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A. Immunohistochemical reaction for macrophage Mac-3 on lung parenchyma of a C57Bl/6J mouse after a 6 month cigarette smoke exposure. B. Macrophage volume density in the lung of C57BL76J mice exposed either to room air or to cigarette smoke for 6 months and treated or not with roflumilast at 2 doses. Air = air exposure; CS = cigarette smoke exposure; R1 = treated with roflumilast at the dose 1 mg/kg po; R5 = treated with roflumilast at the dose 5 mg/kg po; N = 5 in all groups except "CS -" where N = 7, "CS +R1" where N = 6 and "CS +R5" where N = 7; * = p < 0.01 versus air exposed, ++ = < 0.01 versus smoke exposed. Scale Bar = 40 μm.
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Figure 2: A. Immunohistochemical reaction for macrophage Mac-3 on lung parenchyma of a C57Bl/6J mouse after a 6 month cigarette smoke exposure. B. Macrophage volume density in the lung of C57BL76J mice exposed either to room air or to cigarette smoke for 6 months and treated or not with roflumilast at 2 doses. Air = air exposure; CS = cigarette smoke exposure; R1 = treated with roflumilast at the dose 1 mg/kg po; R5 = treated with roflumilast at the dose 5 mg/kg po; N = 5 in all groups except "CS -" where N = 7, "CS +R1" where N = 6 and "CS +R5" where N = 7; * = p < 0.01 versus air exposed, ++ = < 0.01 versus smoke exposed. Scale Bar = 40 μm.

Mentions: The macrophages, which were observed throughout the lung parenchyma (Fig. 2A) were increased by 107% (p < 0.01) in comparison to air exposure (Fig. 2B). Roflumilast, at the dose 1 mg/kg, did not significantly affect (by 19%) the cigarette smoke-induced increase in macrophage VV, but at the dose 5 mg/kg suppressed the increase in macrophage VV by 82% (p < 0.01) (Fig. 2B). This effect is slightly more potent of what previously reported [6].

Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice

Martorana PA, Lunghi B, Lucattelli M, De Cunto G, Beume R, Lungarella G - BMC Pulm Med (2008)

Bottom Line: The higher dose of roflumilast prevented the increase in neutrophil VV by 78%, macrophage by 82%, dendritic cell by 48%, B-lymphocyte by 100%, CD4+ by 98% and CD8+ VV by 88%.The lower dose of roflumilast did not prevent the increase in neutrophil, macrophage and B-cell VV but prevented dendritic cells by 42%, CD4+ by 55%, and CD8+ by 91%.These results indicate (i) chronic exposure to cigarette smoke in mice results in a significant recruitment into the lung of inflammatory cells of both the innate and adaptive immune system; (ii) roflumilast at the higher dose exerts a protective effect against the recruitment of all these cells and at the lower dose against the recruitment of dendritic cells and T-lymphocytes; (iii) these findings underline the role of innate immunity in the development of pulmonary emphysema and (iiii) support previous results indicating that the inflammatory cells of the adaptive immune system do not play a central role in the development of cigarette smoke induced emphysema in mice.

Affiliation: Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy. martorana@unisi.it

ABSTRACT

Background: We reported that roflumilast, a phosphodiesterase 4 inhibitor, given orally at 5 mg/kg to mice prevented the development of emphysema in a chronic model of cigarette smoke exposure, while at 1 mg/kg was ineffective. Here we investigated the effects of roflumilast on the volume density (VV) of the inflammatory cells present in the lungs after chronic cigarette smoke exposure.

Methods: Slides were obtained from blocks of the previous study and VV was assessed immunohistochemically and by point counting using a grid with 48 points, a 20x objective and a computer screen for a final magnification of 580x. Neutrophils were marked with myeloperoxidase antibody, macrophages with Mac-3, dendritic cells with fascin, B-lymphocytes with B220, CD4+ T-cells with CD4+ antibody, and CD8+T-cells with CD8-alpha. The significance of the differences was calculated using one-way analysis of variance.

Results: Chronic smoke exposure increased neutrophil VV by 97%, macrophage by 107%, dendritic cell by 217%, B-lymphocyte by 436%, CD4+ by 524%, and CD8+ by 417%. The higher dose of roflumilast prevented the increase in neutrophil VV by 78%, macrophage by 82%, dendritic cell by 48%, B-lymphocyte by 100%, CD4+ by 98% and CD8+ VV by 88%. The lower dose of roflumilast did not prevent the increase in neutrophil, macrophage and B-cell VV but prevented dendritic cells by 42%, CD4+ by 55%, and CD8+ by 91%.

Conclusion: These results indicate (i) chronic exposure to cigarette smoke in mice results in a significant recruitment into the lung of inflammatory cells of both the innate and adaptive immune system; (ii) roflumilast at the higher dose exerts a protective effect against the recruitment of all these cells and at the lower dose against the recruitment of dendritic cells and T-lymphocytes; (iii) these findings underline the role of innate immunity in the development of pulmonary emphysema and (iiii) support previous results indicating that the inflammatory cells of the adaptive immune system do not play a central role in the development of cigarette smoke induced emphysema in mice.

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