Parental, particularly maternal, smoking increases the risk of childhood allergic asthma and infection. Similarly, in a murine allergic asthma model, prenatal plus early postnatal exposure to secondhand cigarette smoke (SS) exacerbates airway hyperreactivity and Th2 responses in the lung. However, the mechanism and contribution of prenatal versus early postnatal SS exposure on allergic asthma remains unresolved. To identify the effects of prenatal and/or early postnatal SS on allergic asthma, BALB/c dams and their offspring were exposed gestationally and/or 8–10 weeks post-birth to filtered air or SS. Prenatal, but not postnatal SS strongly increased methacholine and allergen (Aspergillus)-induced airway resistance, Th2-cytokines levels and atopy, and activated the Th2 polarizing pathway GATA3/Lck/ERK1/2/STAT6. Either prenatal and/or early postnatal SS downregulated the Th1-specific transcription factor T-bet and, surprisingly, in spite of high levels of IL-4/IL-13, dramatically blocked the allergen-induced mucous cell metaplasia, airway mucus formation, and the expression of mucus-related genes/proteins: Muc5ac, GABAA-receptors, and SPDEF. Given that SS/nicotine exposure of normal adult mice promotes mucus formation, the results suggest that fetal and neonatal lung are highly sensitive to cigarette smoke. Thus, while the gestational SS promotes Th2 polarization/allergic asthma, it may also impair and/or delay the development of fetal and neonatal lung, affecting mucociliary clearance and Th1 responses. Together, this may explain the increased susceptibility of children from smoking parents to allergic asthma and childhood respiratory infections.
Smokers are less likely to develop some inflammatory and allergic diseases. In Brown-Norway rats, nicotine inhibits several parameters of allergic asthma, including the production of Th2 cytokines and the cysteinyl leukotriene LTC4. Cysteinyl leukotrienes are primarily produced by mast cells, and these cells play a central role in allergic asthma. Mast cells express a high-affinity receptor for IgE (FcεRI). Following its cross-linking, cells degranulate and release preformed inflammatory mediators (early phase) and synthesize and secrete cytokines/chemokines and leukotrienes (late phase). The mechanism by which nicotine modulates mast cell activation is unclear. Using α-bungarotoxin binding and quantitative PCR and PCR product sequencing, we showed that the rat mast/basophil cell line RBL-2H3 expresses nicotinic acetylcholine receptors (nAChRs) α7, α9, and α10; exposure to exceedingly low concentrations of nicotine (nanomolar), but not the biologically inactive metabolite cotinine, for ≥8 h suppressed the late phase (leukotriene/cytokine production) but not degranulation (histamine and hexosaminidase release). These effects were unrelated to those of nicotine on intracellular free calcium concentration but were causally associated with the inhibition of cytosolic phospholipase A2 activity and the PI3K/ERK/NF-κB pathway, including phosphorylation of Akt and ERK and nuclear translocation of NF-κB. The suppressive effect of nicotine on the late-phase response was blocked by the α7/α9-nAChR antagonists methyllycaconitine and α-bungarotoxin, as well as by small interfering RNA knockdown of α7-, α9-, or α10-nAChRs, suggesting a functional interaction between α7-, α9-, and α10-nAChRs that might explain the response of RBL cells to nanomolar concentrations of nicotine. This “hybrid” receptor might serve as a target for novel antiallergic/antiasthmatic therapies.
Rationale: Preterm infants exposed to mechanical ventilation and oxygen are at risk for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disorder characterized by arrested alveolar development. Studies have described disruption of microvascular development in BPD, characterized by primitive angioarchitectural patterns reminiscent of the canalicular/saccular stages of lung development. The molecular regulation of this BPD-associated dysangiogenesis remains undetermined. Objectives: Endoglin (CD105), a hypoxia-inducible transforming growth factor-b coreceptor, has been implicated as an important regulator of angiogenesis in various neoplastic and nonneoplastic conditions. The aim of this study was to investigate the expression of endoglin and other angiogenesis-related factors in ventilated preterm human lungs. Methods: We have studied endoglin protein and mRNA expression in postmortem lungs of short-term and long-term ventilated preterm infants. Control subjects were age-matched infants who had lived for less than 1 hour. Measurements and Main Results: Lungs of short-term ventilated preterm infants showed significant upregulation of endoglin mRNA and protein levels, immunolocalized to the microvasculature. Similar but more variable endoglin upregulation was noted in lungs of longterm ventilated infants with BPD. The mRNA levels of vascular endothelial growth factor, angiopoietin-1, and their respective receptors were significantly lower in ventilated lungs than in age-matched nonventilated control lungs. Conclusions: BPD is associated with a shift from traditional angiogenic growth factors (vascular endothelial growth factor, angiopoietin-1) to alternative regulators such as endoglin, which may contribute to BPD-associated microvascular dysangiogenesis.Keywords: chronic lung disease of prematurity; bronchopulmonary dysplasia; neonatal lung disease; angiogenesis Preterm newborns who require mechanical ventilation and supplemental oxygen are at risk for bronchopulmonary dysplasia (BPD), a chronic lung disease of newborn infants associated with significant mortality and morbidity (1). BPD in the postsurfactant era is seen mainly in very low birthweight infants and affects 30% of infants born between 24 and 28 weeks of gestation, many of whom will require long-term respiratory support (2, 3).The dominant pathological finding in postsurfactant BPD is an arrest in alveolar development, resulting in large and simplified airspaces that show varying degrees of interstitial fibrosis (2,(4)(5)(6)(7)(8). Studies have shown that, in addition to impaired alveolar development, there is also a disruption of pulmonary microvascular development in infants with BPD (8-10) or in BPD-like animal models such as chronically ventilated premature baboons (11,12). In view of the intimate relation between alveolar and microvascular development during pulmonary morphogenesis (13-16), disruption of microvascular development in premature lungs has been implicated as a critical factor in the arrest of alveolar development that i...
Premature infants are at risk for bronchopulmonary dysplasia, a complex condition characterized by impaired alveolar development and increased alveolar epithelial apoptosis. The functional involvement of pulmonary apoptosis in bronchopulmonary dysplasiaassociated alveolar disruption remains undetermined. The aims of this study were to generate conditional lung-specific Fas-ligand (FasL) transgenic mice and to determine the effects of FasL-induced respiratory epithelial apoptosis on alveolar remodeling in postcanalicular lungs. Transgenic (TetOp) 7 -FasL responder mice, generated by pronuclear microinjection, were bred with Clara cell secretory protein (CCSP)-rtTA activator mice. Doxycycline (Dox) was administered from embryonal day 14 to postnatal day 7, and lungs were studied between embryonal day 19 and postnatal day 21. Dox administration induced marked respiratory epithelium-specific FasL mRNA and protein up-regulation in double-transgenic CCSP-rtTA
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