Human Recombinant Interferon-α2a and Interferon-αA/D Have Different Effects on Bleomycin-Induced Lung Injury

Berkman, Neville; Kremer, Sarah; Or, Reuven; Christensen, Thomas G.; Goldstein, Ronald H.; Breuer, Raphael

doi:10.1159/000050488

Cited by 17 publications

(23 citation statements)

References 37 publications

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“…The severity of lung fibrosis in Bleo-treated C57BL/6 mice [18, 19, 20, 21]is more extensive than in CyA-pretreated BALB/c mice, suggesting that additional nonimmunological factors may be involved in the Bleo resistance of BALB/c mice. The differential pulmonary fibrosis response of murine strains is not due to pharmacokinetic differences, since the plasma half-life for Bleo is longer and Bleo lung levels are higher in BALB/c strain compared to C57BL/6 mice [23].…”

Section: Discussionmentioning

confidence: 99%

“…The right lung was fixed by IT infusion through the cannula with 4% formalin and 1% glutaraldehyde in 0.1 M cacodylate buffer at pH 7.4 maintained at 25 cm hydrostatic pressure for 5 min and then immersed in fixative for an additional 24 h as previously reported [12, 19, 20]. Only lungs that were well inflated by the fixative were analyzed.…”

Section: Methodsmentioning

confidence: 99%

“…The degree of fibrosis was quantified as previously described [19, 20, 21], using the Optimas image analysis program to analyze slides that were stained with a modified trichrome stain that enhances the blue-stained collagen. By adjusting image contrast, brightness, and color threshold settings, the image analysis program was configured to detect areas of blue-stained collagen within each of 20 randomly selected fields per slide captured using a 40 × objective lens.…”

Section: Methodsmentioning

confidence: 99%

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Cyclosporin A Upmodulates Bleomycin-Induced Pulmonary Fibrosis in BALB/c Mice

Ginzburg²,

Christensen

et al. 2002

Respiration

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Background: Intratracheal instillation of bleomycin (Bleo) into rodents serves as a model for human lung fibrosis. Various mouse strains respond differently to Bleo, and BALB/c mice are relatively resistant. Objective: Since T lymphocytes have been shown to play a major role in this model, the effect of the immunomodulator cyclosporin A (CyA) on lung fibrosis was studied in Bleo-‘resistant’ BALB/c mice. Methods: Pulmonary fibrosis was induced by a single intratracheal (IT) instillation of Bleo. One of the four following treatments was given to one of four groups of female BALB/c mice: (1) Bleo-CyA: IT Bleo and daily intraperitoneal (IP) injections of CyA 100 mg/day starting 1 day before IT instillation of Bleo; (2) Bleo-Sal: IT Bleo and IP injections of saline; (3) Sal-CyA: IT saline and IP CyA 100 mg/kg; (4) Sal-Sal: IT and IP saline. The animals were killed on day 14. Fibrosis was evaluated by analysis of hydroxyproline and by quantitative image analysis of the fibrosis fraction. Ex vivo IFN-γ, IL-4, IL-13 and IL-5 secretion by peribronchial lymphatic tissue lymphocytes was measured. Results: Pretreatment with CyA upmodulated Bleo-induced lung fibrosis in the Bleo-‘resistant’ BALB/c mice; hydroxyproline was higher in Bleo-CyA compared to Bleo-Sal animals and both hydroxyproline and fibrosis fraction measurements were higher in Bleo-CyA compared to Sal-Sal. Cytokine secretion by lymphocytes demonstrated increased IFN-γ/IL-4 and IFN-γ/IL-13 mean secretion ratios in the Bleo-CyA animals compared to the Bleo-Sal animals. Conclusions: These results indicate that CyA upmodulates Bleo-induced lung fibrosis in Bleo-‘resistant’ BALB/c mice by allowing the emergence of a Th1 inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cyclosporin A Upmodulates Bleomycin-Induced Pulmonary Fibrosis in BALB/c Mice

Ginzburg²,

Christensen

et al. 2002

Respiration

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“…Animals were killed for study 14 days following IT instillation. Lung injury was evaluated by analysis of BAL cells, lung hydroxyproline measurement, and quantitative morphological studies as previously described (4,19,23).…”

Section: In Vivo Studies Of Bleomycin Lung Injury In Ifn-␥ Ko Micementioning

confidence: 99%

“…Pathological assessment of the degree of fibrotic lung injury was performed by computerassisted morphometry, using the Optimas image analysis computer program (Optimas, Bothell, WA) as previously described (4,19,23). We quantified the degree of fibrosis by analyzing slides that were stained with a modified trichrome stain, to enhance the blue-stained collagen.…”

Section: In Vivo Studies Of Bleomycin Lung Injury In Ifn-␥ Ko Micementioning

confidence: 99%

Role of interferon-γ in the evolution of murine bleomycin lung fibrosis

Segel¹,

Izbicki²,

Cohen³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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IFN-γ production is upregulated in lung cells (LC) of bleomycin-treated C57BL/6 mice. The present study characterizes the time course, cellular source, and regulation of IFN-γ expression in bleomycin-induced lung injury. IFN-γ mRNA in LC from bleomycin-treated mice peaked 3 days after intratracheal instillation. IFN-γ protein levels were increased at 6 days, as was the percentage of LC expressing IFN-γ. CD4+, CD8+, and natural killer cells each contributed significantly to IFN-γ production. IL-12 mRNA levels were increased at 1 day in LC of bleomycin-treated mice. Anti-IL-12 and anti-IL-18 antibodies decreased IFN-γ production by these cells. To define the role of endogenous IFN-γ in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN-γ gene (IFN-γ knockout) and wild-type mice. At 14 days after intratracheal bleomycin, total bronchoalveolar lavage cell counts and lung hydroxyproline were decreased in IFN-γ knockouts compared with wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN-γ production in the lungs of bleomycin-treated mice is at least partly IL-12 and IL-18 dependent. Absence of IFN-γ in IFN-γ knockout mice does not increase pulmonary fibrosis. Endogenous IFN-γ may play a proinflammatory or profibrotic role in bleomycin-induced lung fibrosis.

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Association of Interferon‐ and Transforming Growth Factor β–Regulated Genes and Macrophage Activation With Systemic Sclerosis–Related Progressive Lung Fibrosis

Christmann

Sampaio-Barros

Stifano

et al. 2014

Arthritis & Rheumatology

175

138

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Objective Systemic sclerosis (SSc)–related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. Methods Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2–3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. Results Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor β (TGFβ)– and interferon (IFN)–regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < −0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. Conclusion These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFβ- and IFN-regulated genes.

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Human Recombinant Interferon-α2a and Interferon-αA/D Have Different Effects on Bleomycin-Induced Lung Injury

Cited by 17 publications

References 37 publications

Cyclosporin A Upmodulates Bleomycin-Induced Pulmonary Fibrosis in BALB/c Mice

Cyclosporin A Upmodulates Bleomycin-Induced Pulmonary Fibrosis in BALB/c Mice

Role of interferon-γ in the evolution of murine bleomycin lung fibrosis

Association of Interferon‐ and Transforming Growth Factor β–Regulated Genes and Macrophage Activation With Systemic Sclerosis–Related Progressive Lung Fibrosis

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