Inflammogenic effect of polyacrylic acid in rat lung following intratracheal instillation

Abstract

Background Some organic chemicals are known to cause allergic disorders such as bronchial asthma and hypersensitivity pneumonitis, and it has been considered that they do not cause irreversible pulmonary fibrosis. It has recently been reported, however, that cross-linked acrylic acid-based polymer, an organic chemical, might cause serious interstitial lung diseases, including pulmonary fibrosis. We investigated whether or not intratracheal instillation exposure to cross-linked polyacrylic acid (CL-PAA) can cause lung disorder in rats. Methods Male F344 rats were intratracheally instilled with dispersed CL-PAA at low (0.2 mg/rat) and high (1.0 mg/rat) doses, and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure to examine inflammatory and fibrotic responses and related gene expressions in the lungs. Rat lungs exposed to crystalline silica, asbestos (chrysotile), and NiO and CeO2 nanoparticles were used as comparators. Results Persistent increases in total cell count, neutrophil count and neutrophil percentage, and in the concentration of the cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2 and C-X-C motif chemokine 5 (CXCL5), which correlated with lung tissue gene expression, were observed in bronchoalveolar lavage fluid (BALF) from 3 days until at least 1 month following CL-PAA intratracheal instillation. Persistent increases in heme oxygenase-1 (HO-1) in the lung tissue were also observed from 3 days to 6 months after exposure. Histopathological findings of the lungs demonstrated that extensive inflammation at 3 days was greater than that in exposure to silica, NiO nanoparticles and CeO2 nanoparticles, and equal to or greater than that in asbestos (chrysotile) exposure, and the inflammation continued until 1 month. Fibrotic changes also progressed after 1 month postexposure. Conclusion Our results suggested that CL-PAA potentially causes strong neutrophil inflammation in the rat and human lung.

Dose–response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats

“…Using a rat intratracheal administration model of CWAAP exposure, Nishida et al . showed that CWAAP treatment caused a sustained increase in not only CINC-1 but also CINC-2 and C-X-C motif chemokine 5 (CXCL5) in the BALF, and an increase in neutrophils in the BALF [ 3 ]. Thus, even though clodronate-mediated macrophage cell death results in increased recruitment of neutrophils into the untreated lung, the overall effect of a reduction of macrophage released neutrophil attractant cytokines in the CWAAP treated lung reduces neutrophil recruitment into the lung in response to CWAAP exposure.…”

“…Notably, five of these workers had a work history of only about 2 years. Based on the results obtained from a clinical research project on this case [ 2 , 3 ], in April 2019 the Ministry of Health, Labor and Welfare certified that five of the workers handling CWAAPs had incurred occupational injuries [ 4 ]. Consequently, to protect the health of workers who are still working in environments where CWAAPs are handled, it is extremely important to characterize the respiratory diseases caused by exposure to CWAAPs and to examine the mechanisms by which CWAAP-exposure causes these diseases.…”

Effect of Different Molecular Weights of Polyacrylic Acid on Rat Lung Following Intratracheal Instillation

“…We measured HO-1 concentration in rat lung induced by PAA as an inflammation-related factor. We previously reported in a comprehensive gene analysis that the upregulation of HO-1 in lung induced by CL-PAA was higher in the group of “response to oxidative stress”, and 4.62 times stronger compared to the control group [ 4 ]. In the present study, the HO-1 protein level in the lung tissue induced by the HMW PAA increased persistently during the observation period compared with that by the LMW.…”

“…Male Fischer 344 rats (8 weeks old) were purchased from Charles River Laboratories International, Inc. (Kanagawa, Japan) and kept for acclimatization for 4 weeks. They were raised under the same conditions as we described previously [ 4 ]. Briefly, they were accommodated in the Laboratory Animal Research Center of the University of Occupational and Environmental Health, Japan with free access to a commercial diet and water under a light/dark 12 h/12 h cycle, 20–25 °C, 40–70% humidity with ventilation 15 times/hour.…”

“…In Japan, it was reported that in a workplace where cross-linked acrylic acid-based polymers (CL-PAA) were handled, six out of tens of workers who had used a powder made of the polymers developed progressive lung disorders such as pneumoconiosis, emphysema and pneumothorax [ 3 ]. Intratracheal exposure to CL-PAA has also been reported to induce pulmonary inflammation in rat lung as severe or equivalent to crystalline silica and asbestos exposure [ 4 ]. It was confirmed from the above that CL-PAA, which is an organic compound, has severe inflammatory and fibrotic potentials in the lung.…”