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COX-Derived Eicosanoids

Environmental Cardiopulmonary Disease Group


The basis of the group's work in this area is the hypothesis that cyclooygenase (COX)-derived eicosanoids (Figure 1) are important modulators of the lung immune response to environmental agents (Figure 2).

 

Zeldin's group was the first to show that COX-1 is the predominant enzyme that biosynthesizes prostaglandin E2 in the lung (Gavett et al., J. Clin. Invest., 1999). 

 

Cyclooxygenase-derived eicosanoids and other arachidonic acid metabolites
Figure 1: Cyclooxygenase-derived eicosanoids and other arachidonic acid metabolites


Proposed effects of prostaglandins in the lung
Figure 2: Proposed effects of prostaglandins in the lung


COX-derived eicosanoids and allergen exposure

The research has demonstrated that airways of allergic COX-1 null mice have a higher number of eosinophils and CD3+/CD4+ lymphocytes called TH cells (Carey et al., Am. J. Respir. Crit. Care Med., 2003).  Bronchoalveolar lavage fluid (BALF) from allergic COX-1 null mice contains significantly higher levels of the TH2 cytokines IL-4, IL-5 and IL-13, increased levels of LTB4 and the cysteinyl leukotrienes, and increased levels of the chemokines TARC and eotaxin. These changes in the COX-1 null mice correlate with increased BALF IgE levels and increased MUC5AC production/mucin secretion. Moreover, the lungs of allergic COX-1 null mice exhibit increased expression of the adhesion molecules VCAM-1 and ICAM-1. TH17 cells comprise another distinct lineage of pro-inflammatory T helper cells that are major contributors to allergic responses. Zeldin's group found that TH17 cell numbers in the lung are significantly lower in COX-2 null mice, but not COX-1 null mice, relative to wild type mice following allergen sensitization/exposure in vivo. Differentiation of naïve T cells to TH17 cells in vitro requires COX-upregulation, prostaglandin production and induction of the RORγt transcription factor. RORγt induction and TH17 differentiation is diminished in COX-2 null cells but can be restored by addition of PGI2 and PGF2α. (Li et al., Am. J. Respir. Crit. Care Med., 2011). 


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COX-derived eicosanoids and lipopolysaccharide (LPS) exposure

The group has examined the effects of disruption of COX genes on pulmonary responses to LPS exposure. Interestingly, while COX-1 deficient mice had increased lung resistance/methacholine responsiveness following LPS exposure, there were no significant differences in inflammatory indices between the genotypes (Zeldin et al., Am. J. Resp. Cell Mol. Biol., 2001).  This data indicated that in COX-1 deficient mice exposed to LPS, airway inflammation and hyperresponsiveness are distinct and that COX-1 is important in regulating physiologic, but not inflammatory, responses to LPS.


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COX-derived eicosanoids and bleomycin-induced fibrosis

The group examined the role of COX-derived eicosanoids in bleomycin-induced fibrosis. Bleomycin is an effective anti-neoplastic agent, although its use is limited due to induction of lung fibrosis. Twenty one days after bleomycin instillation, neither COX-1 null nor COX-2 null mice show changes in the extent or severity of lung fibrosis compared to wild type mice. However, COX-2 null mice have significantly worse lung function compared to wild type or COX-1 null mice (Card, et al., Am J Respir Cell Mol Biol. 2007).  Treatment of mice with either PGE2 or the prostacyclin analog iloprost is protective against the decline in lung function induced by bleomycin (Dackor, et al., Am J Respir Cell Mol Biol. 2011, In Press).  These findings suggest an important regulatory role for COX-2 in the maintenance of lung function in the setting of fibrosis, but not in the progression of the fibrotic process.


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COX-derived eicosanoids and host response to influenza virus infection

In collaboration with Dori Germolec, Ph.D., the group examined the role of COX genes in the host response to influenza virus infection, a significant cause of morbidity and mortality worldwide. The COX pathway is important in modulating immune responses and is also a major target of non-steroidal anti-inflammatory drugs. The group found that influenza A viral infection caused more severe illness in COX-1 deficient mice and less severe illness in COX-2 deficient mice; however, mortality was significantly reduced in COX-2 deficient mice (Carey et al., J. Immunol., 2005).  COX-1 deficient mice had enhanced inflammation and an earlier appearance of pro-inflammatory cytokines, whereas the COX-2-deficient mice exhibited blunted inflammatory and cytokine responses along with increased viral titers. Thus, a deficiency of COX-1 and COX-2 leads to contrasting effects in the host response to influenza infection. COX-1 deficiency is detrimental, whereas COX-2 deficiency is beneficial to the host during influenza viral infection.


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Future studies

The group has recently developed transgenic mice with lung-specific overexpression of human COX-1 using a murine CC10 promoter (Card et al., J. Immunol., 2006)  Studies with these mice will determine the effect of increased COX-derived eicosanoids on lung function at baseline and after various environmental stimuli. Research on the role of COX-derived eicosanoids in modulating the pulmonary immune response to environmental agents and in the pathogenesis of asthma will provide unique opportunities for both mechanistic and translational research.


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