Pirfenidone: Molecular Mechanisms and Potential Clinical Applications in Lung Disease

Ruwanpura, Saleela; Thomas, Belinda; Bardin, Philip G.

doi:10.1165/rcmb.2019-0328tr

Cited by 170 publications

(107 citation statements)

References 113 publications

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“…Small molecule inhibitor of TGF-β1dependent stimulation of proinflammatory cytokines and fibroblast proliferation (Ruwanpura et al 2020).…”

Section: Pirfenidonementioning

confidence: 99%

Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments

Yong¹

2020

Preprint

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Long-haul COVID-19 illness first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is mysterious as it affects COVID-19 survivors at all levels of disease severity, even younger adults and children. While the precise definition may be lacking, the defining symptoms are fatigue, dyspnea, and headache that last for months after hospital discharge. The less typical symptoms may include cognitive impairments, chest and joint pains, myalgia, smell and taste dysfunctions, cough, mood changes, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long-haul COVID-19, which the current review aims to address. In brief, long-haul COVID-19 may be driven by long-term lung and brain damage and unresolved inflammation from multiple sources. The associated risk factors may include female sex, more than five early symptoms, early dyspnea, and specific biomarkers like D-dimer. While only rehabilitation training has been useful for long-haul COVID-19, therapeutics repurposed from mast cell activation syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, and pulmonary fibrosis also hold potential. In sum, this review hopes to provide the current understanding of what is known about long-haul COVID-19.

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“…Small molecule inhibitor of TGF-β1dependent stimulation of proinflammatory cytokines and fibroblast proliferation (Ruwanpura et al 2020).…”

Section: Pirfenidonementioning

confidence: 99%

Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments

Yong¹

2020

Preprint

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“…The better understanding of the pathogenetic processes implicated in fibrosis has helped development of pirfenidone, which is an orally available pyridinone derivative that inhibits collagen formation primarily, but not exclusively, through inhibition of two molecules implicated in fibrosis, such as TGF-beta and PDGF. Pirfenidone has been approved for the treatment of IPF and is being studied for the treatment of other forms of fibrosis [ 9 , 10 , 11 ]. However, response to pirfenidone is suboptimal for most patients and may be associated with some side effects [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Pesce

Bramanti

Iapichino³

et al. 2020

Molecules

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Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.

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“…A third possibility is that the innate tissue properties in the MRL mouse tendon (Paredes et al, 2020) bleomycin induced pulmonary fibrosis is prevented (Shetty et al, 2017) and its absence reduces chronic renal injury (Higgins et al, 2018). Furthermore, the antifibrotic agent used to treat IPF, Pirfenidone, has been shown to induce cell cycle arrest (Ruwanpura et al, 2020, Sun et al, 2018, Usugi et al, 2019. Reduced cell apoptosis, cell cycle regulation through p21 (cdkn1a) (Jablonski et al, 2019, Bedelbaeva et al, 2010, p53 (trp53), and p16 (cdkn2a), increased cell proliferation (Bedelbaeva et al, 2010), and enhanced stem cell function (Naviaux et al, 2009) may command augmented regenerative capacity.…”

Section: Discussionmentioning

confidence: 99%

Altered TGFB1 regulated pathways promote accelerated tendon healing in the superhealer MRL/MpJ mouse

Kallenbach

Freeberg

Abplanalp

et al. 2021

Preprint

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To better understand the molecular mechanisms of tendon healing, we investigated the Murphy Roths Large (MRL) mouse, which is considered a model of mammalian tissue regeneration. We show that compared to C57Bl/6J (C57) mice, injured MRL tendons have reduced fibrotic adhesions and cellular proliferation, with accelerated improvements in biomechanical properties. Transcriptional analysis of biological drivers showed positive enrichment of TGFB1 in both C57 and MRL healing tendons. However, only MRL tendons exhibited downstream transcriptional effects of cell cycle regulatory genes, with negative enrichment of the cell senescence-related regulators, compared to the positively-enriched inflammatory and ECM organization pathways in the C57 tendons. Serum cytokine analysis revealed decreased levels of circulating senescence-associated circulatory proteins (SASP) in response to injury in the MRL mice compared to the C57 mice. These data collectively demonstrate altered TGFB1 regulated inflammatory, fibrosis, and cell cycle pathways in flexor tendon repair.

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Pirfenidone: Molecular Mechanisms and Potential Clinical Applications in Lung Disease

Cited by 170 publications

References 113 publications

Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments

Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Altered TGFB1 regulated pathways promote accelerated tendon healing in the superhealer MRL/MpJ mouse

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