadmium on lung tissue is still poorly understood .
Cadmium induced lung injuries have been recently identified which indicates that it provokes lung damage and inflammation  by involving cytokine production . Cadmium-adapted alveolar epithelial cells are protected from oxidant-induced apoptosis along  with the expression of the numerous genes in acute-phase proteins or inflammatory cytokines . The acquired self tolerance to Cadmium is thought to have some basis in toxicokinetics but primarily concerns with modified tissue responses . Cadmium is one of the inflammation-related xenobiotics and its exposure on the tissues is often accompanied with infiltration of inflammatory cells . Interleukin, such as IL-6 has a key role in the proliferation of lung cell  and Cox-2 is an inducible inflammatory enzyme plays an important role in the progression of human lung adenocarcinoma . Although Cox-2 expression in tumors increases angiogenesis, which is highly associated with induction of various growth factors like IL-6 . Various studies reported that cadmium promotes lung cell proliferation by an immune suppressive network which involves over expression of Cox-2 . On the other hand IL-6 and its receptor interactions activate STAT3 which in turn induce the expression of several anti apoptotic proteins and thereby promotes cell proliferation. It is reported that cell expresses elevated levels of CyclinD1 when stably transfected with a dominant-active STAT3 construct . Therefore the general mode of action of all these signaling molecules are either directly related to the inflammation only or to the development of cell proliferation influenced by chronic inflammation. Although cadmium exposure has been reported to cause neoplastic transformation of human prostatic epithelial cells, but the efficacy of this transformation is highly dependent on the dose of the metal ion [23, 24]. Exposure of normal human prostate epithelial cells to higher dose (10 μM) cadmium transiently increased the expression of p53, c-myc, and c-jun after 2 hr as a prelude to apoptosis  where as lower dose promotes proliferation and resistance to apoptosis.
We are particularly interested in the contribution of low doses (5 mg/kg body weight) of cadmium to the transformation of mice lung. We have found that, due to cadmium exposure, expression of IL-6, STAT3 and inflammatory enzyme MMP-2, Cox-2 increased significantly. Also we have the evidences that increased activity of the Akt signaling axis in lung cells appears to operate in conjunction with or parallel to increased STAT3 activation to induce proliferation programme. We showed that cadmium promotes lung inflammation and cell proliferation both in independent manner. Thus, this study was designed to determine the effects of chronic exposures of low concentration of Cadmium in vivo. It is not worthy that anti-inflammatory drug treatment could not totally inhibit the proliferation process, whereas inflammation was prevented.
Chemicals and reagents
Antibodies against Cyclooxigenase-2 (Cox-2), IL-6, STAT-3, p-STAT3, Akt, p-Akt, CyclinD1, β-actin and anti-mouse-AP, anti-rabbit AP antibodies was obtained from Cell Signaling Technology, Inc. USA. Prestain molecular weight protein marker and standard DNA ladder, goat anti mouse-HRP and anti rabbit-HRP conjugated antibody and DAB developing system for immunohistochemistry were purchased from Bangalore Genei (India). Gelatin substrate for MMP was purchased from Sigma USA. Ibuprofen and the remaining chemicals were purchased from local firms (India) and were of highest purity grade.
Animal models and treatment
All animal experiments were performed following "Principles of laboratory animal care" (NIH publication No. 85-23, revised in 1985) as well as specific Indian laws on "Protection of Animals" under the provision of authorized investigators. Swiss albino mice (~25 g each; 5 mice in each group) were randomly divided into three groups such as (i) Control set, (ii) Cadmium (5 mg/Kg body weight) treated set, (iii) Cadmium and Ibuprofen (50 mg/Kg body weight) treated set. These sets were again divided into four groups according to the time dependent exposure (like 15 days, 30 days, 45 days, 60 days) of Cadmium and Ibuprofen. Cadmium chloride and Ibuprofen were dissolved in sterile pyrogen-free saline water and were given as i.p injection. Control set were given sterile pyrogen-free saline water only as i.p .
Lungs were taken after treatment and were washed in PBS immediately. The tissues were fixed for 24 hours in buffered formaldehyde solution (10% in PBS) at room temperature, dehydrated by graded ethanol and embedded in Paraffin (MERCK, Solidification point 60–62°C, TEST CAS No-8002-74-2). Tissue sections (thickness 5 μm) were deparaffinized with xylene, stained with eosin/haematoxylin, Digital images were captured with Olympus CAMEDIA digital camera, Model C-7070 wide zoom (100×) .
