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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900826v1 183/3/2115    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Singh, S. P. Articles by Sopori, M. L. PubMed PubMed Citation Articles by Singh, S. P. Articles by Sopori, M. L. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information High Risk Pregnancy Secondhand Smoke

Maternal Exposure to Secondhand Cigarette Smoke Primes the Lung for Induction of Phosphodiesterase-4D5 Isozyme and Exacerbated Th2 Responses: Rolipram Attenuates the Airway Hyperreactivity and Muscarinic Receptor Expression but Not Lung Inflammation and Atopy¹

Shashi P. Singh^*, Neerad C. Mishra^*, Jules Rir-sima-ah^*, Mathew Campen^*, Viswanath Kurup, Seddigheh Razani-Boroujerdi^* and Mohan L. Sopori^2,*

^* Respiratory Immunology Division, Lovelace Respiratory Research Institute, Albuquerque, NM 87108; and Veterans Affairs Medical Center and Medical College of Wisconsin, Milwaukee, WI 53295

Airway hyperreactivity (AHR), lung inflammation, and atopy are clinical signs of allergic asthma. Gestational exposure to cigarette smoke (CS) markedly increases the risk for childhood allergic asthma. Muscarinic receptors regulate airway smooth muscle tone, and asthmatics exhibit increased AHR to muscarinic agonists. We have previously reported that in a murine model of bronchopulmonary aspergillosis, maternal exposure to mainstream CS increases AHR after acute intratracheal administration of Aspergillus fumigatus extract. However, the mechanism by which gestational CS induces allergic asthma is unclear. We now show for the first time that, compared with controls, mice exposed prenatally to secondhand CS exhibit increased lung inflammation (predominant infiltration by eosinophils and polymorphs), atopy, and airway resistance, and produce proinflammatory cytokines (IL-4, IL-5, IL-6, and IL-13, but not IL-2 or IFN-). These changes, which occur only after an allergen (A. fumigatus extract) treatment, are correlated with marked up-regulated lung expression of M1, M2, and M3 muscarinic receptors and phosphodiesterase (PDE)4D5 isozyme. Interestingly, the PDE4-selective inhibitor rolipram attenuates the increase in AHR, muscarinic receptors, and PDE4D5, but fails to down-regulate lung inflammation, Th2 cytokines, or serum IgE levels. Thus, the fetus is extraordinarily sensitive to CS, inducing allergic asthma after postnatal exposure to allergens. Although the increased AHR might reflect increased PDE4D5 and muscarinic receptor expression, the mechanisms underlying atopy and lung inflammation are unrelated to the PDE4 activity. Thus, PDE4 inhibitors might ease AHR, but are unlikely to attenuate lung inflammation and atopy associated with childhood allergic asthma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from Flight Attendant Medical Research Institute and the National Institutes of Health (R01 DAO17003 and R01 DAO4208-17).

² Address correspondence and reprint requests to Dr. Mohan L. Sopori, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108. E-mail address: msopori{at}lrri.org

³ Abbreviations used in this paper: CS, cigarette smoke; Af, Apergillus fumigatus extract; AHR, airway hyperreactivity; BAL, bronchoalveolar lavage; BALF, BAL fluid; EOS, eosinophil; FA, filtered air; i.t., intratracheal; mAChR, muscarinic acetylcholine receptor; MCh, methacholine; PDE, phosphodiesterase; qPCR, quantitative RT-PCR; R_L, airway resistance; RP, rolipram; SS, secondhand CS.