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. 2014 Aug;97(1):89-98.
doi: 10.1016/j.yexmp.2014.05.009. Epub 2014 Jun 2.

Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

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Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

Vasanthi R Sunil et al. Exp Mol Pathol. 2014 Aug.

Abstract

Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.

Keywords: Lung injury; Macrophages; Mustards; Oxidative stress; Pentoxifylline; Vesicants.

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Conflict of interest statement

Conflict of interest

The authors do not have any conflict of interest.

Figures

Figure 1
Figure 1
Effects of pentoxifylline on NM-induced alterations in lung structure. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, histologic sections were prepared and stained with H & E. Images were acquired using a VS120 Virtual Microscopy system. One representative lung section from 4–8 rats per treatment group is shown. Left panels: Magnification, 2x; Right panels: Magnification, 100x; squares indicate regions of high power magnification in right panels. a, bronchiectasis, b, hypercellularity of bronchiolar epithelium; c, infiltrating macrophages; d, emphysema; e, edema; f, fibrin deposits.
Figure 2
Figure 2
Effects of pentoxifylline on NM-induced increases in BAL cells and protein. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, BAL was collected and analyzed for cell and protein content. Top panel: Viable cells were enumerated by trypan blue dye exclusion. Bottom panel: Cell-free supernatants were analyzed in triplicate for protein content using a BCA protein assay kit. Each bar is the average ± SE (n = 6–12 rats). *Significantly different (p <0.05) from PBS; #Significantly different (p<0.05) from NM.
Figure 3
Figure 3
Effects of pentoxifylline on BAL levels of Lcn2 and CCSP. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, BAL was collected, concentrated and analyzed for Lcn2 and CCSP levels by western blotting. Each lane represents BAL from 1 rat. Three to six rats per treatment group are shown.
Figure 4
Figure 4
Effects of pentoxifylline on NM-induced HO-1 expression. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, lung sections were prepared and stained with antibody to HO-1. Binding was visualized using a peroxidase DAB substrate kit. One representative section from 4 rats per treatment group is shown (Original magnification, x600).
Figure 5
Figure 5
Effects of pentoxifylline on NM-induced COX-2 and MMP-9 expression. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, lung sections were prepared and stained with antibody to COX-2 or MMP-9. Binding was visualized using a peroxidase DAB substrate kit. One representative section from 4 rats per treatment group is shown (Original magnification, x600).
Figure 6
Figure 6
Effects of pentoxifylline on NM-induced CD163 and galectin-3 (Gal-3) expression. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, lung sections were prepared and stained with antibody to CD163 or Gal-3. Binding was visualized using a peroxidase DAB substrate kit. One representative section from 4 rats per treatment group is shown (Original magnification, x600).
Figure 7
Figure 7
Effects of pentoxifylline on NM-induced pro-SP-C and PCNA expression. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, lung sections were prepared and stained with antibody to pro-SP-C or PCNA. Binding was visualized using a peroxidase DAB substrate kit. One representative section from 4 rats per treatment group is shown (Original magnification, x600).
Figure 8
Figure 8
Effects of pentoxifylline on NM-induced alterations in lung function. Animals were treated with PBS or NM followed by daily administration of pentoxifylline (PX). After 3 d, measurements were made in triplicate of tissue damping and elastance at PEEPs ranging from 1 to 9 cm H2O. Each point is the mean ± SE (n = 6 rats).

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