Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD

α 1

Rationale: α(1)-Antitrypsin (A1AT) was identified as a plasma protease inhibitor; however, it is now recognized as a multifunctional protein that modulates immunity, inflammation, proteostasis, apoptosis, and cellular senescence. Like A1AT, protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, regulates similar biologic processes and plays a key role in chronic obstructive pulmonary disease. Objectives: Given their common effects, this study investigated whether A1AT acts via PP2A to alter tumor necrosis factor (TNF) signaling, inflammation, and proteolytic responses in this disease. Methods: PP2A activity was measured in peripheral blood neutrophils from A1AT-deficient (PiZZ) and healthy (PiMM) individuals and in alveolar macrophages from normal (60 mg/kg) and high-dose (120 mg/kg) A1AT-treated PiZZ subjects. PP2A activation was assessed in human neutrophils, airway epithelial cells, and peripheral blood monocytes treated with plasma purified A1AT protein. Similarly, lung PP2A activity was measured in mice administered intranasal A1AT. PP2A was silenced in lung epithelial cells treated with A1AT and matrix metalloproteinase and cytokine production was then measured following TNF-α stimulation. Measurements and Main Results: PP2A was significantly lower in neutrophils isolated from PiZZ compared with PiMM subjects. A1AT protein activated PP2A in human alveolar macrophages, monocytes, neutrophils, airway epithelial cells, and in mouse lungs. This activation required functionally active A1AT protein and protein tyrosine phosphatase 1B expression. A1AT treatment acted via PP2A to prevent p38 and IκBα phosphorylation and matrix metalloproteinase and cytokine induction in TNF-α–stimulated epithelial cells. Conclusions: Together, these data indicate that A1AT modulates PP2A to counter inflammatory and proteolytic responses induced by TNF signaling in the lung

How amniotic fluid shapes early odor-guided responses to colostrum and milk (and more)

RevueAmong the multiple transitions that characterize mammalian development, birth certainly is the most abrupt and spectacular. It is also the most challenging for newborns when one considers their high mortality rates in any mammalian species. Although evolution has selected newborn organisms that possess the physiological and behavioral keys leading to adapt to this harsh psychobiological challenge, their capabilities cannot be considered separately from the maternal organism and the environment she creates. Mammalian females provide indeed passive (physiological) and/or active (behavioral) assistance to complement and boost their offspring’s capacities. One notable strategy of mammalian females is to generate “sensory continuities” between the consecutive environmental niches their offspring have to go through to survive. Such sensory continuities are produced by different mechanisms based on the basic biological principle that earlier steps in development prepare the organization of the next steps. In vertebrates and invertebrates, the “prenatal” development of sensorimotor and neurocognitive abilities conditions such abilities in postnatal development. These organizational and inductive functions of prenatal experience have been best evidenced in the attunement of sensory systems of newborn organisms. Some stimuli from the complex information flow of the postnatal environment are more salient than others (Alberts, 1987; Smotherman and Robinson, 1987, 1995). This initial neonatal selectivity, often termed “innate” in the soft (etymological) way, is actualized by distress cessation, attention, positive orientation, and coordinated approach responses, as well as facilitated consumption, and eventually metabolic optimization, adapted growth, and cognitive integration. Such transnatal stimulus continuities probably occur in all sensory modalities, as a consequence of their structural and functional construction within the specificities of the fetal ecology proper to each species, and, within species, to local or individual conditions conveyed by and through the maternal organism. First, specialized sensory abilities in neonates may result from perceptual canalization in the species-specific fetal environment, definable as the set of stimuli to which any fetus of a given species is inevitably exposed. These may include tactile cues of body containment, kinesthetic cues caused by regularities in maternal movements, physiological noises related to vascular or heart beats (Salk, 1962; De Casper and Sigafoos, 1983), and possibly odor- or taste-active compounds derived from normal metabolism. Second, local or individual-specific properties of the fetal environment may render neonates selectively reactive to soft tactile stimulations (Scafidi et al., 1990), odorants or tastants transferred into the amniotic fluid from the maternal environment (among which diet, eg, Mennella et al., 2001; Schaal et al., 1995a, 2000), and idiosyncrasies of maternal language, voice, or environmental sounds (De Casper and Fifer, 1980; De Casper and Spence, 1986; Hepper, 1988a; Fifer and Moon, 1995). A third way through which prenatal experience might impinge on neonatal expectations is through nonspecific mechanisms related to the perception of environmental intensity or variability without reference to given qualities. Thus, for example, fetal encoding of generally low-intensity or of different degrees of qualitative variability of the uterine environment, may fix later preferences for low-intensity, or more easily tolerate or appreciate constantly changing stimuli. This chapter will focus on the role of olfaction in the perinatal adaptive responsiveness of mammalian neonates. Specifically, I will address mechanisms by which olfactory experience in the amniotic environment prepare neonates’ selective responsiveness in the postnatal odor environment, especially in the context of the vial ingestion of colostrum and milk, and its consequences for food acceptance in the long run of later life. Although mainly based on studies conducted in human perinates, comparative results obtained with rat, mouse, rabbit, and porcine, ovine or caprine perinates will be mentioned at places, to assess the generality of the phenomena involved in the rapid expression of adaptive responses at birth and after