Pirfenidone regulates LPS mediated activation of neutrophils

Evani, Shankar J.; Karna, S. L. Rajasekhar; Seshu, J.; Leung, Kai P.

doi:10.1038/s41598-020-76271-3

Cited by 15 publications

(12 citation statements)

References 73 publications

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“…In this work, LAS194046 reduced superoxide anion production in neutrophils from severe asthma and COPD patients which is in line with previous results in other cell types. In addition, it is known that LPS promotes the production of ROS in neutrophils 33 , and that ROS can phosphorylate JAK2/STAT3 34 as well as different MAPK, P38 and JNK in macrophages 35 , supporting the anti-inflammatory efficacy of pan-JAK inhibitors in a context of elevated oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

The pan-JAK inhibitor LAS194046 reduces neutrophil activation from severe asthma and COPD patients in vitro

Milara

Ballester

Diego

et al. 2022

Sci Rep

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Non-T2 severe asthma and chronic obstructive pulmonary disease (COPD) are airway chronic inflammatory disorders with a poor response to corticosteroids. LAS194046, a novel pan-Janus kinase (JAK) inhibitor, shows inhibitory effects on T2 allergic lung inflammation in rats. In this work we analyze the effects of LAS194046, fluticasone propionate and their combination in neutrophils from non-T2 severe asthma and COPD patients in vitro. Neutrophils from 23 healthy subjects, 23 COPD and 21 non-T2 severe asthma patients were incubated with LAS194046 (0.01 nM–1 µM), fluticasone propionate (0.1 nM–1 µM) or their combination and stimulated with lipopolysaccharide (LPS 1 µM). LAS194046 shows similar maximal % inhibition and potency inhibiting IL-8, MMP-9 and superoxide anion release in neutrophils from healthy, COPD and asthma. Fluticasone propionate suppresses mediator release only in neutrophils from healthy patients. The combination of LAS194046 with fluticasone propionate shows synergistic anti-inflammatory and anti-oxidant effects. The mechanisms involved in the synergistic effects of this combination include the increase of MKP1 expression, decrease of PI3Kδ, the induction of glucocorticoid response element and the decrease of ERK1/2, P38 and JAK2/STAT3 phosphorylation compared with monotherapies. In summary, LAS194046 shows anti-inflammatory effects in neutrophils from COPD and severe non-T2 asthma patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate.

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Section: Discussionmentioning

confidence: 99%

The pan-JAK inhibitor LAS194046 reduces neutrophil activation from severe asthma and COPD patients in vitro

Milara

Ballester

Diego

et al. 2022

Sci Rep

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“…Additionally, pulmosphere contain multiple cell types [ 8 ], and cell-cell communications as well as cell-autonomous and cell non-autonomous contributions, cytokines and ECM also affect the overall invasiveness of fibroblasts in the pulmosphere. The differential response to the pirfenidone could be explained by heterogenous responses to the cell types including alveolar epithelial cells and neutrophils [ 38 – 40 ].…”

Section: Discussionmentioning

confidence: 99%

Use of a pulmosphere model to evaluate drug antifibrotic responses in interstitial lung diseases

et al. 2023

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Background Interstitial lung diseases (ILD) encompass a heterogenous group of diffuse parenchymal lung disorders characterized by variable degrees of inflammation and fibrosis. Pretherapeutic clinical testing models for such diseases can serve as a platform to test and develop effective therapeutic strategies. In this study, we developed patient derived 3D organoid model to recapitulate the disease process of ILDs. We characterized the inherent property of invasiveness in this model and tested for antifibrotic responses with an aim to develop a potential platform for personalized medicine in ILDs. Methods In this prospective study, 23 patients with ILD were recruited and underwent lung biopsy. 3D organoid-based models (pulmospheres) were developed from the lung biopsy tissues. Pulmonary functioning testing and other relevant clinical parameters were collected at the time of enrollment and follow up visits. The patient derived pulmospheres were compared to normal control pulmospheres obtained from 9 explant lung donor samples. These pulmospheres were characterized by their invasive capabilities and responsiveness to the antifibrotic drugs, pirfenidone and nintedanib. Results Invasiveness of the pulmospheres was measured by the zone of invasiveness percentage (ZOI%). The ILD pulmospheres (n = 23) had a higher ZOI% as compared to control pulmospheres (n = 9) (516.2 ± 115.6 versus 54.63 ± 19.6 respectively. ILD pulmospheres were responsive to pirfenidone in 12 of the 23 patients (52%) and responsive to nintedanib in all 23 patients (100%). Pirfenidone was noted to be selectively responsive in patients with connective tissue disease related ILD (CTD-ILD) at low doses. There was no correlation between the basal pulmosphere invasiveness, response to antifibrotics, and FVC change (Δ FVC). Conclusions The 3D pulmosphere model demonstrates invasiveness which is unique to each individual subject and is greater in ILD pulmospheres as compared to controls. This property can be utilized to test responses to drugs such as antifibrotics. The 3D pulmosphere model could serve as a platform for the development of personalized approaches to therapeutics and drug development in ILDs and potentially other chronic lung diseases.

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“…Evaluating drug interactions with innate immune cells helps to broaden the understanding of anti-fibrotic strategy. A recent study demonstrated the anti-fibrotic potential of pirfenidone by decreasing neutrophil phagocytosis and ROS production (Evani et al, 2020).…”

Section: Therapy Strategies and Perspectivementioning

confidence: 99%

Hypoxia-induced reactive oxygen species in organ and tissue fibrosis

Xie¹,

WANG²,

Ma³

et al. 2023

Biocell

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Fibrosis is the end-stage change of damaged tissues in various human diseases, which can lead to permanent scarring or organ malfunction. Hypoxia leads to oxidative stress, mitochondrial dysfunction, and inflammation in dysfunctional organs and tissues. Oxidative stress resulting from the overproduction of reactive oxygen species plays a central role in the fibrosis of injured organs. This review addresses the updated knowledge of the relationship between hypoxia and tissue fibrosis mediated by the reactive oxygen species pathway. Moreover, novel anti-fibrotic strategies are discussed, which may suppress reactive oxygen species and organ fibrosis.

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Pirfenidone regulates LPS mediated activation of neutrophils

Cited by 15 publications

References 73 publications

The pan-JAK inhibitor LAS194046 reduces neutrophil activation from severe asthma and COPD patients in vitro

The pan-JAK inhibitor LAS194046 reduces neutrophil activation from severe asthma and COPD patients in vitro

Use of a pulmosphere model to evaluate drug antifibrotic responses in interstitial lung diseases

Hypoxia-induced reactive oxygen species in organ and tissue fibrosis

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