Molecular & Cellular Biology 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 normal mouse lung (Gavett et al., J. Clin. Invest., 1999 (http://www.jci.org/cgi/content/abstract/104/6/721) ).
Cyclooxygenase-derived eicosanoids and other arachidonic acid metabolites
Proposed effects of prostaglandins in the lung
The research has also 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 (http://ajrccm.atsjournals.org/cgi/content/abstract/167/11/1509) ). 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.
The group has also 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 (http://ajrcmb.atsjournals.org/cgi/content/abstract/25/4/457) ). 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.
In collaboration with James Bonner, Ph.D., formerly of NIEHS, the group examined the role of COX genes in the lung response to vanadium pentoxide. Following vanadium exposure, COX-2 null mice, but not COX-1 null mice, have increased acute lung inflammation and develop more lung fibrosis compared to wild type mice (Bonner et al., Am. J. Pathol., 2002 (http://ajp.amjpathol.org/cgi/content/abstract/161/2/459) ). Thus, the response of COX-deficient mice varies depending on the environmental stimulus.
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 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16272346&query_hl=136&itool=pubmed_docsum) ). 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.
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 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16982919&query_hl=81&itool=pubmed_docsum) ).
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.