Type 2 cytokines and scleroderma interstitial lung disease

Abstract

Interstitial lung disease (ILD) is a life-threatening complication of systemic sclerosis (SSc). Type 2 (Th2) cytokines play a pivotal role in airway disease. Study aim was to evaluate serum level of Th2 interleukin (IL) and chemokine in SSc-ILD. Serum levels of IL-4, IL-5, IL-11, IL-13, IL-21, IL-31 and CXCL-13 were measured by Bio-Plex Multiplex Immunoassays in 60 SSc patients and 20 healthy controls (HC). Pulmonary function tests with diffusion lung capacity for carbon monoxide (DLco) and high resolution computed tomography (HRCT) were performed in SSc patients. ILD is defined as fibrotic changes (ground glass, reticular and honeycombing), assessed by Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER) software, affecting at least 10% of the lungs. Serum levels of Th2 cytokines were higher in SSc patients than HC. A linear correlation was observed between ground glass and IL-13 (r = 0.342, p < 0.01), IL-21 (r = 0.345, p < 0.01), IL-31 (r = 0.473, p < 0.001), IL-4 (r = 0.863, p < 0.001), IL-5 (r = 0.249, p < 0.05) and peripheral blood eosinophils (r = 0.463, p < 0.001). We found a negative correlation between DLco and IL-4 (r = − 0.511, p < 0.001) and peripheral blood eosinophils (r = − 0.446, p < 0.001). In the logistic regression analysis, IL-4 is associated with DLco ≤ 60% of the predicted [OR 1.039 (CI 95%: 1.015–1.064), p < 0.001], whilst mRSS [OR 1.138 (CI 95%: 1.023–1.266), p < 0.05] and IL-4 [OR 1.017 (CI 95%: 1–1.034), p < 0.05] were associated with ILD. Th2 inflammation could play a key role in early phase of SSc-ILD.

Biomarkers in Systemic Sclerosis: An Overview

“…The SSc vascular damage is characterized by the presence of a characteristic processes with a vasomotor instability with an imbalance of vasoactive factors: overproduction of vasoconstrictors (ET-1) and underproduction of vasodilators (NO and prostacyclin) [6][7][8][9][10][11][12][13][22][23][24][25][106][107][108][109]. The free radical nitric oxide (NO) is a potent vasodilator and is synthesized from L-arginine by NO synthase (NOS) [10][11][12][13][14][15][16][17][18][19][22][23][24][25][40][41][42][43][44][45][46][47][48][106][107][108][109][110][111][112][113]. Endothelial isoforms of NOS (eNOS or NOS 3) has been identified with a constitutive expression, other isoforms are shown...…”

“…Endothelial isoforms of NOS (eNOS or NOS 3) has been identified with a constitutive expression, other isoforms are shown in other cell types. Furthermore, an inducible expression (iNOS or NOS 2) in response to a variety of stimuli is possible, with NO-mediated signalling apparent in the skin [10][11][12][13][14][15][16][17][18][19][40][41][42][43][44][45][46][47][48][106][107][108][109][110][111][112][113]. Several studies reported that NO have a biphasic effect in physiological and pathological conditions, being both beneficial and detrimental depending on the concentration and local environment [10][11][12][13][14][15][16][17][18][19][40][41][42][43][44][45][46][47][48].…”

“…Furthermore, an inducible expression (iNOS or NOS 2) in response to a variety of stimuli is possible, with NO-mediated signalling apparent in the skin [10][11][12][13][14][15][16][17][18][19][40][41][42][43][44][45][46][47][48][106][107][108][109][110][111][112][113]. Several studies reported that NO have a biphasic effect in physiological and pathological conditions, being both beneficial and detrimental depending on the concentration and local environment [10][11][12][13][14][15][16][17][18][19][40][41][42][43][44][45][46][47][48]. Recently observation proposed the regulation of NO by endogenous levels of the NOS inhibitor asymmetric dimethylarginine (ADMA) [10]…”

“…The pathogenesis of SSc is complex and not yet completely understood, however the events involved in SSc pathogenesis can be schematically summarized in three main phases: (a) vascular damage, mainly of microcirculation; (b) immune system activation/autoimmunity/inflammation and (c) fibrosis [4][5][6][7][8][9][10]. Fibrosis of the skin and internal organs may be considered the main clinical hallmark of the disease and it is due to fibroblasts activation and dysfunction with the acquisition of a "myofibroblast phenotype" [1,2,[11][12][13][14][15][16][17][18]. Skin manifestations can be recognized and studied by using the modified Rodnan skin score (mRss), the validated method for assessing the severity of skin involvement in SSc and distinguishing the different subsets of skin involvement in SSc [6][7][8][9][10].…”

“…Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, along with anticentromere, anti-Th/To, and anti-topoisomerase I antibodies, which are considered the classic biomarkers present in 60% of SSc patients and help to define precise clinical classifications [4,7,[29][30][31][32][33][34][35][36][37]. Other autoantibodies, such as those directed against the endothelium or fibroblasts, against angiotensin II type 1 receptor, endothelin-1 type A receptor, platelet-derived growth factor receptor (anti-PDGFR), and extracellular matrix (ECM) proteins [16][17][18][19][20][38][39][40][41][42][43][44][45] are also found in SSc patients. More complex autoantibody systems against G-protein-coupled receptors, growth factors, and respective receptors have also been described in SSc [21,[45][46][47][48][49].…”