The Role of Interleukin-6 in Pulmonary Inflammation and Injury Induced by Exposure to Environmental Air Pollutants

Abstract

This study was designed to examine the role of the cytokine interleukin-6 (IL-6) in environmental air pollutant-induced pulmonary inflammation, injury, and repair. IL-6 knockout (KO) mice and wild-type (WT) mice were exposed to filtered air; aged and diluted cigarette smoke (ADSS), a surrogate for environmental tobacco smoke; ozone; or ADSS followed by ozone (ADSS/ozone). The proportion of monocytes and neutrophils recovered by bronchoalveolar lavage (BAL) as well as the level of total protein in BAL fluid were significantly increased in both IL-6 KO and WT mice following exposure to ozone or to ADSS/ozone. However, bromodeoxyuridine (BrdU) labeling within terminal bronchiolar epithelium and proximal alveolar regions in IL-6 KO mice exposed to ozone or to ADSS/ozone was significantly reduced compared with IL-6 sufficient mice (WT). WT mice treated with IL-6 antibodies also demonstrated a reduction in BrdU cell labeling similar to that observed in IL-6 KO mice following exposure to ozone or ADSS/ozone. Clara cell secretory protein (CCSP) abundance, a marker of Clara cell maturation and function, was markedly reduced in the terminal bronchiolar epithelium of WT mice following exposure to ADSS and/or ozone, whereas CCSP abundance was unchanged in IL-6 KO mice. We conclude that endogenous IL-6 in mice plays a critical role in the progress of lung inflammation/injury, but CCSP may also play a role to protect the lungs of mice exposed to toxic air pollutants. Data from this study further suggest that IL-6 antibody treatment modalities may be a means to attenuate pulmonary inflammation and injury.

Effect of obesity on pulmonary inflammation induced by acute ozone exposure: role of interleukin-6

“…3A). Significantly greater increases in BAL protein, another marker of O 3 -induced lung injury (1,3,21,29,30,36,56), were also observed in obese vs. lean mice (Fig. 3B), consistent with previous reports (26,34,46).…”

“…3). O 3 exposure leads to neutrophil influx into the lungs (10,13,25,28,35,42,56). Our results using IL-6 blocking antibodies ( Figs.…”

“…IL-6 is also expressed in the lung following acute O 3 exposure (10,12,24,25,56), likely from bronchial epithelial cells and macrophages (12). Indeed, IL-6 is among the genes most strongly induced by acute O 3 exposure (55).…”

“…Indeed, IL-6 is among the genes most strongly induced by acute O 3 exposure (55). Experiments using anti-IL-6 antibodies (Ab) and IL-6-deficient mice indicate that IL-6 also contributes to O 3 -induced pulmonary injury and inflammation (25,56). Hence, the purpose of this study was to examine the hypothesis that IL-6 mediates the exaggerated inflammatory responses to O 3 observed in obese mice.…”

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

“…For example, IL-6 deficiency augmented hydrogen peroxideinduced murine alveolar epithelial cell death (57), and anti-IL-6 antibody treatment significantly increased neutrophilic inflammation caused by O 3 exposure in rats (58). However, converse effects have also been reported, and IL-6 was determined to be proinflammatory during the early phase of O 3 exposure in mice (59,60). Figure 8 depicts a schematic representation of the molecular mechanisms that we have investigated and identified as putative signal transduction pathways leading to pulmonary toxicity caused by inhaled O 3 .…”