Impact of Adiponectin Deficiency on Pulmonary Responses to Acute Ozone Exposure in Mice

Abstract

Obese mice have increased responses to acute ozone (O 3) exposure. T-cadherin is a binding protein for the high-molecular weight isoforms of adiponectin, an anti-inflammatory hormone that declines in obesity. The objective of the present study was to determine whether adiponectin affects pulmonary responses to O 3 , and whether these effects are mediated through T-cadherin. We performed bronchoalveolar lavage (BAL) and measured pulmonary responsiveness to methacholine after acute air or O 3 exposure (2 ppm for 3 h) in adiponectin-deficient (Adipo 2/2) or T-cadherindeficient (T-Cad 2/2) mice. O 3 increased pulmonary responses to methacholine and increased BAL neutrophils and protein to a greater extent in wild-type than in Adipo 2/2 mice, whereas T-cadherin deficiency had no effect. O 3-induced increases in BAL IL-6 and keratinocyte-derived chemokine (KC), which contribute to O 3induced pulmonary neutrophilia, were also greater in wild-type than in Adipo 2/2 mice. In contrast, responses to O 3 were not altered by transgenic overexpression of adiponectin. To determine which adiponectin isoforms are present in the lung, Western blotting was performed. The hexameric isoform of adiponectin dominated in serum, whereas BAL was dominated by the high-molecular weight isoform of adiponectin. Interestingly, serum adiponectin was greater in T-Cad 2/2 versus wild-type mice, whereas BAL adiponectin was lower in T-Cad 2/2 versus wild-type mice, suggesting that T-cadherin may be important for transit of high-molecular weight adiponectin from the blood to the lung. Our results indicate that adiponectin deficiency inhibits pulmonary inflammation induced by acute O 3 exposure, and that T-cadherin does not mediate the effects of adiponectin responsible for these events.

Obesity and Asthma

“…BAL levels of leptin, IL-6, and IL-8, but not adiponectin, tended to correlate with those found in visceral adipose tissue of subjects with asthma. Others have reported discordance between serum and BAL adiponectin (19); this could be related to transport of adiponectin isoforms from serum into the lung (20). The reason that BAL leptin, IL-6, and IL-8 tend to correlate with those in visceral adipose tissue in people with asthma is not known, but could relate to the relatively high level of these mediators in asthmatic visceral adipose tissue, which drains into the portal circulation and subsequently passes through the vasculature of the lung.…”

“…Shore and coworkers (23) have previously shown that allergen challenge decreases pulmonary expression of adiponectin receptors 1 and 2 and T-cadherin in mice, and that T-cadherin may be involved in transport of adiponectin into the lungs. The lower expression of T-cadherin in people with asthma may point to an abnormality in adiponectin trafficking in the airway of obese people with asthma compared with obese control subjects, although the functional significance of this and the increased AdipoR2 expression clearly require further study (20). Although adipokines may directly affect the airway, obesity also causes profound changes in immune cell function (38).…”

Low Serum Adiponectin Predicts Future Risk for Asthma in Women

“…Compared with men, women have higher concentrations of the high-molecularweight isoform (38,39). The latter isoform is also the dominant isoform in murine lung (21) and may be the most biologically relevant isoform. Our study, however, did not measure adiponectin isoforms.…”

“…Adiponectin and all of the known receptors for adiponectin (AdipoR1, AdipoR2, T-cadherin, and calreticulin) are expressed on multiple cell types in the lung (18)(19)(20). Adiponectin is also transported from blood into the alveolar lining fluid via the T-cadherin molecule on the endothelium (20,21).A causative role for adiponectin in asthma has been better established in mice than in humans (22). Murine studies have, however, shown that this association is bidirectional, whereby exogenous adiponectin attenuates airway changes of asthma and allergen-induced bronchoprovocation decreases adiponectin concentrations (22).…”

“…Adiponectin and all of the known receptors for adiponectin (AdipoR1, AdipoR2, T-cadherin, and calreticulin) are expressed on multiple cell types in the lung (18)(19)(20). Adiponectin is also transported from blood into the alveolar lining fluid via the T-cadherin molecule on the endothelium (20,21).…”