Lipoxygenase Pathway Mediates Increases of Airway Resistance and Lung Inflation Induced by Exposure to Nanotitanium Dioxide in Rats

Abstract

Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNFα), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNFα; NO; hydroxyl radicals; and blood WBC, NO, hydrogen peroxide, and LDH levels rose. Obstructive ventilatory insufficiency was observed. MK571 and MK886 both attenuated the systemic inflammation and lung function changes. We conclude that inhaled nTiO2 induces systemic inflammation, cytokine release, and oxidative and nitrosative stress in the lung. The lipoxygenase pathway products, mediated by oxygen radicals and WBC, play a critical role in the obstructive ventilatory insufficiency induced by nTiO2.

Leukotrienes in exhaled breath condensate and fractional exhaled nitric oxide in workers exposed to TiO 2 nanoparticles

“…A few studies measured lung functions and found that exposure to TiO 2 nanoparticles was associated with airway hyperresponsiveness, an increase in airway resistance, and a decrease of peak expiratory flow (PEF) [16]. These results are in agreement with another study regarding rats exposed by inhalation to nanoTiO 2 [17]. Leukotriene (LT) C4 increase in the lung lavage was observed in addition to pulmonary and systemic inflammation and oxidative stress in the lung.…”

“…Aerosolized nanoparticles of TiO 2 induced a significant rise of nitric oxide in blood and BAL fluid. These results suggest that the production of LTs, mediated by oxygen radicals, may play a critical role in the obstructive ventilatory insufficiency induced by nanoTiO 2 [17]. Accordingly, as previously mentioned, several experimental studies reported histological emphysematous structure [14].…”

Mechanisms involved in inflammatory pulmonary fibrosis induced by lunar dust simulant in rats

“…Therefore, the increase of iNOS expression induced by LDS may be caused by these cytokines or by other mechanisms. A recent research has shown that exposure to nanotitanium dioxide particle (nTiO2) causes decreased eNOS expression and increased iNOS expression . The impact of fine particles on eNOS levels is uncertain.…”

Markers of Oxidative Stress in the Exhaled Breath Condensate of Workers Handling Nanocomposites

“…These sequential molecular and cellular events are known to cause oxidative stress, followed by severe cellular genotoxicity and then programmed cell death. Both experimental and epidemiological studies have indicated that chronic inflammation is involved in and plays a critical role in several chronic diseases, including respiratory and cardiovascular diseases, and lung tumorigenesis [ 17 , 19 , 20 , 21 ]. However, there is no evidence that particles below 100 nm show any step-change in their hazard meaning that there is no evidence of any novel “nano-specific hazard”.…”