Long-term treatment with royal jelly improves bleomycin-induced pulmonary fibrosis in rats

This study investigated the anti-fibrotic potential of royal jelly (RJ) powder against bleomycin-induced pulmonary fibrosis in rats. The rats were given RJ orally (25, 50, and 100 mg/kg per day) for 7 consecutive days before the administration of single intratracheal instillation of bleomycin (BLM) at 7.5 IU/kg. RJ doses were continued for 21 days after BLM exposure. Fibrotic changes in the lungs were studied by cell count and analysis of cytokine levels in the bronchoalveolar lavage fluid (BALF), histopathological examination, and assaying oxidative stress biomarkers in lung tissue. The results showed that BLM administration significantly increased the fibrotic changes, collagen content, and levels of malondialdehyde and decreased total thiol and glutathione peroxidase antioxidant contents in the rats’ lung tissue. An increase in the level of cell counts and pro-inflammatory and pro-fibrotic cytokines such as TNF-α and TGF-β in BALF was observed. Also, it significantly decreased IFN-γ, an anti-fibrotic cytokine, in BALF. However, RJ (50 and 100 mg/kg) reversed all of these biochemical indices as well as histopathological alterations induced by BLM. The present study demonstrates that RJ, by its antioxidant and anti-inflammatory properties, attenuates oxidative damage and fibrosis induced by BLM.

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Inflammogenic Effect of Polyacrylic Acid in Rat Lung Following Intratracheal Instillation

10.21203/rs.3.rs-147025/v1 ◽

2021 ◽

Author(s):

Chinatsu Nishida ◽

Taisuke Tomonaga ◽

Hiroto Izumi ◽

Ke-Yong Wang ◽

Toru Ishidao ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Tissue ◽

Polyacrylic Acid ◽

Intratracheal Instillation ◽

Allergic Diseases ◽

Lavage Fluid ◽

Interstitial Lung Diseases ◽

Organic Chemical ◽

Heme Oxygenase 1 ◽

Gene Expressions

Abstract BackgroundOrganic chemicals are known to cause allergic diseases 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.MethodsMale 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.ResultsPersistent increases in total cell count, neutrophil count and neutrophil percentage, and in the concentration of the cytokine-induced neutrophil chemoattractants (CINC)-1, CINC-2 and C-X-C motif chemokine 5 (CXCL5) (which had the highest expression of all chemokines by cDNA microarray using the lung tissue) 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. ConclusionOur results suggest that CL-PAA may potentially cause strong neutrophil inflammation in the rat and human lung.

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Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension

Thorax ◽

10.1136/thoraxjnl-2016-209701 ◽

2017 ◽

Vol 73 (6) ◽

pp. 581-583 ◽

Cited By ~ 21

Author(s):

Luca Richeldi ◽

Michael Kreuter ◽

Moisés Selman ◽

Bruno Crestani ◽

Anne-Marie Kirsten ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Term Treatment ◽

Adverse Event Profile ◽

Open Label ◽

Comparator Group ◽

Long Term Treatment ◽

Open Label Extension ◽

Rate Of Decline

The TOMORROW trial of nintedanib comprised a randomised, placebo-controlled, 52-week period followed by a further blinded treatment period and an open-label extension. We assessed outcomes across these periods in patients randomised to nintedanib 150 mg twice daily or placebo at the start of TOMORROW. The annual rate of decline in FVC was −125.4 mL/year (95% CI −168.1 to −82.7) in the nintedanib group and −189.7 mL/year (95% CI −229.8 to −149.6) in the comparator group. The adverse event profile of nintedanib remained consistent throughout the studies. These results support a benefit of nintedanib on slowing progression of idiopathic pulmonary fibrosis beyond 52 weeks.

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The Effects of Lung-Moistening Herbal Medicines on Bleomycin-Induced Pulmonary Fibrosis Mouse Model

Processes ◽

10.3390/pr8010102 ◽

2020 ◽

Vol 8 (1) ◽

pp. 102

Author(s):

Junmo Ahn ◽

Hyejin Joo ◽

Jihye Park ◽

Jae-Woo Park ◽

Kwan-Il Kim ◽

...

Keyword(s):

Lung Cancer ◽

Pulmonary Fibrosis ◽

Mouse Model ◽

Molecular Mechanisms ◽

Immune Cell ◽

Herbal Medicines ◽

Intratracheal Instillation ◽

Lavage Fluid ◽

Septal Thickness ◽

Different Doses

In traditional medicine, lung-moistening herbal medicines (LMHM) are regarded as a major option for treating symptoms of pulmonary fibrosis (PF) including dry cough and dyspnea. As PF agents are being applied to the development of lung cancer agents, PF and lung cancer are reported to have high pathological and pharmacological relationships. This study was proposed to identify candidates for the treatment of PF via investigating the effect of LMHM on PF mouse model. PF was induced by intratracheal instillation of bleomycin. Six water extracts of LMHM such as Farfarae Flos (FAF), Trichosanthis Semen (TRS), Lilii Bulbus (LIB), Adenophorae Radix (ADR), Asteris Radix (ASR), and Scrophulariae Radix (SCR) were prepared and administered (300 mg/kg) orally for 10 days after induction. The changes in body weight, histopathology, and immune cell of bronchoalveolar lavage fluid (BALF) were investigated. Among those, LIB and ADR significantly decreased the deposition of collagen and septal thickness of alveolar and terminal bronchiole. Moreover, SCR, TRS, LIB, and ADR decreased total cells, macrophages, and lymphocytes in BALF. Taken together, ADR and LIB could be the candidates to reduce PF. Further studies on their effects at different doses and analysis of their underlying molecular mechanisms are needed.

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Safety And Tolerability Of Long-term Treatment With Aerosolized Interferon Gamma In Idiopathic Pulmonary Fibrosis

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a3990 ◽

2010 ◽

Author(s):

Kristy Bauer ◽

Keith Diaz ◽

Lorraine Morra ◽

Gerald Smaldone ◽

Rany Condos

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Interferon Gamma ◽

Term Treatment ◽

Long Term Treatment

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Long‐term treatment with nintedanib in Asian patients with idiopathic pulmonary fibrosis: Results from INPULSIS®‐ON

Respirology ◽

10.1111/resp.13647 ◽

2019 ◽

Vol 25 (4) ◽

pp. 410-416 ◽

Cited By ~ 5

Author(s):

Jin Woo Song ◽

Takashi Ogura ◽

Yoshikazu Inoue ◽

Zuojun Xu ◽

Manuel Quaresma ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Term Treatment ◽

Asian Patients ◽

Long Term Treatment

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JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-210911 ◽

2017 ◽

Vol 76 (8) ◽

pp. 1467-1475 ◽

Cited By ~ 18

Author(s):

Yun Zhang ◽

Ruifang Liang ◽

Chih-Wei Chen ◽

Tatjana Mallano ◽

Clara Dees ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Chronic Treatment ◽

Term Treatment ◽

Janus Kinase ◽

Prolonged Treatment ◽

Therapeutic Effects ◽

Long Term Treatment ◽

Jak2 Inhibition ◽

Jak2 Inhibitors

ObjectivesJanus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-β. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts.MethodsThe antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance.ResultsThe antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis.ConclusionFibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.

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