Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

Besnard, Valérie; Jeny, Florence

doi:10.3390/jcm9082445

Cited by 14 publications

(8 citation statements)

References 159 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As noted in a recent review of in vitro/in vivo sarcoidosis models, more innovative approaches are needed to explore the pathogenesis and pathophysiology of sarcoidosis [ 67 ]. A focus on granuloma formation alone is insufficient to provide information on mechanisms of fibrosis formation which affects some 20% of sarcoidosis patients [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis

Barna

Malur

Thomassen

2021

IJMS

View full text Add to dashboard Cite

Poorly soluble environmental antigens, including carbon pollutants, are thought to play a role in the incidence of human sarcoidosis, a chronic inflammatory granulomatous disease of unknown causation. Currently, engineered carbon products such as multiwall carbon nanotubes (MWCNT) are manufactured commercially and have been shown to elicit acute and chronic inflammatory responses in experimental animals, including the production of granulomas or fibrosis. Several years ago, we hypothesized that constructing an experimental model of chronic granulomatosis resembling that associated with sarcoidosis might be achieved by oropharyngeal instillation of MWCNT into mice. This review summarizes the results of our efforts to define mechanisms of granuloma formation and identify potential therapeutic targets for sarcoidosis. Evidence is presented linking findings from the murine MWCNT granuloma model to sarcoidosis pathophysiology. As our goal was to determine what pulmonary inflammatory pathways might be involved, we utilized mice of knock-out (KO) backgrounds which corresponded to deficiencies noted in sarcoidosis patients. A primary example of this approach was to study mice with a myeloid-specific knock-out of the lipid-regulated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) which is strikingly depressed in sarcoidosis. Among the major findings associated with PPARγ KO mice compared to wild-type were: (1) exacerbation of granulomatous and fibrotic histopathology in response to MWCNT; (2) elevation of inflammatory mediators; and (3) pulmonary retention of a potentially antigenic ESAT-6 peptide co-instilled with MWCNT. In line with these data, we also observed that activation of PPARγ in wild-type mice by the PPARγ-specific ligand, rosiglitazone, significantly reduced both pulmonary granuloma and inflammatory mediator production. Similarly, recognition of a deficiency of ATP-binding cassette (ABC) lipid transporter ABCG1 in sarcoidosis led us to study MWCNT instillation in myeloid-specific ABCG1 KO mice. As anticipated, ABCG1 deficiency was associated with larger granulomas and increased levels of inflammatory mediators. Finally, a transcriptional survey of alveolar macrophages from MWCNT-instilled wild-type mice and human sarcoidosis patients revealed several common themes. One of the most prominent mediators identified in both human and mouse transcriptomic analyses was MMP12. Studies with MMP12 KO mice revealed similar acute reactions to those in wild-type but at chronic time points where wild-type maintained granulomatous disease, resolution occurred with MMP12 KO mice suggesting MMP12 is necessary for granuloma progression. In conclusion, these studies suggest that the MWCNT granuloma model has relevance to human sarcoidosis study, particularly with respect to immune-specific pathways.

show abstract

Section: Discussionmentioning

confidence: 99%

Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis

Barna

Malur

Thomassen

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…evidence suggests that Th17 +sarcoidosis granulomas formation & maintenance. According to the popular view, antigen persistence causes inflammatory cascade intensification & prolongation (with tumor necrosis factor increase), while stoppage of the inflammatory cascade and disease remission occur following the antigen clearance [7].…”

Section: Recentmentioning

confidence: 99%

Usage of Tofacitinib as a Steroid-sparing Therapy in Pulmonary and Cutaneous Sarcoidosis

