Elsevier

Clinics in Chest Medicine

Volume 29, Issue 3, September 2008, Pages 445-458
Clinics in Chest Medicine

Markers of Inflammation in Sarcoidosis: Blood, Urine, BAL, Sputum, and Exhaled Gas

https://doi.org/10.1016/j.ccm.2008.03.004Get rights and content

Sarcoidosis is characterized by intense inflammation at the different sites of localization. Many different mediators, such as cytokines, chemokines, and other proteins with various functions, that participate in its complex pathogenesis have been proposed as markers of inflammation. This article examines the principal literature on these different markers analyzed in serum, bronchoalveolar lavage, expired breath, and urine. After many years of research, no single marker sufficiently sensitive and specific for diagnosis of sarcoidosis has yet been found. Greater correlation with clinical parameters is needed and proper validation.

Section snippets

Angiotensin-converting enzyme

Serum ACE activity has been used as a diagnostic and prognostic marker of sarcoidosis since Lieberman [17] revealed its elevation in patients with active disease in 1975. ACE is an acid glycoprotein (molecular weight 140,000 d) that converts angiotensin I into angiotensin II by cleaving the dipeptide histidine and leucine C-terminal of angiotensin I [17]. It is secreted by monocytes and macrophages and in sarcoidosis by pulmonary endothelial cells that release ACE into blood vessels where it

Lysozyme

Lysozyme, produced by the monocyte-macrophage system, is another enzyme that can be considered a potential marker of sarcoidosis severity. Enhanced activity of phagocytes in sarcoidosis may determine an increase in lysozyme in serum of these patients. This enzyme was first discovered in 1922 by Fleming who reported that it had antibacterial activity through cleavage of β1-4 glycoside bonds in cell walls of certain bacteria. Lysozyme is normally present in the granules of monocytes, macrophages,

Chitotriosidase

Chitotriosidase is a member of family 18 of glycosylhydrolases (or chitinases), enzymes involved in the degradation of chitin (an abundant polymer of N-acetylglucosamine) and chitin-like substrate [43]. The enzyme is expressed by activated macrophages and elevated activity has been observed in serum of patients with atherosclerosis, β-thalassemia, acute Plasmodium falciparum malaria, and visceral leishmaniasis, and in cerebrospinal fluid of patients with multiple sclerosis [44], [45], [46].

Cytokines and chemokines

Many cytokines and chemokines have been analyzed in serum and BAL of sarcoidosis patients [3], [54]; some of these mediators, together with immunocompetent cells, are involved in the inflammatory processes occurring in this disease and may have a potential clinical application (Box 1, Fig. 3) [1], [12]. They have been studied singly and in panels to evaluate Th1/Th2 profile. BAL seems to have the potential to provide useful diagnostic parameters; however, no single biochemical marker

Markers of oxidative stress

Oxidative stress is the result of an imbalance between oxidant and antioxidant molecules and may cause cell damage. Inflammatory cells, such as neutrophils and macrophages, release reactive oxygen species, such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, which act as oxidants during inflammatory processes, damaging neighboring cells [98]. Reactive oxygen species affect different cell components, such as cell membrane lipids, DNA, and proteins [98]. Oxidative stress can be

Other markers of sarcoidosis

Immunologic studies on serum, tissue, and BAL have highlighted a polyclonal hypergammaglobulinemia (with a predominance of IgG) in sarcoidosis patients [33], [57], [107] and formation of circulating immune-complexes [107]. Their clinical value, however, is poorly defined.

Other markers of inflammation have been analyzed in different human biologic fluids by different methods. For example, endothelin-1, a vasoactive bronchoconstrictive peptide involved in lung fibroproliferative processes, has

Proteomic approach

A more recent approach to the analysis of sarcoidosis markers is the application of proteomics. Proteome analysis enables one simultaneously to analyze all proteins present in a biologic sample and to define protein profiles characteristic of a disease [86], [123]. This approach is independent of any a priori hypothesis about specific proteins, implying high potential for new discoveries [86], [104], [124], [125], [126], [127], [128], [129], [130], [131], [132]. Many techniques with different

Summary

Sarcoidosis is characterized by intense inflammation at the different sites of localization full-stop. According to a recent classification, has also been included among autoinflammatory diseases [133]. Many different mediators, such as cytokines, chemokines, and other proteins with various functions, participate in its complex pathogenesis and some have been proposed as markers of inflammation. These generally increase during the active phase of the disease and they are considered markers of

Acknowledgments

The authors thank C. Madioni, C. Olivieri, and F, Mezzasalma for their contribution.

References (134)

  • J. Hankiewicz et al.

    Lysozyme in human body fluids

    Clin Chim Acta

    (1974)
  • A. Wajner et al.

    Biochemical characterisation of chitotriosidase enzyme: comparison between normal individuals and patients with Gaucher and with Niemann-Pick diseases

    Clin Biochem

    (2004)
  • E. Bargagli et al.

    Chitotriosidase in BAL of patients with diffuse lung diseases

    Respir Med

    (2007)
  • K. Antoniou et al.

    Perforin down-regulation and adhesion molecules activation in pulmonary sarcoidosis

    Chest

    (2006)
  • J.C. Grutters et al.

    Serum soluble IL2 receptor measurement in patients with sarcoidosis

    Chest

    (2003)
  • A. Somoskovi et al.

    Polymorphism at position -308 in the promoter region of the TNF-α and in the first intron of the TNF-β genes and spontaneous and lipopolysaccharide-induced TNF-α release in sarcoidosis

    Cytokine

    (1999)
  • R. Kieszko et al.

