From granuloma to fibrosis

Abstract

Purpose of review Up to twenty percent of patients with sarcoidosis develop pulmonary fibrosis, transforming an often benign disease into a highly morbid and potentially fatal one. We highlight the fibrotic pulmonary sarcoidosis phenotype as an area of intense clinical and translational investigation, review recent developments in treatment, and provide a roadmap for future research in sarcoidosis associated pulmonary fibrosis. Recent findings Granulomatous inflammation in a lymphatic distribution is the hallmark finding of pulmonary sarcoidosis and the nidus for fibrosis. Recent research demonstrates that fibrotic sarcoidosis begins in the setting of persistent, uncontrolled inflammation, and is aided by pro-fibrotic genetic features and immune responses. Comparison to other fibrotic lung diseases also reveals key features that inform our understanding of common pathways in fibrosis. Summary Understanding the mechanisms of fibrotic transformation in sarcoidosis enhances clinical care and facilitates development of novel therapeutic options. The impact of these findings in fibrotic sarcoidosis may be amplified through application to other interstitial lung diseases marked by inflammatory to fibrotic transformation. Important aspects of clinical management of fibrotic sarcoidosis include surveillance for co-morbidities, such as pulmonary hypertension, airway disease, and infection, and assessment for pulmonary disease activity that may benefit from immunosuppression.

Transcriptome profiles in sarcoidosis and their potential role in disease prediction

“…Although neither a significant overlap in miRNA expression nor of their chromosomal location was found between lung and PBMC, predicted targets of differentially expressed mRNA were commonly linked to TGF-beta and WNT regulated pathways. These findings support the notion that cell profiles of lung tissues and blood are very different, but at the same time implicated in same pathways that are known to provide links between innate and adaptive immunity [14–16], fibroproliferation [17–19], granuloma formation and resolution [19,20]. Limitations of the study were small numbers of tissues (Table 1) that allowed for limited detection of significant differentially expressed mRNA and miRNA and the lack of a mechanism that proves the role of miRNA and their targets in TGF-beta and WNT pathways in the context of sarcoidosis development and pulmonary outcome.…”

Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice

“…The inhalation of DE increased the HOP content in the lung tissues in Nrf2 +/+ mice independently of TGF-β in the present study; this result may be caused by similar mechanisms, which is a subject for future analysis. Recent research also demonstrates that the progression from granuloma to fibrosis begins with persistent, uncontrolled inflammation and is associated with pro-fibrotic genetic features and immune responses [45]. …”

Key Players and Biomarkers of the Adaptive Immune System in the Pathogenesis of Sarcoidosis

“…These cells secrete IL-10, a suppressive cytokine that typically inhibits TH1 cell responses and counteracts the actions of inflammatory cytokines [ 16 ]. Although acute sarcoidosis is generally characterized by a proinflammatory TH1/M1 cell response, increased IL-10 messenger RNA (mRNA) levels have been detected in newly diagnosed patients with active sarcoidosis [ 17 , 18 ]. The indications that these two opposing subtypes of CD4 + T-cells and macrophages coexist seem counter-intuitive.…”

“…About two-thirds of patients diagnosed with acute sarcoidosis enter remission with good long-term outcomes, while one-third go on to develop chronic sarcoidosis [ 17 ].…”