Unbalanced MMP/TIMP-1 expression during the development of experimental pulmonary fibrosis with acute paraquat poisoning

Abstract

Abstract. Paraquat (PQ)-induced pulmonary toxicity is known to result in pulmonary edema, infiltration of inflammatory cells and damage to the alveolar epithelium, which may progress to severe fibrosis. Matrix metalloproteinases (MMPs) and their physiological inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), which degrade and remodel the excess extracellular matrix, are believed to play an important role in the development of fibrotic tissue. In this study, we examined the sequential expression of MMP-2, MMP-9 and TIMP-1 in a rat model of pulmonary fibrosis induced by PQ. Adult male Sprague-Dawley rats were treated intraperitoneally with PQ (20 mg/kg) and saline (control group). Rats were sacrificed at days 1, 3, 7 and 21 after the PQ treatment. Lungs were excised for histological evaluation and immunohistochemical analyses, as well as the determination of collagen content, gene expression by fluorimeter-based quantitive RT-PCR assay and gelatinolytic activity by zymography. Lung MMP-2 and -9 mRNA expression progressively increased and reached a peak on day 7 after PQ treatment, while TiMP-1 mrna levels in the PQ-treated lungs reached a peak on day 21 after modeling. Lung zymography revealed an increase in progelatinase B, progelatinase a and their active forms. In conclusion, unbalanced MMP/TIMP-1 expression and excessive gelatinolytic activity contribute to PQ-induced pulmonary fibrosis. Their precise role should be studied in depth as they may represent relevant therapeutic targets for PQ poisoning-induced pulmonary fibrosis.

Pathophysiology of Lung Injury Induced by Common Bile Duct Ligation in Mice

“…(data not shown) In addition to these data, we investigated the presence of fibrosis in lungs after CBDL using Masson trichrome staining, since we assumed that our model had the possibility of causing pulmonary fibrosis due to the high level of MMP expression. [20]–[22] However, the results showed that our model did not induce the development of pulmonary fibrosis at either 2 or 3 weeks after CBDL compared with sham operated mice (data not shown).…”

“…In our model, the reason that lung fibrosis, which was assessed with Masson trichrome staining, was not strongly induced might be explained as follows; firstly, MMP-9, which is secreted from increased neutrophils during inflammation plays a role in suppression of fibrosis in the tissue [20]. Secondly, unbalanced MMP and TIMP expression during the time course we used was reported to contribute to development of experimental pulmonary fibrosis: lung MMP-2 and MMP-9 m-RNA levels have peak levels and less pulmonary fibrosis is present 1 week after induction, while MMPs inhibitors, such as TIMPs, have a different peak and are present at higher levels 3 weeks after pulmonary fibrosis induction [21], [22] Lastly, the mice strain used, which was Balb/c, might have affected the development or severity of pulmonary fibrosis, as Walkin et al described that this strain is resistant to pulmonary fibrosis, but susceptible to hepatic fibrosis. [41] …”

Total glucosides of Danggui Buxue Tang attenuates bleomycin-induced pulmonary fibrosis via inhibition of extracellular matrix remodelling

“…In our study, MMP‐1, MMP‐9 and TIMP‐1 mRNA were significantly elevated in the lung after bleomycin‐induced injury and development of fibrosis. However, in the late phase of disease, production of MMP‐9 was gradually decreased, but the expression of TIMP‐1 continued to rise, which may lead to a MMP‐9/TIMP‐1 imbalance, resulting in ECM accumulation and remodelling [26,35,36] . Coadministration of DBTG with bleomycin reduced the bleomycin‐induced elevation in lung MMP‐9 mRNA levels, and particularly decreased TIMP‐1 expression, which determined the nature of the remodelling process.…”

Effect of Yangyinqingfei decoction on radiation-induced lung injury via downregulation of MMP12 and TIMP-1 expression

“…In addition, the destruction of the basement membrane, which regulates lung epithelial permeability, may promote migration of fibroblasts, as well as deposition of the alveolar cavity collagen fiber, and cause pulmonary fibrosis. TIMPs are endogenous inhibitors of MMPs, and it has been demonstrated that the MMP/TIMP and ECM metabolic imbalance is involved in the development and progression of pulmonary fibrosis (32). Selman et al (33) showed that in patients with IPF, dominant active TIMP expression resulted in filamentous collagen degradation, which caused the occurrence of pulmonary fibrosis.…”