Preparation of Cytosol
Lung were homogenized in homogenizing buffer (0.25 M sucrose, 5 mM HEPES buffer, and 1 mM EDTA, pH 7.2), containing protease inhibitor PMSF (SRL, India). The homogenate was centrifuged at 500 × g to pellet nuclei and the resulting supernatant was centrifuged at 100,000 × g (29,000 rpm) for 60 min at 4°C in a 50.2 Ti rotar. Cytosolic supernatant was collected and aliquots were frozen by immersion in liquid nitrogen. It was stored at -80°C until use.
Zymographic Analysis of MMP Activity
Cytosolic extracts of lungs were prepared and protein concentration was determined by Bradford method. Gelatinase zymography was performed in 10% NOVEX Pre-Cast SDS Polyacrylamide Gel (Invitrogen Corp.) in the presence of 0.1% gelatin under non reducing conditions. Protein lysate of lungs were mixed with sample buffer and loaded for SDS-PAGE with tris glycine SDS buffer as suggested by the manufacturer (Novex). Samples were not boiled before electrophoresis. Following electrophoresis the gels were washed twice in 2.5% Triton X-100 for 30 min at room temperature to remove SDS. The gels were then incubated at 37°C overnight in substrate buffer containing 50 mM Tris-HCl and 10 mM CaCl2 at pH 8.0 and stained with 0.5% Coomassie Blue R250 in 50% methanol and 10% glacial acetic acid for 30 min and destained. Upon renaturation of the enzyme, the gelatinases digest the gelatin in the gel and give clear bands against an intensely stained background. Protein standards were run concurrently and approximate molecular weights were determined by plotting the relative mobilities of known proteins. After destaining, the bands were quantified using the UVTtech software (GAS 9500/9511, SRL No-0710161, Cambridge) .
Lungs were dissected out after the stimulation of 5 mg/Kg body weight Cadmium for two months and were homogenized in homogenizing buffer, and then supernatants were collected and stored at -80°C. Cox-2 and IL-6 in the supernatants were measured by ELISA according to the manufacturers' instructions (Cell Signaling manual).
Sections (5 μm) were cut from paraffin embeddedtissues and mounted on positively charged Super frost slides (Export Mengel CF). Tissues were deparaffinized, rehydrated through graded alcohols, and then blocked for endogenous peroxidase in 3% hydrogen peroxide in methanol. All tissues were preblocked in Tris-buffered saline containing 0.3% Triton, and 0.5% blocking agent (BSA, SRL, India, and batch No-832095) and incubated with Cox-2 (Cell signaling Technologies, USA), primary antibody (1:30) overnight at 4°C for positive control. Antisera specific for Cox-2 were diluted 1:30 in Tris-buffered saline containing 0.3% Triton, and 0.5% blocking agent. Immunoreactive complexes were detected using DAB system (Bangalore GeNei DAB system, Cat #SFE5). Slides were counterstained briefly in haematoxylin (MERCK), mounted in DPX (MERCK). Slides for negative control were treated with no primary antibody.
Western blot analysis
For western blot analysis of IL-6, p-Akt, Cox-2, p-STAT3 and CyclinD1, cell lysate was loaded into a 10%–15% SDS-polyacrylamide gel. After electrophoresis the gel was transferred to nitrocellulose membrane and blocked with nonfat dry milk in TBS containing Tween-20. Each primary antibody was diluted at 1:1000 ratio in TBS and after overnight incubation, the membrane was again blocked with nonfat dry milk in TBS containing Tween-20. Secondary antibody was diluted at 1:1000 ratio and after 2 hours incubation the membrane was developed by NBT/BCIP (HIMEDIA, Cat# RM 578, RM 2577). β-actin was chosen for constitutive expression.
For immunoprecipitation, cleared lysate was prepared and about 100 μg of protein were immunoprecipitated using 10 μl of anti-cdk4 (Cell signaling Technologies, USA) for overnight at 4°C with gentle rotation. 25 μl Protein G CL-Agarose (Bangalore Genei, India, Cat # LIA 43S) was added to the previous mixture, depending on the experiment and allowed it to mix for 4 hours at 4°C with gentle rotation. It was then centrifuged at 3000 rpm for 2 min. The immunoprecipitates were washed extensively with sterile PBS and separated by SDS-PAGE, followed by western analyses with anti CyclinD1 antibody (Cell signaling Technologies, USA) as described above.
Isolation of the lung cell & cell viability assay
Lung was removed from mice aseptically followed by addition of collaginase. Single cell suspensions were made in RPMI 1640 by passing the cell population through a nylon mesh with 50 μm pore size. The leukocyte population was then allowed to adhere in Petri dishes at 37° for 1 hour. The non-adherent cell populations were collected and subjected to Ficoll-Hypaque density gradient separation. The buffy layer was collected, washed and used as the source of cells. Viable lung cells were counted in haemocytometer by trypan blue exclusion test and used for further analysis.
