Effects of ozone on the epithelial and inflammatory responses in the airways: Role of tumor necrosis factor

Abstract

We have investigated the possibility that tumor necrosis factor alpha (TNF) plays a role in the increased airway permeability and an inflammatory response following an acute ozone (O3) exposure. Male Sprague-Dawley rats were injected, intraperitoneally, with either rabbit anti-mouse antibody to TNF (anti-TNF) or preimmune rabbit serum, 2 h before a 3-h exposure to O3 or purified air. Permeability, as determined by [99mTc] diethylenetriamine pentaacetate (DTPA) transport, total protein and albumin concentrations in the bronchoalveolar lavage (BAL), and the inflammatory cell response in the BAL were assessed 10 h after the exposure was completed. The O3-exposed group that was injected with anti-TNF showed a significant decrease in permeability to DTPA in comparison to the O3- exposed group injected with preimmune rabbit serum. There was no difference between the anti-TNF group and the purified air group. In contrast, the total protein and albumin levels in the BAL were significantly greater in both of the O3-exposed groups than in the purified air group. The concentrations of protein and albumin in the anti-TNF group did, however, show an attenuating trend when compared to the preimmune O3-exposed group. The polymorphonuclear leukocytes (PMNs) in BAL of the anti-TNF group also showed an attenuating trend when compared to the preimmune O3-exposed group, but both of these O3-exposed groups were significantly greater than the purified air group. Lung sections stained with naphthol AS-D chloroacetate esterase showed an increase in the number of stained PMNs in the anti-TNF group in comparison to the preimmune O3- and air-exposed groups. These data suggest that TNF plays a role in the increase in tracheal permeability as determined by DTPA transport, while the contributing role that TNF plays in bronchoalveolar permeability and the inflammatory response seen following an acute exposure to 0.8 ppm O3 is less evident.

Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation

“…Although TNF-α is chemotactic for neutrophils and enhance the movement of inflammatory cells (27), ozone-induced neutrophil migration was not affected in p55/p75 TNF-receptor knockout mice following a 2ppm exposure for 3 hours, but ozone-induced AHR was reduced (28), implicating a non-neutrophilic TNF-α dependent AHR. Furthermore, ozone-induced changes in tracheal permeability which may contribute to airway wall oedeama and may also facilitate the recruitment of inflammatory cells into BALF and tissues (9) are inhibited by an anti-TNF-α blocking antibody (29). Taken together, our data confirm previouslypublished data and support in part the premise that IL-6 is primarily involved in…”

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

“…Our findings that mice lacking TNFα are protected from ozone-induced injury are consistent with this idea. A similar protective effect against ozone-induced injury has been reported in TNFR1 and/or TNFR2 knockout mice Shore et al, 2001;Cho et al, 2007), and in mice pretreated with anti-TNFα antibodies (Piguet and Vesin, 1994;Young and Bhalla, 1995;Kleeberger et al, 1997;Cho et al, 2001;Bhalla et al, 2002).…”

“…This is supported by findings that administration of antibodies to TNFα attenuates ozone-induced increases in macrophage adherence, neutrophil accumulation and IL-1 and IL-6 expression in the lung, and that ozone-induced inflammation and macrophage activation are reduced in TNFR1 knockout mice (Young and Bhalla, 1995;Kleeberger et al, 1997;Pearson and Bhalla, 1997;Cho et al, 2001;Bhalla et al, 2002).…”

Signal Transduction Pathways of Tumor Necrosis Factor–mediated Lung Injury Induced by Ozone in Mice

“…In support of this hypothesis, we and others have demonstrated that lack of TNF response provided significant protection from O 3 -induced inflammation and airway hyperreactivity in rodent lungs (16)(17)(18)(19)(20). Moreover, recent studies (21,22) demonstrated in human subjects an association of O 3 -induced lung functional changes with a TNF polymorphism haplotype including -308A, which is also known to be involved in increased risk of asthma (23).…”

“…inflammation, hyperpermeability, and cell proliferation after acute or subacute O 3 exposure in rodents (17,19,20,36). Lung inflammation and epithelial injury were also reduced after subacute O 3 exposure in mice genetically deficient in TNF-R (Tnfr1…”