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Year : 2021  |  Volume : 64  |  Issue : 4  |  Page : 644-650
Experimental study on the effect of Si and P ion content in SiO2 exposure environment on the degree of pulmonary fibrosis

Department of Respiratory Medicine, Xuzhou Mining Group General Hospital; Department of Respiratory Medicine, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China

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Date of Submission24-Apr-2020
Date of Decision04-May-2020
Date of Acceptance21-May-2020
Date of Web Publication20-Oct-2021


Background: Silicosis is a public health issue in developing countries for long and cannot be completely cured. Objective: To study the changes of ion content with TNF-α and TGF-β expression in alveolar lavage fluid (BALF) at different time points in rats exposed to silica and to investigate their correlation with pulmonary fibrosis. Methods: 42 rats were randomly divided into control group (n = 12) and exposure group (n = 30). Tissues of right lower lungs were collected and fixed for further Hematoxylin-eosin (HE) and Masson staining. We collected the BALF to examine the inflammatory cytokines of TNF-α and TGF-β and measured the ion contents in BALF. Results: The increase of TNF-α level was earlier than TGF-β. The content of silica in BALF was significantly increased after exposure and reached the maximum at 7th day, similar to the curve of cytokine TGF-β level. However, phosphorus ions increased quickly after gradual decline of silicon ion and roughly proportional to the curve of degree of fibrosis. Conclusions: Crystalline silica exposure can cause changes in TGF-β and TNF-α in BALF and accompanied with fibrosis and ions content variation. The abnormal expression of phosphorus ion may have significance in the occurrence and development of silicosis.

Keywords: Pulmonary fibrosis, silicosis, SiO2 exposure environment

How to cite this article:
Hang W, Zhao J, Li Y, Wang L, Li H. Experimental study on the effect of Si and P ion content in SiO2 exposure environment on the degree of pulmonary fibrosis. Indian J Pathol Microbiol 2021;64:644-50

How to cite this URL:
Hang W, Zhao J, Li Y, Wang L, Li H. Experimental study on the effect of Si and P ion content in SiO2 exposure environment on the degree of pulmonary fibrosis. Indian J Pathol Microbiol [serial online] 2021 [cited 2023 Jan 31];64:644-50. Available from:

   Introduction Top

Silicosis is a fibrotic lung disease caused by inhalation of free crystalline silica (CS)-containing dust and the most common occupational diseases.[1],[2] It is the cause of death in thousands of workers exposed to CS.[3] In the newest occupational disease report of China, the pneumoconiosis accounts for 84.8% of the total occupational diseases, in which, the proportion of silicosis is as high as 93.6%. The prevention and treatment of silicosis is unsatisfying. The average age of occurrence in workers is decreased to 15 years, which is close to the level of early 1960.[4]

The precise mechanism of silicosis has not fully elicited yet and no effective treatment is available to reverse its process.[5] But it is known that the cumulative dose of silica should be the most important factor in silicosis development,[6] which can lead to constant inflammatory reactions of the lung and severe oxidative damage, and associated with several disorders, including tuberculosis, pulmonary obstructive disease and lung cancer.[7],[8],[9] Silicosis may also cause idiopathic pulmonary fibrosis (IPF), which is a progressive and diffuse parenchymal disease accompanied with fatal consequences.[10],[11] The effect of crystalline silica particles leading to silicosis has been proposed to relate with cytokine release, oxidative stress, and excessive cell death mediated by apoptosis. The proposed mechanisms include immediate cytotoxicity to alveolar cells, stimulation of inflammatory cytokines secretion, activation of oxidant generation and promotion of fibrogenic mediators from alveolar macrophages.[12],[13],[14]

In addition, some other researches had done to explore the pathogenesis of silicosis. For example, some researchers found that L-selectin may participate in silicosis.[15],[16] Malondialdehyde (MDA) is a lipid peroxidation product,which can measure the oxidative stress in cells. After exposure to CS, MDA may increase the oxidative stress can cause inflammation.[17],[18] CXCL2 and CXCL8 may also involve in the inflammatory reaction in CS exposed workers. MDA levels have negative correlation with the gene expression of CXCL2 and CXCL8 chemokines.[19] It was also found that DNA damage in blood and lymphocytes of silica-exposed workers.[20] However, different results were discovered as levels of these gene expressions are variated.[21],[22] Among them, inflammatory cytokines, such as TNF-α, is of great importance in inflammation and fibrosis.[23],[24],[25] Additionally, TGF-β, may be linked with fibroblast activation, may play a part in the pathogenesis.[26]

In summary, there are many factors that are involved in the pathogenesis of silicosis. Due to the refractory nature of silicosis (no specific effective treatment available) and carcinogenic effect of CS,[27],[28],[29] it is important for developing more precise techniques and biomarkers to detect early changes caused by CS exposure. In this study, in order to detect the concentration of CS well and truly, scanning electron microscope (SEM) and energy dispersive spectrometer (EDS) analysis method were used to measure the content of various ions such as silicon ion and phosphorus ions, etc. The relationship of ion contents with cytokines of TNF-α and TGF-β, and their significances in fibrosis caused by exposure of CS were discussed. The results of this study are of great significance to find out the influence of early markers on the health of silicosis patients.