    Tumor necrosis factor receptors (TNFRs) on T lymphocytes and soluble TNFRs in different clinical courses of sarcoidosis

    Respir Med

    (2007)
  • E. Yamaguchi et al.

    The gene polymorphism of tumor necrosis factor-ß, but not that of tumor necrosis factor-α, is associated with the prognosis of sarcoidosis

    Chest

    (2001)
  • H.L. Moses et al.

    TGF β stimulation and inhibition of cell proliferation: new mechanistic insights

    Cell

    (1990)
  • A. Kruit et al.

    Transforming growth factor-ß gene polymorphisms in sarcoidosis patients with and without fibrosis

    Chest

    (2006)
  • B. Wysoczanska et al.

    Combined association between IFN-gamma 3,3 homozygosis and DRB1%66D03 in Lofgren's syndrome patients

    Immunol Lett

    (2004)
  • J.S. Johansen et al.

    Increased serum YKL-40 in patients with pulmonary sarcoidosis: a potential marker of disease activity?

    Respir Med

    (2005)
  • F. Mrazek et al.

    Expression of the chemokine PARC in BAL of patients with sarcoidosis

    Immunol Lett

    (2002)
  • I. Rahman et al.

    Oxidant and antioxidant balance in the airways and airway diseases

    Eur J Pharmacol

    (2006)
  • D.R. Moller

    Potential etiologic agents in sarcoidosis

    Proc Am Thorac Soc

    (2007)
  • M. Drent et al.

    Sarcoidosis

    European Respiratory Monograph

    (2005)
  • M.W. Ziegenhagen et al.

    Exaggerated TNF alpha release of alveolar macrophages in corticosteroid resistant sarcoidosis

    Sarcoidosis Vasc Diffuse Lung Dis

    (2002)
  • M.C. Iannuzzi et al.

    Sarcoidosis

    N Engl J Med

    (2007)
  • O.A. Aladesanmi

    Sarcoidosis: an update for the primary care physicians

    MedGenMed

    (2004)
  • O.P. Sharma et al.

    Clinical value of ACE genotyping in diagnosis of sarcoidosis

    Lancet

    (1997)
  • G.S. Stokes et al.

    Influence of ACE genotype on interpretation of diagnostic tests for serum ACE activity

    Aust N Z J Med

    (1999)
  • S. Rothkrantz-Kos et al.

    Potential usefulness of inflammatory markers to monitor respiratory functional impairment in sarcoidosis

    Clin Chem

    (2003)
  • M.W. Ziegenhagen et al.

    BAL and serological parameters reflecting the severity of sarcoidosis

    Eur Respir J

    (2003)
  • P. Rottoli et al.

    Is bronchoalveolar lavage obsolete in the diagnosis of interstitial lung disease?

    Curr Opin Pulm Med

    (2003)
  • S.P. Kantrow et al.

    The CD4/CD8 ratio in BAL fluid is highly variable

    Eur Respir J

    (1997)
  • G.W. Hunninghake et al.

    Pulmonary sarcoidosis: a disorder mediated by excess helper T lymphocyte activity at sites of disease activity

    N Engl J Med

    (1981)
  • P.L. Haslam et al.

    Guidelines for measurement of acellular components and standardization of BAL

    Eur Respir J

    (1999)
  • P.R. Studdy et al.

    Angiotensin-converting enzyme and its clinical significant: a review

    J Clin Pathol

    (1983)
  • C. Gronhagen-Riska et al.

    Angiotensin-converting enzyme and lysozyme in silicosis and asbestosis

    Scand J Respir Dis

    (1978)
  • J. Lieberman et al.

    Update on SACE assays for diagnosis and evaluation of sarcoidosis

    (1974)
  • J. Lieberman et al.

    Serum angiotensin-converting enzyme in leprosy and coccidioidomycosis

    Ann Intern Med

    (1977)
  • J.A. Casal et al.

    Relationships between serum markers of monocyte/macrophage activation in type 1 Gaucher's disease

    Clin Chem Lab Med

    (2002)
  • B. Kennon et al.

    ACE gene polymorphism and diabetic complications: is there a connection?

    BioDrugs

    (2000)
  • R.C. Smallridge et al.

    Serum angiotensin-converting enzyme: alterations in hyperthyroidism, hypothyroidism and subacute thyroiditis

    JAMA

    (1983)
  • M. Schurmann

    Angiotensin converting enzyme gene polymorphism in patients with pulmonary sarcoidosis: impact on disease severity

    Am J Pharmacogenomics

    (2003)
  • F. Cambien et al.

    Familial resemblance of plasma ACE level: the Nancy study

    Am J Hum Genet

    (1998)
  • B. Rigat et al.

    An insertion/deletion polymorphism in the angiotensin I converting enzyme gene accounting for half the variance of serum enzyme levels

    J Clin Invest

    (1990)
  • P. Alia et al.

    Association between ACE gene I/D polymorphism and clinical presentation and prognosis of sarcoidosis

    Scand J Clin Lab Invest

    (2005)
  • E. Bargagli et al.

    Chitotriosidase levels in BAL of patients with sarcoidosis

    Sarcoidosis Vasc Diffuse Lung Dis

    (2007)
  • C. Prior et al.

    Lavage versus serum measurements of lysozyme, angiotensin-converting enzyme and inflammatory markers in pulmonary sarcoidosis

    Eur Respir J

    (1990)
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