Comet assays were performed under alkaline conditions to determine the amount of double-strand DNA breaks. Lungs from the mice treated with different concentrations of Cadmium chloride were trypsinized and washed in PBS before being added to preheated (37°C) low-melting point agarose. The solution was pipetted onto slides precoated with 1% agarose. The chilled slides were allowed to lyse for 40 min at 4°C in 2.5 M NaCl, 100 mM NaEDTA (pH 10), 10 mM Tris Base, 1% SDS, 1% Triton X-100 prior to immersion in alkaline electrophoresis solution (300 mM NaOH, 1 mM EDTA, pH 13). After 30 min, slides were placed into a horizontal electrophoresis chamber samples for 30 min (1 V/cm at 4°C). The slides were washed with deionized H2O to remove the alkaline buffer, dehydrated in 70% ice-cold EtOH and air-dried overnight. Slides were stained with EtBr (50 μg/ml) and examined by microscopy (Lica, China). Tail length (TL) was used to quantify the DNA damage. Image analysis and quantification has been performed with Motic Image software.
Scanning Electron microscopy
Lungs from normal, Cadmium treated (5 mg/Kg body weight) and Cadmium plus Ibuprofen treated (50 mg/Kg body weight) were dissected out from the mice and were immediately washed into the phosphate buffer saline (PBS) to remove any mucus, blood or any other contaminant. Tissues were fixed with 2.5% glutaraldehyde in 0.1 M phosphate buffer pH 7.2–7.4 for 24 hours. Tissues were then dehydrated with graded Acetone (MERCK) (50%–100%, 20 minutes each). We did not perform the Critical point drying (CPD) step as the lung tissues were very fragile. Sample were cut into small part and placed on the stab and put into the IB-2 ion coater for gold coating. After coating the sample were observed by S530-Hitachi SEM instrument (Department of USIC, University of Burdwan).
Cell cycle analysis by flowcytometry
Lung cells were fixed with p-formaldehyde, permeabilized with Triton X-100, and nuclear DNA was labeled with propidium iodide (PI). Cell cycle phase distribution of nuclear DNA was determined on FACS (Fluorescence-Activated Cell Sorter) having fluorescence detector equipped with 488 nm argon laser light source and 623 nm band pass filter (linear scale) using Cell Questpro software (Becton Dickinson). Total 10,000 events were acquired and flowcytrometric data were analyzed using Cell Questpro software.
For DNA laddering assay, lungs were first placed into liquid nitrogen for immediate hardening. It was crushed then into powder and followed the extraction protocol as described in Molecular Cloning, Vol-1, Sambrook, Russell (Chapter-6, Unit-6.4).
Values are shown as Standard error of mean, except where otherwise indicated. Data were analyzed and, when appropriate, significance of the differences between mean values was determined by the Student-T test. Results were considered significant at p < 0.05.
Determination of LD50 and dose for experiments
Prolonged exposure of low dose of Cadmium induces lung oedema and inflammation
Zymography proves MMP-2 but not MMP-9 is one of the mediators of such type of inflammation
Cyclooxygenase-2, IL-6, p-STAT3 and p-Akt expression are the key regulators of cadmium induced lung inflammation
Immunohistochemical expression of Cox-2
Low-dose Cadmium exposure increased cell number
DNA damage analysis clearly suggests that cellular effect of cadmium is totally dose dependent
Evaluation of cell cycle pattern after cadmium treatment
Scanning Electron Microscopy
Cadmium Induced CyclinD1 Regulation in lung Cell
In this study we tried to reveal the mechanistic details of Cadmium induced inflammation and proliferation in lung. An association between the development of cancer and inflammation has long been appreciated . The chronic inflammatory states associated with infection and irritation may lead to environments that foster genomic lesions and tumor initiation . The results of the present study showed that chronic exposure of cadmium compound induces lung cell proliferation which may be independent of lung inflammation. We hypothesized that cadmium exposure induces the inflammatory cytokines along with the cell proliferating factors in the lungs of mice.