   Methods Top

Experimental animals

42 male Sprague Dawley (SD) rats with weight ranged from 180 g to 220 g were fed under standard housing conditions (temperature of 18-24oC; relative humidity of 45-60%) and were acclimatized for 7 days before the initiation of the experiment. Our study was conducted in conformity to the requirements of the Chinese Association of Laboratory Animal Care.

42 adult male SD rats were randomly divided into two groups. The rats in control group (n = 12) were exposed to 0.9% saline and the rats in exposure group (n = 30) were exposed to silica. They were all administered by intratraecheal instillation.

Silica preparation

Silica dust (Sigma-Aldrich, St Louis, MO, USA) were added with saline to prepare suspension of 50 mg/ml in aseptic condition and autoclave sterilized to add 8000 U penicillin, thus forming the final silicon suspension.

Silica-induced silicosis in rats

The endotracheal intubation perfusion method was used to administer single intratracheal injection of 1 ml SiO2 suspension (50 mg/ml). The rats were intraperitoneal injected with chloral hydrate and were fixed to inject solution by lung perfusion needle. The control group was instilled with equal amount of 0.9% saline. After perfusion, the rats were placed in a warm ventilated environment. They were sacrificed for further study at 1, 3, 7, 14, 21, 28 day (n = 2 for control group, n = 5 for exposure group) after silica/saline instillation. Tissues of right lower lung were collected and fixed for further Hematoxylin-eosin (HE) and Masson staining to evaluate histopathology changes and collagen deposition.

Collection of bronchoalveolar lavage fluid (BALF)

The right lower lobe of lung in rats were ligated at the bronchi and fixed in 10% formalin. The left lung were washed by 2 ml saline of 37°C through trachea cannula for three times to collect BALF. The procedures were conducted under aseptic condition. Bronchoalveolar lavage fluid was collected and centrifuged at 15000 rpm at 4°C for 15 min. Supernatant was extracted and downline loading in 15 ml test tube and stored at -80oC. Sediment was washed with alcohol by ultrasonic cleaning machine for three times and then conducted for SEM and EDS analysis.

Histopathological and fibrotic examination

The rats were sacrificed by bleeding from abdominal aorta after anesthesia. The right lower lobes were fixed in 10% formalin. The size of section was prepared as 4 mm each and stained with HE for histopathology and Masson staining for fibrotic examination.

The degree of alveolitis was evaluated by HE staining depending on its severity. A score ranging from 0 to 3+ was graded by the criteria introduced by Szapiel et al.[30] andthe average score was calculated for each group at different time points. The severity of fibrosis was determined by Masson staining method. The grade of pulmonary fibrosis was blindly scored by Szapiel et al.'s method with grades range from 0 to 3+.

Inflammatory cytokine measurement

The BALF was obtained from each sample in vivo and centrifuged. Supernatants were collected for the measurement of TNF-α, TGF-β by enzyme-linked immunosorbent assay (ELISA) kit (BioLegend, Inc., CA, USA). 10% fetal bovine serum was used to block the plate for 1 hour. Then the cytokines or sample supernatants was added. With further incubation for 3 h, the wells were washed followed by the addition of detection reagent. Then the wells were washed again after 1 h incubation and substrate were added. The optical density (OD) was analyzed by microplate reader.

SEM and EDS analysis

The sediment was placed on a glass slide and waited for its natural drying. Slide was adhered to the sample holder with a conductive paste and sprayed a layer of conductive plating gold film in the vacuum coating machine. The microscopic morphology of the samples under different magnification were observed and photographed by SEM (S- 3000N, Hitachi, Japan). The acceleration voltage of SEM during test was 20 kV. The ion compositions of samples were then analyzed by the EDS element analysis function.

Statistical analysis

The statistical analyses were performed by SPSS 20.0 software. The counting data were presented as the mean ± standard deviation (SD). One-way analysis of variance was used to analyze the significance of differences between groups. Pearson correlation analyses were used to investigate the correlation between P and Si ions and pulmonary fibrosis. Results were considered significant if the P value was less than 0.05.

