Immunology 906 Ferreira SC et al. Creatine Impairs Lung Epithelial Inflammation … Int J Sports Med 2010; 31: 906–912 accepted after revision August 26, 2010 Bibliography DOI http://dx.doi.org/ 10.1055/s-0030-1267160 Published online: November 11, 2010 Int J Sports Med 2010; 31: 906–912 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0172-4622 Correspondence Dr. Rodolfo Paula Vieira Albert-Ludwigs University of Freiburg, Pneumology Breisacher Straße 5 79106 Freiburg Germany Tel.: + 49/761/270 6363 Fax: + 49/761/270 6363 rodrelena@yahoo.com.br Key words ● ▶ creatine monohydrate ● ▶ airway epithelium ● ▶ cytokines ● ▶ growth factors ● ▶ allergy Creatine Activates Airway Epithelium in Asthma muscular inflammation that results from over- training and overuses [25], and in clinical prac- tice, Cr is used in the treatment of certain neuromuscular diseases [8]. Cr has been also administered to patients with chronic diseases such as heart disease [24], myopathies [8], chronic obstructive pulmonary disease [10] and cystic fibrosis [2]. Although creatine supplementation usually induces an anti-inflammatory response, we recently demonstrated that Cr exacerbates aller- gic chronic lung inflammation [30], suggesting that creatine supplementation might have dele- terious effects in individuals with allergic condi- tions such as asthma. This finding might be particularly important among athletes and sportsmen, a group with high prevalence of asthma and with indiscriminate use of Cr supple- mentation. We showed that the effects of Cr on airways of sensitized animals occur primarily via increased expression of interleukin (IL)-4, IL-5 and IGF-1. However, the effects of creatine sup- plementation on the epithelial allergic inflam- matory response have not been investigated. Introduction ▼ The airway epithelium can modulate inflamma- tory processes and airway remodelling in asthma by secreting different inflammatory mediators such as extracellular ATP, cytokines, chemokines, eicosanoids and growth factors [1, 3, 7, 20, 23]. Alterations in airway epithelial structure and mucus synthesis have been demonstrated in humans and in experimental models of allergic asthma and manifest mainly as an increase in the number of epithelial secretory cells and mucus production, events that greatly contribute to air- way obstruction [3, 15, 16, 19]. Cytokines and chemokines released by epithelial cells are also involved in eosinophil and Th 2 lymphocyte recruitment [19, 23, 24]. Creatine (Cr) is a nitrogenous amino acid deriva- tive found in beef and fish and is produced endog- enously from arginine, methionine and glycine [4, 10, 25, 30, 31]. It is widely used as a nutritional supplement by athletes to increase muscle mass and strength [4]. In sports medicine, Cr supple- mentation has the beneficial effect of decreasing Authors S. C. Ferreira 1 , A. C. Toledo 2 , M. Hage 1 , A. B. G. Santos 1 , M. C. R. Medeiros 1 , M. A. Martins 2 , C. R. F. Carvalho 3 , M. Dolhnikoff 4 , R. P. Vieira 5 Affiliations Affiliation addresses are listed at the end of the article Abstract ▼ Airway epithelium plays important roles in the pathophysiology of asthma. Creatine supple- mentation (Cr) was shown to increase asthma features in a murine model of allergic asthma; however, the role of the airway epithelium in this inflammatory response is not known. BALB/c mice were divided into control, creatine supple- mentation, ovalbumin-sensitized (OVA) and OVA plus creatine supplementation groups. OVA sen- sitization occurred on days 0, 14, 28 and 42, and ovalbumin challenge from days 21–53. Cr was also given on days 21–53. Total and differential cells counts in BALF were evaluated. Quantita- tive epithelial expression of interleukin (IL)-4, IL-5, IL-13, CCL11, CCL5, CCL2, iNOS, VCAM-1, ICAM-1, NF- κB, VEGF, TGF- β, IGF-1, EGFR, TIMP-1, TIMP-2, MMP-9, MMP-12 and arginase II were performed. Cr increased the number of total cells and eosinophils in BALF, the epithelial content of goblet cells and the epithelial expression of IL-5, CCL2, iNOS, ICAM-1, NF- κB, TGF- β, TIMP-1 and MMP-9 when compared to the control group (p < 0.05). Creatine supplementation also exac- erbated goblet cell proliferation, and IL-5 and iNOS expression by epithelial cells compared to the OVA group (p < 0.01). Creatine up-regulates the pro-inflammatory cascade and remodelling process in this asthma model by modulating the expression of inflammatory mediators by epithe- lial cells.