title: TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis.
abstract: Despite abundant evidence documenting the importance of TNF-alpha in the pathogenesis of pulmonary fibrosis, its actual role has not been fully elucidated. Recent observations also indicate that eosinophils found in fibrotic lung express elevated levels of cytokines known to be important in lung fibrosis. These findings suggest a possible role for TNF-alpha in eosinophil recruitment and cytokine expression in this disease. To examine this hypothesis, pulmonary fibrosis was induced in mice by endotracheal bleomycin treatment, and separate groups of animals were also treated with either anti-TNF-alpha Ab or control serum. On days 7 and 14 post-bleomycin treatment, lungs were harvested and analyzed for fibrosis, cytokine expression, and eosinophil influx. Anti-TNF-alpha caused a significant reduction in lung fibrosis, as indicated by a reduction in hydroxyproline content, which was accompanied by suppression of lung TGF-beta1, IL-5, and JE mRNA expression. Examination of tissue sections revealed a significant reduction in lung eosinophils and overall cellularity by anti-TNF-alpha treatment without a significant effect on the number of lung macrophages. The number of IL-5-expressing cells was also significantly reduced by anti-TNF-alpha treatment. Since IL-5 is important in eosinophil differentiation, activation, and recruitment, these findings suggest a novel mechanism by which TNF-alpha could mediate pulmonary fibrosis via induction of IL-5-mediated eosinophil recruitment and fibrogenic cytokine production. Since these eosinophil-derived cytokines include JE/monocyte chemotactic factor-1 and TGF-beta1, this cytokine networking orchestrated by TNF-alpha could, in turn, amplify the inflammatory response and drive the progression to fibrosis and end-stage lung disease.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Gharaee-Kermani
authors.forename: B
authors.initials: B
authors.lastname: McGarry
authors.forename: D
authors.initials: D
authors.lastname: Remick
authors.forename: S H
authors.initials: SH
authors.lastname: Phan
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000633:toxicity; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism*; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015848:Interleukin-5 / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines; D015848:Interleukin-5; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin