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Highlights of the March Issue

¹ Editor, AJRCMB, North Carolina State University, Raleigh, North Carolina; and ² Deputy Editor, AJRCMB, University of Alabama at Birmingham, Birmingham, Alabama

ADENOSINE MODULATES INFLAMMATION

Adenosine, the breakdown product of ATP, is present in the normal epithelial lining fluid and its concentration increases significantly during inflammation and tissue injury. For example, significantly higher levels of adenosine have been reported in lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma. Four distinct adenosine G protein–coupled receptors—type 1 (A1), type 2a (A2a), type 2b (A2b), and type 3 (A3)—are present in the lungs of mice and rats (1). In general, stimulation of A1R and A3R receptors inhibit, while stimulation of A2R activates adenylate cyclase and increases cAMP. Previous studies published in the American Journal of Respiratory Cell and Molecular Biology indicated that stimulation of A3R decreased inflammation, but not the degree of fibrosis, in bleomycin-treated mice (2). Inhibition of the A2bR in human bronchial epithelial cells increased chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR), resulting in significantly lower levels of airway surface liquid, which had adverse effects on mucus viscocity (3), indicating an important role of adenosine in CFTR stimulation. In this issue (pp. 251–259), Scheibner and colleagues (4) describe a novel and potentially important anti-inflammatory function of adenosine: during tissue injury, fragments of the extracellular matrix component hyaluronan (HA) promote inflammation by inducing proinflammatory genes. Using peritoneal macrophages, the authors conclusively demonstrated that specific agonists of A2a (but not of A1 or A3) receptors decreased HA-induced proinflammatory gene expression (TNF-, MIP-2, KC, and MIP-) and at the same time increased mRNA expression of IL-12, an anti-inflammatory cytokine. These effects were prevented by incubation of macrophages with exchange protein activated by cAMP (EPAC) siRNA but not with H89, a specific PKA inhibitor, indicating downstream involvement of Rap GTPases in this process. Peritoneal macrophages from A2aR-null mice had considerably higher levels of TNF- expression as compared with wild-type controls. Finally, intratracheal instillation of bleomycin into the lungs of A2aR-null mice resulted in higher inflammation, lung injury, and HA accumulation. However, the effects of intratracheal instillation of adenosine were not investigated, and it is possible that there is a biphasic effect of adenosine on inflammation, as demonstrated by Factor and colleagues (1) on ion transport. Taken as a whole, these very interesting studies indicate that stimulation of A2aR reduces inflammation via EPAC-dependent mechanisms, and that agents which stimulate A2aR could potentially decrease inflammation in a variety of human diseases.

"INSTANT CARMA'S GONNA GET YOU ..."

In this issue of the Journal, the paper "CARMA3 mediates lysophatidic acid stimulated secretion by bronchial epithelial cells" by Medoff and colleagues (pp. 286–294) (5), including investigators from Massachusetts General Hospital and Harvard Medical School, implicates CARMA3, also known as CARD10, in activation of NF-B and resultant proinflammatory responses in airway epithelial cells in response to lysophosphatidic acid, a lipid mediator that is elevated in asthma. The fact that NF-B is involved in numerous proinflammatory events in airway epithelium is almost dogmatic, and there appear to be numerous pathways capable of transducing stimulation at the cell surface to activation of this well-studied and -characterized transcription factor in several disease states. Oxidant stress, arginase-dependent regulation of nitric oxide levels (6), and MAP kinase pathway–associated molecules, among others, have all been implicated. Here, Medoff and colleagues (5) bring another potential regulatory molecule, CARMA3, into the mix. CARMA3 is a member of the caspase recruitment domain (CARD) family of proteins that are differentially expressed in several cell and tissue types and are known to affect NF-B activity in response to a variety of stimuli. The interesting finding in this article is that CARMA3 (CARD10) is specific for airway epithelium and that its expression leads to NF-B activation. Downstream of this pathway of lysophosphatidic acid–induced NF-B activation, thymic stromal lymphopoietin and CCL20 expression is enhanced in these cells. An interesting potential mechanism downstream of NF-B activation related to its proinflammatory properties might relate to chromatin modification of proinflammatory genes, as described by Yang and colleagues (7). In any case, implication of CARMA3 represents another potential player in airway epithelial inflammation related to NF-B activation.

