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Lung Inflammation and Atopy Muscarinic Receptor Expression

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Lung Inflammation and Atopy Muscarinic Receptor Expression The Journal of Immunology 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. Sopori2* Airway hyperreactivity (AHR), lung inflammation, and atopy are clinical signs of allergic asthma. Gestational exposure to ciga- rette 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 phosphodi- esterase (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 Journal of Immunology, 2009, 183: 2115–2121. he adverse health effects of cigarette smoke (CS)3 are well sponses differently (12, 13). For example, some allergic diseases recognized, and smoking is associated with increased risk and ulcerative colitis are less common in adult smokers than non- T for lung cancer and respiratory infections (1). Increasing smokers (1, 14–18), whereas ex-smokers are more likely to develop evidence suggests that chronic exposure to environmental or sec- asthma than current smokers (19, 20). Moreover, in animal models, ondhand CS (SS) also causes significant health effects (2–4). chronic exposure of adult animals to mainstream CS or nicotine sup- Moreover, strong epidemiological evidence indicates parental presses innate and adaptive immune responses (1, 21–24), and even smoking, particularly maternal smoking during pregnancy, in- SS moderates some parameters of allergic asthma in mice (25). In creases the risk of allergic asthma in children (4–10). Yet in the Brown Norway rats, chronic exposure to nicotine attenuates the rag- United States alone, nearly 12% of prospective mothers continue weed/house dust mite-induced lung inflammation and atopy (13). to smoke during pregnancy (11). Interestingly, prenatal and post- Thus, in adult humans and animals, chronic CS/nicotine exposure natal exposure to CS may affect immune and inflammatory re- may attenuate some parameters of allergic inflammation in the lung. In contrast, in utero exposure to mainstream CS exacerbates allergic *Respiratory Immunology Division, Lovelace Respiratory Research Institute, Albu- and inflammatory responses in the offspring (26), and it is likely that querque, NM 87108; and †Veterans Affairs Medical Center and Medical College of the mechanisms by which CS modulates the allergic responses in Wisconsin, Milwaukee, WI 53295 utero and during adult life do not totally overlap. Received for publication March 13, 2009. Accepted for publication May 26, 2009. The mechanism(s) by which gestational exposure to CS affects The costs of publication of this article were defrayed in part by the payment of page the lung function in children is not clearly understood. In an es- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tablished murine model of bronchopulmonary aspergillosis, in 1 This work was supported in part by grants from Flight Attendant Medical Re- which Aspergillus fumigatus extract (Af) induces allergic asthma search Institute and the National Institutes of Health (R01 DAO17003 and R01 (26, 27), we have shown that exposure of mothers to mainstream DAO4208-17). CS throughout the gestational period increases airway hyperreac- 2 Address correspondence and reprint requests to Dr. Mohan L. Sopori, Lovelace tivity (AHR) after an acute exposure to the allergen (Af) and the Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108. E-mail address: [email protected] increased AHR is related to elevated expression of phosphodies- 3 Abbreviations used in this paper: CS, cigarette smoke; Af, Apergillus fumigatus terase (PDE)4 in the lungs of the progeny (26). However, unlike extract; AHR, airway hyperreactivity; BAL, bronchoalveolar lavage; BALF, BAL chronic Af sensitization (27), single exposure to the allergen did fluid; EOS, eosinophil; FA, filtered air; i.t., intratracheal; mAChR, muscarinic ace- tylcholine receptor; MCh, methacholine; PDE, phosphodiesterase; qPCR, quantitative not induce significant lung inflammation and atopy (26). There- RT-PCR; RL, airway resistance; RP, rolipram; SS, secondhand CS. fore, in addition to the mechanism of allergen-induced increase in www.jimmunol.org/cgi/doi/10.4049/jimmunol.0900826 2116 SS EXPOSURE IN UTERO PROMOTES ALLERGIC ASTHMA AHR, the effects of gestational CS exposure on lung inflammation Bronchoalveolar lavage (BAL) and cell collection and atopy are unknown. In this communication, we show that fe- Mice were anesthetized and euthanized by exsanguination 24 h after the tuses are highly sensitive to CS, and maternal exposure to even SS last allergen (Af) challenge. Before excision of the lungs, the trachea was strongly exacerbates the allergen-induced AHR through up-regu- surgically exposed and cannulated. The left lung lobe was tied off with a lated expression of M1, M2, and M3 muscarinic receptors and the silk thread suture, and the right lobe was lavaged with 1 ml of PBS (2ϫ) PDE4 isozyme PDE4D5 in the lung. In addition, SS markedly and pooled for each animal. BAL cells were collected by centrifugation and resuspended in PBS. Approximately 5 ϫ 104 cells from each sample were intensifies lung inflammation, Th2 cytokine production, and atopy cytospun on duplicate slides and stained with Diff Quik (Baxter Health- induced through allergic sensitization. Although the PDE4-selec- care) to score eosinophils (EOS), macrophages, neutrophils, and lympho- tive inhibitor rolipram (RP) decreased muscarinic receptor expres- cytes using standard hemocytologic criteria. At least 200 cells from each sion and AHR, it essentially failed to affect the allergen-induced slide were counted to obtain the differential cell count. atopy and lung inflammation. Analysis of cytokines/chemokines in the BAL fluid (BALF) BALF was analyzed for cytokines and chemokines by the commercially Materials and Methods available mouse cytokine Ten-Plex ELISA kit (BioSource International; Animals Invitrogen) and used according to the manufacturer’s directions. Cytokine concentrations were determined using Bioplex manager software with Pathogen-free BALB/c mice were obtained from the Frederick Cancer four-parameter data analysis. The sensitivity of the assay was Ͻ10 pg/ml. Research Facility. Animals were housed in shoe box-type plastic cages with hardwood chip bedding and conditioned to whole-body exposure Quantitative RT-PCR (qPCR) analysis in exposure chambers (H1000; Hazleton Systems) for 2 wk before ex- posure to SS. The chamber temperature was maintained at 26 Ϯ 2°C, Total RNA was extracted from the lung samples using TRI reagent (Mo- and lights were set to a 12-h on/off cycle. Food and water were provided lecular Research Center) and quantified following the manufacturer’s in- ad libitum. All animal protocols used in this study were approved by structions. The lung expression of cytokines (IL-4, IL-5, IL-6, and IL-13), Lovelace Respiratory Research Institute’s Institutional Animal Care muscarinic receptors (M1, M2, and M3), 18S RNA, and GAPDH was and Use Committee. determined by qPCR using the One-Step RT-PCR Master Mix and specific labeled primer/probe set (Applied Biosystems). The relative expression of Abs and reagents each mRNA was calculated, as previously described (13). Ab to PDE4 (ab14628) was obtained from Abcam. All the other reagents, Total serum IgE unless otherwise stated, were bought from Sigma-Aldrich. Blood from the mice was collected on the day of sacrifice, centrifuged in a serum separator, and stored at Ϫ80°C until analysis. Total serum IgE CS generation and exposure titers were determined by the ELISA method, as previously described (30). Mice were exposed to whole-body SS (the smoke released from the burn- Western blot analysis ing end of a cigarette) or filtered air (FA) for 6 h/day, 7 days/wk, as described (26). Briefly, a smoking machine
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