Am. J. Respir. Cell Mol. Biol., Volume 25, Number 2, August, 2001 245-253

Cytokine Inhibition of Fibroblast-Induced Gel Contraction Is Mediated by PGE₂ and NO Acting Through Separate Parallel Pathways

Yun Kui Zhu, X. D. Liu, Magnus C. Sköld, Takeshi Umino, Hangjun Wang, Debra J. Romberger, John R. Spurzem, Tadashi Kohyama, Fu-Qiang Wen, and Stephen I. Rennard

Jincheng Hospital, Lan Zhou, China; Pulmonary and Critical Care Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medicine, Karolinska Hospital, Stockholm, Sweden; and Pulmonary Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Contraction of three-dimensional collagen gels is a model of the contraction that characterizes normal healing and remodeling after injury. In the current study, we evaluated the hypothesis that a number of inflammatory factors, including tumor necrosis factor (TNF)-, interleukin (IL)-1, and interferon (IFN)-, modulate this process by induction of prostaglandin (PG) E₂ and nitric oxide (NO) production and that these secondary mediators function in an autocrine or paracrine manner to modulate contraction. Human fetal lung fibroblasts (HFL) were cultured in type I collagen gels and floated in medium containing TNF-, IL-1, or IFN- alone or in combination (cytomix). All cytokines inhibited the contraction significantly. The potency order was IL-1, TNF-, IFN-. The cytomix was no more potent than was IL-1 alone. PGE₂ production was increased by TNF- (5.0 versus 0.16 ng/ml, P < 0.01), IL-1 (5.3 versus 0.16 ng/ml, P < 0.01), and cytomix (5.9 versus 0.16 ng/ml, P < 0.01), and was completely inhibited by indomethacin. Indomethacin (P < 0.05) and L-NG-monomethyl arginine citrate (L-NMMA) (P < 0.05) alone both partially attenuated the inhibition of contraction caused by cytokines alone or by cytomix. Indomethacin and L-NMMA together attenuated inhibition more than either alone (P < 0.05). Exogenous PGE₂ and exogenous NO donors (DETA nononate and 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride) inhibited the contraction significantly. The protein kinase A inhibitor KT5270 and the protein kinase G inhibitor Rp-pCPT-cGMPS attenuated the inhibition induced by PGE₂ and NO, respectively. In summary, PGE₂ and NO appear to function in parallel as autocrine/paracrine mediators of cytokine-driven fibroblast inhibition of the contraction of collagen gels and may contribute to remodeling during repair and inflammation in lung disorders.

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