Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis

Respiratory Research

Kenneth L Brigham³  Gayle King³  Richard Pierson¹  James E Loyd³  Kirk B Lane³  Ryszard Dworski³  Arlene A Stecenko³  Roberto Cruz-Gervis² 

[1] Department of Surgery, Vanderbilt University, Nashville, Tennessee, USA;Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, USA;Center for Lung Research, Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA

关键词: thromboxane;    pulmonary fibrosis;    prostaglandins;    prostacyclin;    lung fibroblasts;   

Others  :  1227403
DOI  :  10.1186/rr166

 received in 2001-05-29, accepted in 2001-12-21,  发布年份 2002

【 摘 要 】

Background

Prostanoids are known to participate in the process of fibrogenesis. Because lung fibroblasts produce prostanoids and are believed to play a central role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), we hypothesized that fibroblasts (HF) cultured from the lungs of patients with IPF (HF-IPF) have an altered balance between profibrotic (thromboxane [TX]A₂) and antifibrotic (prostacyclin [PGI₂]) prostaglandins (PGs) when compared with normal human lung fibroblasts (HF-NL).

Methods

We measured inducible cyclooxygenase (COX)-2 gene and protein expression, and a profile of prostanoids at baseline and after IL-1β stimulation.

Results

In both HF-IPF and HF-NL COX-2 expression was undetectable at baseline, but was significantly upregulated by IL-1β. PGE₂ was the predominant COX product in IL-1β-stimulated cells with no significant difference between HF-IPF and HF-NL (28.35 [9.09–89.09] vs. 17.12 [8.58–29.33] ng/10⁶ cells/30 min, respectively; P = 0.25). TXB₂ (the stable metabolite of TXA₂) production was significantly higher in IL-1β-stimulated HF-IPF compared to HF-NL (1.92 [1.27–2.57] vs. 0.61 [0.21–1.64] ng/10⁶ cells/30 min, respectively; P = 0.007) and the ratio of PGI₂ (as measured by its stable metabolite 6-keto-PGF_1α) to TXB₂ was significantly lower at baseline in HF-IPF (0.08 [0.04–0.52] vs. 0.12 [0.11–0.89] in HF-NL; P = 0.028) and with IL-1β stimulation (0.24 [0.05–1.53] vs. 1.08 [0.51–3.79] in HF-NL; P = 0.09).

Conclusion

An alteration in the balance of profibrotic and antifibrotic PGs in HF-IPF may play a role in the pathogeneses of IPF.

