Idiopathic Pulmonary Fibrosis

Lederer, David J.; Martínez, Fernando J.

doi:10.1056/nejmra1705751

Cited by 1,450 publications

(1,274 citation statements)

References 93 publications

Supporting

Mentioning

1,245

Contrasting

Unclassified

Order By: Relevance

“…Ninety 4‐ to 5‐week‐old male C57BL/6J mice, weighing between 20 and 22 g, were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Male mice were selected for these experiments because IPF is more prevalent in men than in women (King et al., ; Lederer & Martinez, ; Raghu et al., ). Male mice also have a greater response to BLM than female mice irrespective of age (Redente et al., ).…”

Section: Methodsmentioning

confidence: 99%

“…One of the most widespread forms of lung fibrosis is idiopathic pulmonary fibrosis (IPF; Lederer & Martinez, ). Features of IPF include varying degrees of inflammation, aberrant fibroblast proliferation and extracellular matrix deposition, resulting in loss of lung function (Lederer & Martinez, ). Idiopathic pulmonary fibrosis is more prevalent in males than in females in their fifth or sixth decade of life (King, Pardo, & Selman, ; Lederer & Martinez, ; Raghu, Weycker, Edelsberg, Bradford, & Oster, ).…”

Section: Introductionmentioning

confidence: 99%

“…Features of IPF include varying degrees of inflammation, aberrant fibroblast proliferation and extracellular matrix deposition, resulting in loss of lung function (Lederer & Martinez, ). Idiopathic pulmonary fibrosis is more prevalent in males than in females in their fifth or sixth decade of life (King, Pardo, & Selman, ; Lederer & Martinez, ; Raghu, Weycker, Edelsberg, Bradford, & Oster, ). This may be because of the effect of oestrogens on collagen metabolism protecting premenopausal women, or some X‐linked genes that attenuate the development of fibrosis (Tatler et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…Idiopathic pulmonary fibrosis is more prevalent in males than in females in their fifth or sixth decade of life (King, Pardo, & c 2018 The Authors. Experimental Physiology c 2018 The Physiological Society Selman, 2011;Lederer & Martinez, 2018;Raghu, Weycker, Edelsberg, Bradford, & Oster, 2006). This may be because of the effect of oestrogens on collagen metabolism protecting premenopausal women, or some X-linked genes that attenuate the development of fibrosis (Tatler et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…This may be because of the effect of oestrogens on collagen metabolism protecting premenopausal women, or some X-linked genes that attenuate the development of fibrosis (Tatler et al, 2016). A history of smoking and inhalation exposure to environmental toxicants, such as mining dust, have been associated with an increased risk of IPF (Costabel, 2015;Lederer & Martinez, 2018;Ley & Collard, 2013). In addition to these environmental risk factors, genetic factors have been associated with IPF, the most prevalent being variations of the MUC5B gene (Dickey & Whitsett, 2017;Lederer & Martinez, 2018;Seibold et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Headley

Wilson

et al. 2018

Experimental Physiology

View full text Add to dashboard Cite

New Findings What is the central question of this study?When do alterations in pulmonary mechanics occur following chronic low‐dose administration of bleomycin? What is the main finding and its importance?Remarkably, we report changes in lung mechanics as early as day 7 that corresponded to parameters determined from single‐frequency forced oscillation manoeuvres and pressure–volume loops. These changes preceded substantial histological changes or changes in gene expression levels. These findings are significant to refine drug discovery in idiopathic pulmonary fibrosis, where preclinical studies using lung function parameters would enhance the translational potential of drug candidates where lung function readouts are routinely performed in the clinic. Abstract Idiopathic pulmonary fibrosis (IPF) is the most widespread form of interstitial lung disease and, currently, there are only limited treatment options available. In preclinical animal models of lung fibrosis, the effectiveness of experimental therapeutics is often deemed successful via reductions in collagen deposition and expression of profibrotic genes in the lung. However, in clinical studies, improvements in lung function are primarily used to gauge the success of therapeutics directed towards IPF. Therefore, we examined whether changes in respiratory system mechanics in the early stages of an experimental model of lung fibrosis can be used to refine drug discovery approaches for IPF. C57BL/6J mice were administered bleomycin (BLM) or a vehicle control i.p. twice a week for 4 weeks. At 7, 14, 21, 28 and 33 days into the BLM treatment regimen, indices of respiratory system mechanics and pressure–volume relationships were measured. Concomitant with these measurements, histological and gene analyses relevant to lung fibrosis were performed. Alterations in respiratory system mechanics and pressure–volume relationships were observed as early as 7 days after the start of BLM administration. Changes in respiratory system mechanics preceded the appearance of histological and molecular indices of lung fibrosis. Administration of BLM leads to early changes in respiratory system mechanics that coincide with the appearance of representative histological and molecular indices of lung fibrosis. Consequently, these data suggest that dampening the early changes in respiratory system mechanics might be used to assess the effectiveness of experimental therapeutics in preclinical animal models of lung fibrosis.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Headley

