Single intratracheal administration of cross-linked water-soluble acrylic acid polymer causes acute alveolo-interstitial inflammation and the subsequent fibrotic formation possibly via the TGF-β1 pathway in the lung of rats

Suka, Machi; Kido, Takamasa; Yoshioka, Wataru; Hachisuka, Eri; Okoshi, Hiroto; Yamauchi, Takashi; Hano, Hiroshi; Okano, Takashi; Yokoyama, Masayuki; Yanagisawa, Hiroyuki

doi:10.1016/j.tox.2020.152647

Cited by 12 publications

(21 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reports on pulmonary toxicity induced by CL-PAA have been inconsistent, with some reports showing inflammation and fibrosis [19][20][21][22], and other reports not showing inflammation and fibrosis [21]. This difference in pulmonary toxicity may be related to the difference of the physicochemical properties of CL-PAA.…”

Section: Discussionmentioning

confidence: 99%

Inflammogenic effect of polyacrylic acid in rat lung following intratracheal instillation

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Inflammogenic effect of polyacrylic acid in rat lung following intratracheal instillation

et al. 2022

View full text Add to dashboard Cite

show abstract

“…S11). In addition, a previous study reported that a single intratracheal administration of CWAAP at 0.1 mg/rat (about 0.43 mg/kg) caused a moderate inflammatory response [5]. Therefore, the dose of CWAAPs was set at 1 mg/kg, and the administration interval set at two weeks.…”

Section: Intratracheal Instillationmentioning

confidence: 99%

“…A recent study suggests that a single intratracheal administration of CWAAP to rats caused transient acute inflammation [5]. However, there is no similar evidence from inhalation exposure of CWAAPs, and in particular, the emergence of chronic pulmonary diseases such as fibrotic changes that occurred in the workers mentioned above has not been reported in animal studies.…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 14, 2021. ; https://doi.org/10.1101/2021.11. 13.468475 doi: bioRxiv preprint rats caused transient acute inflammation [5]. However, there is no similar evidence from inhalation exposure of CWAAPs, and in particular, the emergence of chronic pulmonary diseases such as fibrotic changes that occurred in the workers mentioned above has not been reported in animal studies.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pathological characteristics of pulmonary toxicity in F344 rats exposed by inhalation to cross-linked water-soluble acrylic acid polymers

Yamano

Takeda

Goto

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundRecently in Japan, six workers at a chemical plant that manufactures resins developed interstitial lung diseases after being involved in loading and packing cross-linked water-soluble acrylic acid polymers (CWAAPs). Since CWAAPs are not on the list of occupational diseases, the present study examined the lung damage potential of two CWAAPs (CWAAP-A and CWAAP-B) in rats, investigated pathological mechanisms, and established a method to rapidly evaluate the harmfulness of CWAAPs.MethodsUsing a whole-body inhalation exposure system, male F344 rats were exposed once to 40 or 100 mg/m3 of CWAAP-A for 4 hours or to 15 or 40 mg/m3 of CWAAP-A for 4 hours per day once per week for 2 months (a total of 9 exposures). In a separate set of experiments, male F344 rats were administered 1 mg/kg CWAAP-A or CWAAP-B by intratracheal instillation once every two weeks for 2 months (a total of five doses). Lung tissues, mediastinal lymph nodes, and bronchoalveolar lavage fluid were collected and subjected to biological and histopathological analyses.ResultsA single 4-hour exposure to CWAAP caused alveolar injury, and repeated exposures resulted in regenerative changes in the alveolar epithelium with activation of TGFβ signaling. During the recovery period after the last exposure, some alveolar lesions were partially healed, but other lesions developed into alveolitis with fibrous thickening of the alveolar septum. Rats administered CWAAP-A by intratracheal instillation developed qualitatively similar pulmonary pathology as rats exposed to CWAAP-A by inhalation. At 2 weeks after intratracheal instillation, rats administered CWAAP-B appeared to have a slightly higher degree of lung lesions compared to rats administered CWAAP-A, however, there was no difference in these lesions of CWAAP-A and CWAAP-B in rats examined 18 weeks after administration of these materials.ConclusionsThe present study provides evidence of rat lung pathogenesis after inhalation exposure to CWAAP-A. This study also demonstrates that the lung pathology of rats exposed to CWAAP-A by systemic inhalation was qualitatively similar to that of rats administered CWAAP-A by intratracheal instillation. The use of intratracheal instillation as an adjunct to systemic inhalation is expected to significantly accelerate the risk assessment for a variety of CWAAPs.

show abstract

“…Notably, five of these workers had a work history of only about two 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.…”

Section: Introductionmentioning

confidence: 99%

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

Takeda¹,

Yamano²,

Goto³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: In Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose-response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace. Methods: Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m3 CWAAP-A for 6 hours/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 hour, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 hours/day for 2 days. Results: CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m3 and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m3. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m3 CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m3 was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages. Conclusions: Pulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m3 CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined.

show abstract

Single intratracheal administration of cross-linked water-soluble acrylic acid polymer causes acute alveolo-interstitial inflammation and the subsequent fibrotic formation possibly via the TGF-β1 pathway in the lung of rats

Cited by 12 publications

References 20 publications

Inflammogenic effect of polyacrylic acid in rat lung following intratracheal instillation

Inflammogenic effect of polyacrylic acid in rat lung following intratracheal instillation

Pathological characteristics of pulmonary toxicity in F344 rats exposed by inhalation to cross-linked water-soluble acrylic acid polymers

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

Contact Info

Product

Resources

About