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

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 (250 g; 8–10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histolopathological changes in the lung within 3 d 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 3 d 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.

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma — a review

“…Other compounds with remarkably good anti-oxidative and anti-inflammatory effects have been studied for the purpose of reducing the inflammatory effects of the oxidative stress on pulmonary tissue, among which pentoxifylline [115], apocynin-nitrone [116], narginin [117], sphingisylphosphorylcholine [118], usnic acid [119], zinc aspartate [120], trapidil [121] or melatonin [122].…”

Inflammatory mechanisms of pulmonary injury induced by mustards

“…As observed in humans, exposure of rats to SM or NM induces progressive histopathologic changes in the trachea, bronchi and lung (Malaviya et al, 2010; Malaviya et al, 2012; Sunil et al, 2011b; Sunil et al, 2014). Focal attenuation of tracheal epithelium, detachment of epithelium from the mucosa, loss of cilia, and accumulation of fibrin in the lumen are prominent.…”

“…1). These effects occur early after mustard exposure and persist for at least 28 days (Malaviya et al, 2010; Malaviya et al, 2012; Sunil et al, 2011b; Sunil et al, 2014). Similar persistent histological changes have been described in the lung up to 14 d after exposure of rodents to NM, as well as SM (Calvet et al, 1994; Ucar et al, 2007; Yaren et al, 2007).…”

The effects of various chemicals on lung, skin and eye: a review

“…(c) Nano material (3) Noxious fumes from pesticides (4) Smoke (from house fires and wildfires) (Moritz et al, 1945;Sunil et al, 2014;Wallace, 1973). Chronic chemical pneumonitis can occur only after low levels of exposure to the irritant over a long time.…”

“…The lung is one of the most fundamental organs to chemical agents such as SM gas, NM. Airway hyper responsiveness and lung inflammation are reported in chemical warfare victims (Sunil et al, 2014). If the cells in the alveoli become inflamed, as the picture shows, the volume of the lumen, and consequently lung function, is reduced (Holtzman et al, 1983;Koren et al, 1989) (Figure 1).…”