We found that cadmium causes cell death at high concentration but at low level it is capable of inducing proliferation. Evidences are there indicate that low dose of cadmium can induce neoplastic transformation of human prostate epithelial cells . Lung epithelial cells of cadmium treated (5 mg/Kg body weight) mice exhibits elevated level of cellular proliferation along with the accumulation of inflammatory molecules and cytokines. Therefore, in search of the mechanism behind it we found that cadmium induced the cellular signals to shift towards the proliferation as a whole, but prior to the development of cell proliferation cadmium initiated sever lung inflammation. There is a supportive evidence that, lung cell is able to become gradually resistant in response to cadmium . We observed that IL-6 and inducible inflammatory enzyme Cox-2 elevated significantly in cadmium exposed mice. We also observed the expression level of TNFα, IL-1β, Hsp70, in cadmium treated lung cell (data not shown), but we did not find any significant change in their expression. That is why we mainly focused to see the role of cadmium on influencing the cellular expression of Cox-2, IL-6 and their down stream mediators, because of the fact that along with inflammation, these are the two known parameters of tumor development. Currently, Cox-2 inhibitors are being assessed in clinical trials for chemoprevention and as an adjuvant for conventional therapy in lung cancer . Additionally, anti-IL-6 therapy has shown promising results in metastatic condition . In the current study, we showed that elevated IL-6 and Cox-2 expression could be reduced by non steroidal anti-inflammatory drug like Ibuprofen. But at the same time molecular mechanisms of their regulation remains under observation (Data not shown here). Morphological differences between lungs of control and treated mice clearly suggest the development of edema. In inflammatory setting the inducible Cox-2 are detected in various reports . We showed it also through ELISA and immunohistochemistry. In our consideration lung cells switch on such signaling which helps to proliferate against the stressed environment. It is already suggested by various scientists that IL-6-activated Janus kinase which leads to the activation of signal transducer and activator of transcription (STAT) and Akt signaling cascades . There are supportive evidences that cadmium increases IL-6 production  and Akt activation in cancer cell . On the other hand IL-6 induced ICAM-1 expression is mediated via JAK/STAT signaling pathway in which STAT3 phosphorylation followed by its binding to IRE which are in the promoter of cell cycle-related genes including CyclinD1. Constitutive activation of STAT3 signaling contributes to oncogenesis by preventing apoptosis and enhancing cell proliferation. Moreover, Cox-2 dependent expression of IL-6 has been implicated in STAT3 activation and IL-6-dependent STAT3 activation has been shown to increase angiogenesis in several cancers . We showed that though Ibuprofen reduces the expression level of Cox-2 and IL-6, it could not prevent the expression of p-STAT3 and p-Akt and CyclinD1. So, due to chronic exposure, cadmium promoted inflammation independent of signaling towards. Our flowcytometric results suggest cell cycle progression. It has been reported that STAT3 activation up regulates target genes, such as CyclinD1, that leads to cell cycle progression or prevention of apoptosis and STAT3 inhibition results in the down-regulation of CyclinD1. As we know that CyclinD1 is responsible for G0/G1/S and S/G2/M transition , therefore, we have correlated both of the background information to test the expression of CyclinD1 and found that CyclinD1 was upregulated in lung cell after cadmium treatment, suggesting these pathways may operate in our system. Collectively, these findings suggest an important role for IL-6, Cox-2, STAT3, Akt and CyclinD1 in cadmium induced inflammation and lung cell proliferation.
We exposed mice to different concentrations of Cadmium and found that low levels of Cadmium (5 mg) consistently increased cell viability but higher levels of cadmium inevitably led to cell death with same exposure. A similar biphasic response has been reported previously by in vitro study . So it is the first in vivo study which might provide a mechanistic explanation for Cadmium-induced cell proliferation independent of inflammation in normal lung cells. Many of the observations described cells are adapted when cadmium exposure continued for a longer period . Similar observations of chronic pulmonary inflammation reported in cigarette smoke exposed mice . We proved that for the first time that cadmium exposure promotes pulmonary inflammation but this may not be the cause of lung cell proliferation.
These data provide a new insight into the relation between chronic inflammation and cell proliferation in vivo. Involvement of different inflammatory, signaling and cell cycle regulatory molecules in cadmium induced mice lung cell require further investigation. Our experimental model have both limitations and advantages. However, one major point should be taken into consideration before comparing our results obtained in mice model with human is that, though minute amount of cadmium deposit in lung if administered intraperitoneally or through contaminating food, it can still induces inflammation and proliferation due to persistent presence in lung cell but this two events may occur independently. Further in vitro studies in progress to delineate the cross-talk of inflammation and proliferation by cadmium.
signal transducer and activator of transcription factor 3
enzyme-linked immunosorbent assay
scanning electron microscopy
non steroidal anti-inflammatory drug.
Authors want to thank to Dr. Palash Kr. Mandal (Medical College, Kolkata) and Dr. Sabasti Roy, (Thakurpukur cancer Hospital) for there guide in histopathology and immunohistochemical analysis. Authors are very much grateful to Dr. Srikanta Chakraborty and Prof. A. Bhattacharyya of University Burdwan, West Bengal, India, for their unconditional help during SEM (Scanning electron microscopy) analysis. This work was supported by grants from Department of Science and Technology, Govt. of India (SR/FT/L-42/2006). Also we like to thank Department of Biotechnology, Govt. of India (BT/PR9779/GBD 27/67/2007) and Indian Council of Medical Research, Govt. of India (Immuno/18/11/21/ECD-1-2002) for equipment support.
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