Pulmonary hypertension associated with sarcoidosis

Abstract

Pulmonary involvement is common in sarcoidosis, an immune-mediated inflammatory disorder that is characterized by non-caseating granulomas in tissue. Sarcoid patients with advanced pulmonary disease, especially end-stage pulmonary fibrosis, risk developing pulmonary hypertension (World Health Organization group III pulmonary hypertension secondary to hypoxic lung disease). Increased levels of endothelin (ET)-1 in plasma and bronchoalveolar lavage of some sarcoid patients suggest that ET-1 may be driving pulmonary fibrosis and sarcoidosis-associated pulmonary hypertension. Although a relationship between raised levels of ET-1 and clinical phenotype is yet to be identified, early evidence from studies of ET-1 blockade with drugs such as bosentan is encouraging. Such therapy possibly could be combined with standard anti-inflammatory agents to improve outcome.

Figure 1

Inflammatory reaction of sarcoidosis. The initial response of sarcoidosis is mediated by CD4 and APCs which release a large number of cytokines. Over time, the granuloma can either resolve or go on to form fibrosis. Fibrosis is associated with TNF, IL-8 and ET-1. Ag, antigen; APC, antigen-presenting cell; ET, endothelin; HLA, human leucocyte antigen; IFN, interferon; IL, interleukin; TNF, tumour necrosis factor. Reproduced with permission from Baughman et al.: Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. Biodrugs 2003, 17(6):425–431. © Wolters Kluwer Health [5].

Figure 2

Endothelin-1 levels in BAL fluid from patients with interstitial lung disease, COPD, and control individuals. Levels of endothelin (ET)-1 in bronchoalveolar lavage (BAL) fluid specimens taken from patients with sarcoidosis (Sarc; n = 8), idiopathic pulmonary fibrosis (IPF; n = 9), fibrosing alveolitis in systemic sclerosis (PSS; n = 13) and chronic obstructive pulmonary disease (COPD; n = 8) were examined. A heterogeneous group of 19 patients served as control individuals. *Significantly higher than controls of COPD [18].

Figure 3

Endothelin-1 levels in bronchoalveolar lavage fluid (BAL) fluid in sarcoid patients and healthy controls. Endothelin-1 levels were measured by enzyme immunoassay and were corrected by albumin concentration in recovered BAL fluid. The data represent values ± standard error of the mean in both groups. *P < 0.05. Reproduced with permission from Terashita et al. Respirology 2006. © Blackwell Publishing [19].

Figure 4

Histological evidence of endothelin-1 in macrophages from sarcoid patients. Immunocytochemical detection of endothelin-1 in bronchoalveolar lavage (BAL) cells from patients with sarcoidosis and control individuals, using rabbit monoclonal antibody to human endothelin-1. Cytoplasm of BAL cells from sarcoidosis was strongly stained relative to controls. Immunostaining also demonstrated that most of the immunopositive cells were macrophages. Reproduced with permission from Terashita et al. Respirology 2006. © Blackwell Publishing [19].

Figure 5

Sarcoidosis before and after treatment: chest radiography. Shown are pretreatment (2003) and post-treatment (2006) chest radiographs in a patient with steroid-refractory sarcoidosis treated with bosentan and infliximab. Arrows indicate areas of infiltrates within both lung fields. The infiltrates have improved between 2003 and 2006 with treatment for the patient's sarcoidosis.