Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine

Abstract

Inhalation of ozone (O₃), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O₃-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O₃ (2 parts/million). In wild-type mice, O₃ exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O₃-exposed wild-type mice. O₃ exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O₃ exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O₃ exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O₃ and functionally contributes to the development of O₃-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine.

Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α

“…5C). These data provide evidence of increased oxidative stress in lungs of obese mice even in the absence of a stressor such as O 3 .…”

“…2). Hyaluronan fragmentation and osteopontin are both required for O 3 -induced AHR in lean mice (3,14). O 3 increased both BAL hyaluronan and BAL osteopontin to a greater extent in Cpe fat than WT mice, and both BAL hyaluronan and BAL osteopontin were further augmented in Cpe fat / TNF-␣ Ϫ/Ϫ vs. Cpe fat mice (Fig.…”

“…There is also evidence that the matrix protein osteopontin contributes to O 3 -induced AHR in lean mice (3). O 3 increased both BAL hyaluronan (Fig.…”

“…In lean mice, TNFR2 deficiency reduces O 3 -induced AHR but does not affect O 3 -induced inflammation (10,51,59), whereas in obese mice TNFR2 deficiency augments O 3 -induced AHR but reduces O 3 -induced changes in baseline pulmonary mechanics and O 3 -induced recruitment of neutrophils and macrophages to lungs (59). The impact of overall TNF-␣ deficiency on obesity-related changes in the response to O 3 has not yet been assessed but could differ from the impact of TNFR2 deficiency because of differences in TNFR1 and TNFR2 signaling described above.…”

Ovary-dependent emphysema augmentation and osteopontin induction in adult female mice

“…Elevated OPN levels have been reported in the lungs of patients with asthma, COPD, or pulmonary fibrosis, or a combination of the above [7e11] and are linked to pathological features of these diseases, including eosinophil and neutrophil infiltration [12,13], goblet cell hyperplasia [14,15], airway hyper-responsiveness [13,14], and fibrosis [11,15,16]. Shan et al have recently demonstrated in mice that chronic exposure to CS induces Opn mRNA expression in lung dendritic cells, which in turn stimulates differentiation of Th17 cells and thus interleukin 17A (IL-17A)-driven inflammation, eventually leading to emphysema [17,18].…”