Moursi

Ali

2023

JAMMR

View full text Add to dashboard Cite

Background: Sarcoidosis is a multisystem, granulomatous & chronic illness which typically affecting lymph nodes & lungs also any organ system. We aimed to evaluate the tofacitinib effectiveness as cutaneous & pulmonary sarcoidosis steroid-sparing treatment. Methods: This retrospective cohort observational research was performed on 45 cases aged from 20 to 65 years old, both sexes, a forced vital capacity (FVC) >50%, histology consistent with sarcoidosis, pulmonary sarcoidosis definition by association for Sarcoidosis and other Granulomatous Disorders (WASOG) & disease progression or symptoms necessitating 15-30 mg/day prednisone (or comparable corticosteroids) as a consistent dose of for at least 4 weeks before enrolment. The definition of Steroid-dependent disease was the necessity for steroids for disease symptoms or progression control, but pulmonary impairment on pulmonary function testing was not required. Additionally, all instances with a history of failed attempts to reduce corticosteroid doses, and their treating physicians urged steroid-sparing therapy. Results: Pulmonary function tests (FVC, FEV1, FEV1/ FVC ratio) were significantly improved after treatment compared to baseline (P value <0.001). 41 (91.1%) patients showed pulmonary improvement. The last evaluated CSAMI activity score was significantly lower compared to baseline CSAMI activity score (6.38 ± 2.7 vs. 39.51 ± 14.1, P <0.001). The mean CSAMI activity score decrease was 33.13± 11.4%. Conclusions: Tofacitinib is a promising strategy for of cutaneous & pulmonary sarcoidosis treatment.

show abstract

“…Animal models of sarcoidosis are difficult to induce, the previous attempts to evaluate the causes of the disease progression and the etiology-based treatment were unsuccessful ( 48 ). Animal studies have mainly demonstrated the development of pulmonary granulomas without fibrosis following exposure to various antigens ( M. Tuberculosis peptides , P. Acne , carbon nanoparticles).…”

Section: Animal Modelsmentioning

confidence: 99%

“…The granulomas observed in the experiment were shown to exist only if there was a continuous exposure to the adjuvant. We believe that sarcoidosis patients are chronically exposed by one or several triggers that contribute development and persistence of granulomas ( 48 ) or autoimmune inflammation ( 6 ).…”

Section: Animal Modelsmentioning

confidence: 99%

“…Some clinical characteristics such as extrapulmonary manifestations (especially cardiac sarcoidosis or neurosarcoidosis), composite physiologic index (CPI) - the index of lung function variables, which correlates with the degree of interstitial disease and CT measurements - the degree of fibrosis, enlargement of the pulmonary artery and the measures of diffuse lung carbon monoxide (DLCO) percentages were shown as markers of severity of pulmonary sarcoidosis ( 36 , 48 , 55 , 56 ).…”

Section: The Predictors Of the Progression Of Sarcoidosismentioning

confidence: 99%

See 1 more Smart Citation

Sarcoidosis: Progression to the chronic stage and pathogenic based treatment (narrative review)

et al. 2022

View full text Add to dashboard Cite

Many factors confirm the autoimmune nature of sarcoidosis and help in determining the strategy of patient management and treatment initiation. However, the causes and the mechanisms of disease progression that result in fibrosis and insufficiency of the affected organ remain unclear. This narrative review aims to analyse the mechanisms and biomarkers of sarcoidosis progression, as well as the pathogenetic basis of sarcoidosis therapy. The following characteristics of progressive chronic sarcoidosis were revealed: the disease develops in patients with a genetic predisposition (SNP in genes GREM1, CARD15, TGF-β3, HLA-DQB1*06:02, HLA-DRB1*07/14/15), which contributes either the decreased ability of antigen elimination or autoimmune inflammation. Various prognostic biomarkers of disease progression (decreased levels of neopterin, elastase, sIL-2R, chitotriosidase, glycoprotein Krebs von den Lungen, Th17 cell count, reduced quantity of TNF-α in peripheral blood or bronchoalveolar lavage fluid) have been described and can potentially be used to determine the group of patients who will benefit from the use of corticosteroids/cytostatic drugs/biologics.

show abstract

Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

Cited by 14 publications

References 159 publications

Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis

Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis

Usage of Tofacitinib as a Steroid-sparing Therapy in Pulmonary and Cutaneous Sarcoidosis

Sarcoidosis: Progression to the chronic stage and pathogenic based treatment (narrative review)

Contact Info

Product

Resources

About