Wilson

et al. 2018

Experimental Physiology

View full text Add to dashboard Cite

show abstract

Lifestyle Choices and Environmental Exposures That Contribute to Pulmonary Disease: An AMA Guides Sixth Edition Perspective

Brigham,

Demeter,

Hoo

2023

Guides Newsletter

View full text Add to dashboard Cite

show abstract

The Future of Clinical Trials in Idiopathic Pulmonary Fibrosis

Podolanczuk

Richeldi

Martínez

2023

JAMA

Self Cite

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) currently affects about 100 000 individuals in the US, and millions globally. Patients living with IPF experience disabling symptoms and progressive loss of lung function. 1 The 2 treatments approved by the US Food and Drug Administration to treat IPF, nintedanib and pirfenidone, slow disease progression but do not stop or reverse lung fibrosis. 2,3 Both drugs are poorly tolerated by a substantial number of patients, and use is further limited by high cost and lack of perceived benefit on symptoms and quality of life. Many patients with IPF are eager to participate in clinical trials. Yet in the era of approved antifibrotic therapy, patients and their physicians must consider how potential investigational drugs will fit into the current standard of care.In this issue of JAMA, the results from the ISABELA 1 and ISABELA 2 randomized clinical trials, 4 one of the first phase 3 clinical trial programs in IPF to be completed since the approval of nintedanib and pirfenidone, are presented. The 2 identically designed trials randomized a total of 1306 patients to 1 of 2 doses of oral ziritaxestat (an autotaxin inhibitor that lowers levels of lysophosphatidic acid, which is a profibrotic mediator) or placebo. The trials allowed the continuation or initiation of background antifibrotic therapy.The trials were terminated early after an interim analysis raised safety concerns and revealed a lack of efficacy in the treatment groups. Neither dose of ziritaxestat demonstrated any benefit on the rate of decline for forced vital capacity (FVC) over 52 weeks. There was no benefit on any of the reported secondary outcomes. In fact, time to first respiratory-related hospitalization, respiratory-related mortality, and first acute IPF exacerbation were all worse in the ziritaxestat groups. All-cause mortality was highest in the high-dose ziritaxestat group, and in the ISABELA 2 trial, all-cause mortality was double that of placebo. Respiratory-related deaths were the primary cause of death.The ISABELA trials highlight the complexity of conducting IPF clinical trials in the era of approved antifibrotic therapy. 5 Each trial had 3 groups: high-dose ziritaxestat (600 mg/d), lowdose ziritaxestat (200 mg/d), and placebo. It also had 3 standard of care treatment options: pirfenidone, nintedanib, and neither; there was approximately equal distribution of participants among these 3 options. The study was well designed and conducted. Participants were recruited from 227 sites in 26 countries. There were missed clinic visits due to the COVID-19 pandemic, but this does not seem to have impacted the results. The enrolled patients had a centrally reviewed diagnosis of IPF and mild to moderate disease. There was good target engagement. Despite early termination, the 15. Martinez FJ, Yow E, Flaherty KR, et al; CleanUP-IPF Investigators of the Pulmonary Trials Cooperative. Effect of antimicrobial therapy on respiratory hospitalization or death in adults with idiopathic pulmonary fibrosis: the CleanUP-IPF randomized...

show abstract

Idiopathic Pulmonary Fibrosis

Cited by 1,450 publications

References 93 publications

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Lifestyle Choices and Environmental Exposures That Contribute to Pulmonary Disease: An AMA Guides Sixth Edition Perspective

The Future of Clinical Trials in Idiopathic Pulmonary Fibrosis

Contact Info

Product

Resources

About