   Results Top

HE staining

[Figure 1] showed the H and E staining in lung tissues of two groups at different time points. The histopathologic changes of control group exhibited normal lung morphology, which characterized by fine interalveolar septa and well-formed alveolar space with no obvious inflammatory changes observed nearby. However, the lung tissue of the silica-exposed group showed progressive inflammatory changes over time. A single dose silica instillation could produce 1+-2+ grade alveolitis in early stage (d1, d7, d14), which exhibited ill-structured alveolar, thickened alveolar septa and dramatic inflammatory cells infiltration in alveolar space and interstitial lung. At 21 and 28 days after silica exposure, lung tissue instilled with silica had conspicuous 2+-3+ grade alveolitis consisting of significant collapsed alveolar space with obvious formation of silicon nodules, which represent the further exacerbation of fibrosis.
Figure 1: H and E staining of lung tissue in two groups at different time points (×100) (a) control group, day 7, normal lung morphology; (b) exposure group, day 1; (c) exposure group, day 3; (d) exposure group, day 7; (e) exposure group, day 14; (f) exposure group, day 21; (g) exposure group, day 28

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Masson staining

In Masson stained sections [Figure 2], the control group had a small amount of blue collagen fibers distributed in alveolar septum. At 7th day of silica instillation in exposure group, lung tissues exhibited thickened alveolar septum, with a large number of inflammatory cells and macrophages clustered and a few scattered collagen fibers. At the 14th day, collagen fibers were significantly increased and were irregularly arranged in the nodules, which showed 1+-2+ grade of fibrosis. At the 28th day, 2+-3+ grade of fibrosis was seen in lung tissues, which was characterized by more densified collagen deposition and more severe fibrosis.
Figure 2: Masson staining of lung tissue in two groups at different time points (×100) (a) control group, day 7, normal lung morphology; (b) exposure group, day 1; (c) exposure group, day 3; (d) exposure group, day 7; (e) exposure group, day 14; (f) exposure group, day 21; (g) exposure group, day 28

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SiO2 induces elevation of TNF-α and TGF-β in BALF

To investigate the mechanism of particle-induced fibrosis, levels of TNF-α and TGF-β were measured by ELISA. In comparison with the control group, the TNF-α level in BALF of rats was significantly increased after exposure and reached the maximum on the third day and then followed by a gradual decline (P < 0.05), as shown in [Figure 3]a. There was also a remarkable increase of TGF-β in rats in comparison with the control group, which peaked on day 7, as shown in [Figure 3]b (P < 0.05).
Figure 3: (a) TNF-α and (b) TGF-β expression in BALF

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Results of SEM and EDS in BALF

The microscopic morphology of the samples under different magnification were observed and photographed by scanning electron microscope, as shown in [Figure 4]. [Figure 5] showed the content of ions in BALF at different time points in two groups. The control group has extremely small amount of Si ions in BALF but the content of Si ions increased immediately after exposure and reached a peak value of 47.12% on the 7th day [Figure 5]e. Afterwards, the Si ion content gradually decreased and lowered to 10.94% on the 28th day [Figure 5]h. The content of Cl ions in the lavage fluid fluctuated at 30% in exposure group with no statistically significant relationship with the length of exposure but generally 20% to 30% lower than the control group. What was beyond our expectation is that the P ion content in BALF of exposure group growing progressively with time and the value can reached to 53.41% on the 28th day [Figure 5]h.
Figure 4: Microscopic morphology of the samples (a) ×500, (b) ×1000

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Figure 5: Content of ions in BALF at different time points in two groups (a) control group, day 7; (b) control group, day 14; (c) exposure group, day 1; (d) exposure group, day 3; (e) exposure group, day 7; (f) exposure group, day 14; (g) exposure group, day 21; (h) exposure group, day 28

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   Discussion Top

Silicosis is the most common occupational disease. It is important to understand the pathogenic mechanism of CS in the lung to prevent silicosis formation and to improve the living quality of patients. The induction of cytotoxicity to alveolar cells and stimulation of inflammatory response are generally accepted mechanisms of silicosis. They may cause collagen gene expression enhancement and collagen deposition in the lungs,and resulted in the formation of fibroblast foci.[31] In this experiment, we adopted H and E staining to observe the distribution of inflammatory cells and Masson staining to examine collagen deposition in lung interstitium as to evaluate the progression of pulmonary fibrosis differences between groups. According to the staining presentation and formation of the silicon nodules in the later days of experiment [Figure 1] and [Figure 2], it is valid that the silicosis animal model has successfully established. These results can prove that CS was capable in induction of pulmonary inflammation and fibrosis.[32]

The pulmonary inflammation caused by silica may be a special regulatory mechanism of the production of inflammatory cytokines induced by silica. Among them, the role of TNF-α has attracted a lot of attention. It has been shown that TNF-α receptor signaling is necessary in the process of pulmonary fibrosis. In addition, as a multi-source cytokine, TGF-β can be secreted by a large number of cells including macrophages and damaged epithelial cells. Therefore, the role of TGF - β in the process of pulmonary fibrosis has also been widely concerned.[33],[34],[35] In our study, we demonstrated that the increase of TNF-α level is earlier than TGF-β and the later grow rapidly after the TNF-α reached its maximum, as shown in [Figure 3]. In this case, we can confirm that TNF-α is a cytokine and it works before TGF-β. The inflammatory cytokine of TNF-α may participate in silica-induced TGF-β production. After a short period of latency following exposure to silica, the later may strongly induced to play a follow-up effect which has not fully been understood currently. After the cytokines were fully activated, severe pulmonary inflammation and fibrosis begins to from.