【 授权许可】

   
2002 Cruz-Gervis et al., licensee BioMed Central Ltd

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Gauldie J, Jordana M, Cox G: Cytokines and pulmonary fibrosis. Thorax 1993, 48:931-935.
• [2]Tremblay GM, Jordana M, Gauldie J, Sarnstrand B: Fibroblasts as effector cells in fibrosis. In In Pulmonary Fibrosis; Lung Biology in Health and Disease,. Volume 80. Edited by Phan SH, Thrall RS. New York: Marcel Dekker; 1995::541-577.
• [3]Crystal RG, Ferrans VJ, Basset F: Biologic basis of pulmonary fibrosis. In In The Lung: Scientific Foundations.. Edited by Crystal RG, West JB. New York: Raven Press; 1991:2031-2046.
• [4]Strieter RM, Keane MP, Standiford TJ, Kunkel SL: Cytokine biology and the pathogenesis of interstitial lung disease. In In Interstitial Lung Disease.. Edited by Schwarz MI, King TE. Hamilton: B.C. Decker; 1998:181-205.
• [5]Elias J: Tumor necrosis factor interacts with interleukin-1 and interferons to inhibit fibroblast proliferation via prostaglandin-dependent and independent mechanisms. Am Rev Respir Dis 1988, 131:94-99.
• [6]Goldstein R, Polgar P: The effect and interaction of bradykinin and prostaglandins on protein and collagen production by lung fibroblasts. J Biol Chem 1982, 257:8630-8633.
• [7]Korn J, Halushka P, Leroy E: Mononuclear cell modulation of connective tissue function: suppression of fibroblast growth by stimulation of endogenous prostaglandin production. J Clin Invest 1980, 65:543-554.
• [8]Baum B, Moss S, Breul R, Crystal R: Effect of cyclic AMP on the intracellular degradation of newly synthesized collagen. J Biol Chem 1980, 255:2843-2847.
• [9]Baud L, Perez J, Denis M, Ardaillou R: Modulation of fibroblast proliferation by sulfidopeptide leukotrienes: effect of indomethacin. J Immunol 1987, 138:1190-1195.
• [10]Agro A, Langdon C, Smith F, Richards CD: Prostaglandin E2 enhances interleukin 8 (IL-8) and IL-6 but inhibits GMCSF production by IL-1 stimulated human synovial fibroblasts in vitro. J Rheumatol 1996, 23:862-868.
• [11]Hinson RM, Williams JA, Shacter E: Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2. Proc Natl Acad Sci USA 1996, 93:4885-4890.
• [12]Wilborn J, Crofford L, Burdick MD, Kunkel SL, Streiter RM, Peters-Golden M: Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2. J Clin Invest 1995, 95:1861-1868.
• [13]Murota SI, Morita I, Abe M: The effects of Thromboxane B2 and 6-ketoprostaglandin F1α on cultured fibroblasts. Biochim Biophys Acta 1977, 479:122-125.
• [14]Mene P, Abboud HE, Dunn MJ: Regulation of human mesangial cell growth in culture by thromboxane A2 and prostacyclin. Kidney Int 1990, 38:232-239.
• [15]Dorn GW II: Role of thromboxane A2 in mitogenesis of vascular smooth muscle cells. Agents Actions 1997, 48:43-61.
• [16]Pakala R, Willerson JT, Benedict CR: Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth cell proliferation. Circulation 1997, 96:2280-2286.
• [17]Sinzinger H, Fitscha P, Kritz H: Antimitotic actions of vasodilatory prostaglandins-clinical aspects. Agents Actions 1997, 48:93-106.
• [18]Gallagher AM, Yu H, Printz MP: Bradykinin-induced reductions in collagen gene expression involve prostacyclin. Hypertension 1998, 32:84-88.
• [19]Funk CD: Molecular biology in the eicosanoid field. Progress Nucleic Acid Res and Mol Biol 1993, 45:67-98.
• [20]Vancheri C, Sortino MA, Tomaselli V, Mastruzzo C, Condorelli F, Bellistri G, Pistorio MP, Canonico PL, Crimi N: Different expression of TNF-α receptors and prostaglandin E2 production in normal and fibrotic lung fibroblasts: potential implications for the evolution of the inflammatory process. Am J Respir Cell Mol Biol 2000, 22:628-634.
• [21]Keerthisingam CB, Jenkins RG, Harrison NK, Hernandez-Rodriguez NA, Booth H, Laurent GJ, Hart SL, Foster ML, McAnulty RJ: Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-β in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 2001, 158:1411-1422.
• [22]Kumar RK, Bennett RA, Brody AR: A homologue of platelet-derived growth factor produced by rat alveolar macrophages. FASEB J 1988, 2:2272-2277.
• [23]Dworski R, Sheller JR, Wickersham NE, Oates JA, Brigham KL, Roberts LJ II, Fitzgerald GA: Allergen-stimulated release of mediators into sheep bronchoalveolar lavage fluid; effect of cyclooxygenase inhibition. Am Rev Respir Dis 1989, 139:46-51.
• [24]Fitzsimmons C, Proudfoot D, Bowyer DE: Monocyte prostaglandins inhibit procollagen secretion by human vascular smooth muscle cells: implications for plaque stability. Atherosclerosis 1999, 142:287-293.
• [25]Zucker TP, Bonisch D, Muck S, Weber AA, Bretschneider E, Glusa E, Schror K: Thrombin-induced mitogenesis in coronary artery smooth muscle cells is potentiated by thromboxane A2 and involves upregulation of thromboxane receptor mRNA. Circulation 1998, 97:589-595.
• [26]Grosser T, Zucker TP, Webber AA, Schulte K, Sachinidis A, Vetter H, Schror K: Thromboxane A2 induces cell signaling but requires platelet-derived growth factor to act as a mitogen. Eur J Pharmacol 1997, 319:327-332.
• [27]Polgar P, Taylor L: Alterations in prostaglandin synthesis during senescence of human lung fibroblasts. Mech Ageing Dev 1980, 12:305-310.
• [28]Murota S, Matsuoka K, Mitsui Y, Morita I, Kurata M: Age-related shift from the biosynthesis of prostacyclin to thromboxane A2 and change in cyclic AMP production in response to prostacyclin in human diploid fibroblasts. Adv Prostaglandin Thromboxane Leukot Res 1983, 12:319-325.