Taurine Protects Against Ozone-induced Airway Hyperresponsiveness and Oxidative Stress in Paraoxonase 1 Knockout Mice

Rationale: Ozone (O3) is a common air pollutant that exacerbates asthma and other respiratory diseases by increasing oxidative stress. The paraoxonase (PON) family, which includes PON1, PON2, and PON3, are antioxidant proteins that protect from oxidative damage. Initially, we hypothesized that following O3 exposure PON1 absence would lead to increased methacholine-induced airway hyperresponsiveness (AHR) and lung oxidative stress. Surprisingly, our findings showed that Pon1 knockout (Pon1 KO) mice were protected from O3-induced AHR in the absence of upregulation of PON2 or PON3. This unexpected finding led us to hypothesize that taurine, a prevalent antioxidant and anti-inflammatory non-protein amino acid, may compensate for the absence of Pon1 by protecting from O3-induced oxidative stress and inflammation.Methods: Eight- to ten-week-old male C57BL/6J wild-type (WT) and Pon1 KO mice were exposed to filtered air (FA) or ozone (2 ppm) for three hours. AHR to acetyl-β-methacholine (10-100 mg/ml) was measured 24 hours post-exposure. Lung tissues were processed for immunohistochemistry, gene expression analysis by quantitative real-time polymerase chain reaction (qRT-PCR), and protein analysis by western blot. Taurine levels in lung homogenates were quantified after filtration, and total protein concentration in bronchoalveolar lavage (BAL) fluids was measured. Cytokines and oxidative stress markers were assessed in plasma and BAL fluids using enzyme-linked immunosorbent assay (ELISA).Results: Pon1 KO mice displayed reduced AHR compared to WT mice. We examined toll-like receptor 4 (TLR4), a key molecule in O3 signaling, and observed a 50% decrease in Tlr4 mRNA expression in Pon1 KO mice following O3 exposure (p<0.05). Additionally, the expression of endogenous TLR4 agonists, serum amyloid A3 (SAA3) and S100A8, were reduced. We also found decreased levels of the inflammatory marker, monocyte chemoattractant protein-1 (MCP-1 or CCL2), in BAL fluids and plasma (p<0.05). Using qRT-PCR in whole lung, we detected a significant reduction in multiple CC chemokines and oxidative stress markers following O3 challenge in Pon1 KO mice compared to WT. Lung taurine and expression of taurine transporter (TauT) and cysteine dioxygenase type 1 (CDO1), an enzyme in taurine biosynthesis, at both mRNA and protein levels of Pon1 KO mice were increased post-O3 exposure.Conclusions: This study is the first to examine the effects of Pon1 deficiency in the lung following O3 exposure. Contrary to expectations, Pon1 KO mice exhibited reduced oxidative stress and inflammatory responses. Our findings suggest that taurine compensates for Pon1 deficiency to protect the lungs from oxidative stress.

Duke Scholars

Author Jennifer Leigh Ingram Medicine, Pulmonary, Allergy, and Critical Care Medicine

Author Robert Matthew Tighe Medicine, Pulmonary, Allergy, and Critical Care Medicine