NOVEL MARKERS OF EPITHELIAL SECRETORY CELL DIFFERENTIATION AND REPAIR

In this issue of the AJRCMB (pp. 340–348), Zemke and colleagues from the University of Pittsburgh (8) report a novel mRNA repertoire expressed by secretory cells of the conducting airways, using a combination of cell ablation techniques and microarray screening. According to this study, these genes could be grouped into three different categories based on their order of developmental maturation, as well as recovery after the lungs of mice were treated with naphthalene. The first category was composed mostly of genes considered to be late markers of Clara cell maturation in developing and/or injured and repairing airways, and consisted of phase I metabolizing genes such as Paraoxonase I (Pon1), flavin monooxygenase 3 (Fmo3), and aldehyde oxidase 3 (Aox3), all regulated by the Clara cell–specific xenobiotic metabolizing enzyme Cyp2f2. The second category of genes reflected an intermediate stage of Clara cell maturation and included CCSP and the related secretoglobin Scgb3a2, which is considered as a secreted anti-inflammatory protein (9). The third category included the novel gene Claudin 10 (Cldn10), which was considered as a marker of immature airway epithelial cells and localized by immunohistochemistry to the entire lateral surface of CCSP-expressing cells in both the proximal and distal airways in mice. This finding of novel marker genes allows for following secretory cell differentiation and maturation in both developing and repairing lungs, and certainly can form the basis to allow for better defining the kinds of aberrations in these processes that may be associated with remodeling in the lung.

References

1. Factor P, Mutlu GM, Chen L, Mohameed J, Akhmedov AT, Meng FJ, Jilling T, Lewis ER, Johnson MD, Xu A, et al. Adenosine regulation of alveolar fluid clearance. Proc Natl Acad Sci USA 2007;104:4083–4088.[Abstract/Free Full Text]
2. Morschl E, Molina JG, Volmer JB, Mohsenin A, Pero RS, Hong JS, Kheradmand F, Lee JJ, Blackburn MR. A3 adenosine receptor signaling influences pulmonary inflammation and fibrosis. Am J Respir Cell Mol Biol 2008;39:697–705.[Abstract/Free Full Text]
3. Rollins BM, Burn M, Coakley RD, Chambers LA, Hirsh AJ, Clunes MT, Lethem MI, Donaldson SH, Tarran R. A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system. Am J Respir Cell Mol Biol 2008;39:190–197.[Abstract/Free Full Text]
4. Scheibner KA, Boodoo S, Collins S, Black KE, Chan-Li Y, Zarek P, Powell JD, Horton MR. The adenosine A2a receptor inhibits matrix-induced inflammation in a novel fashion. Am J Respir Cell Mol Biol 2009;40:251–259.[Abstract/Free Full Text]
5. Medoff BD, Landry AL, Wittbold KA, Sandall BP, Derby MC, Cao Z, Adams JC, Xavier RJ. CARMA3 mediates lysophosphatidic acid stimulated cytokine secretion by bronchial epithelial cells. Am J Respir Cell Mol Biol 2009;40:286–294.[Abstract/Free Full Text]
6. Ckless K, van der Vliet A, Janssen-Heininger Y. Oxidative-nitrosative stress and post-translational protein modifications: implications to lung-structure relation. Arginase modulated NF-B activity via a nitric oxide-dependent mechanism. Am J Respir Cell Mol Biol 2007;36:645–653.[Abstract/Free Full Text]
7. Yang SR, Valvo S, Yao H, Kode A, Rajendrasozhan S, Edirisinghe I, Caito S, Adenuga D, Henry R, Fromm G, et al. IKK alpha causes chromatin modification on pro-inflammatory genes by cigarette smoke in mouse lung. Am J Respir Cell Mol Biol 2008;38:689–698.[Abstract/Free Full Text]
8. Zemke AC, Snyder JC, Brockway BL, Drake JA, Reynolds SD, Kaminski N, Stripp BR. Molecular staging of epithelial maturation using secretory cell–specific genes as markers. Am J Respir Cell Mol Biol 2009;40:340–348.[Abstract/Free Full Text]
9. Tomita T, Yamada A, Miyakoshi M, Kido T, Sheikh F, Srisodsai A, Miyajima A, Donnelly RP, Kimura S. Oncostatin M regulates secretoglobin 3A1 and 3A2 expression in a bidirectional manner. Am J Respir Cell Mol Biol [online ahead of print] Oct. 31, 2008; DOI: 1165/rcmb.2008-0062oc.

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