There have been many theories to explore the pathogenesis of silicosis, and a variety of hypotheses have been proposed, but it is very clear that SiO2 dust is a key pathogenic factor on the incidence of silicosis. The cumulative dose of silica, which is characterized by repeated inhalation and prolonged duration, could be the key factor in silicosis development.[6] However, many previous researches suggested that silica-induced lung inflammation and fibrosis were insignificant or moderate in the early period of exposure.[36],[37] In order to detect the content of silica in BALF to understand the relationship of silica with cytokines TNF-α and TGF-β as well as histopathological changes after silica-exposure, we adopted EDS analysis to measure ion contents. SiO2 is not soluble in water, so we made suspension by adding normal saline with silica dust and the content of SiO2 wouldn't be reduced. We could accurately determine the silicon ion content in BALF through EDS, and the data reliability would be guaranteed. In our study, we conducted the microscopic morphology of the samples under different magnification and photographed by scanning electron microscope to observe the particles in BALF following centrifugation and desiccation. The ion compositions of samples analyzed by the EDS element analysis showed that the content of silica in BALF was significantly increased after exposure and reached the maximum at 7th day, similar to the curve of cytokine TGF-β level, but not parallel to degree of pulmonary fibrosis. It should be related to the interaction with cells in lung and activation of signaling pathways after silica-exposure.

Some studies have shown that alveolar macrophages (AMs) can capture and remove dust particles entering the alveoli. In this process, AMS is activated and releases inflammatory mediators, such as cytokines and growth factors.[38],[39],[40] In our study, the maximum level of TNF-α appears on the third day, which is earlier than the maximum value of silicon in BALF of 7th day [as shown in [Figure 3]a and [Figure 5], we speculate that silica-induced acute inflammation (activation of cytokine network) is severe in early time and more important than the ingestion of silicon. The silica-ingested AMs may undergo apoptosis and trigger another phagocytosis and inflammation cycle to produce long-term and chronic effects.

Surprisingly, fibrogenesis did not occur as the silicon ions in BALF reached its highest on the 7th day, and the level of silicon had a sustained downward trend when the lung fibrosis was getting serious [Figure 6]a. Therefore, we speculate that ingested silicon itself is not the most important factor in chronic silicotic pulmonary fibrosis. However, phosphorus ions increased quickly after gradual decline of silicon ion and roughly proportional to the curve of degree of fibrosis. It reached its highest level on the 28th day, which was also the time point of most severe fibrosis happened in our study, as shown in [Figure 6]b. Accordingly, we hypothesized that the phosphorus ions may participate in the mechanism concerned with fibrosis after exposure of silica. Many studies have shown the phosphorylation mechanism involved in formation of fibrosis. SiO2 exposure may result in JNK, p38, Erk, MAPK, and PI3K/Akt phosphorylation in AMs.[41],[42] Meanwhile, protein phosphorylation in NF-kB and NLRP3 signaling pathways and TGF-β-Smad3 signaling are both in crucial in the advancing of fibrosis.[43],[44] At this time, there has no evidence that changes in phosphorous ions are related to these phosphorylation mechanism, and further experiments need to be done on account of the current research.
Figure 6: Correlation of (a) Si and (b) P ion content with degree of fibrosis

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   Conclusions Top

Our study demonstrated that crystalline silica exposure can cause changes in TGF-β and TNF-α in BALF, which is related to the change trend of silicon ions. The abnormal expression of phosphorus ion may have certain effect in the occurrence and development of silicosis. In the future study, we will make further efforts on the relationship of phosphorus ions variation with protein phosphorylation in signaling pathways. If this assumption is valid, EDS analysis may serve as the testing method in fibosis disease detection and phosphorus ion can be the early biomarkers of fibrosis for early response to crystalline silica exposure.

Ethical considerations

Ethical issues (Including plagiarism, Informed Consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.

Financial support and sponsorship

This study was supported by Xuzhou Science and Technology Bureau (KC18021), Xuzhou Mining Group General Hospital Scientific Research Project (Y2016009), and Xuzhou Medical University Scientific Research Project (2015KJ10).

Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Haiquan Li
Xuzhou Mining Group General Hospital, #32 Meijian Road, Xuzhou, Jiangsu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_433_20

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