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Background Pancreatic digestive enzymes present in meconium might be responsible for meconium-induced lung injury. The local Renin Angiotensin System plays an important role in lung injury and inflammation. Particularly, angiotensin converting enzyme-2 (ACE-2) has been identified as a protective lung enzyme against the insult. ACE-2 converts pro-apoptotic Angiotensin II to anti-apoptotic Angiotensin 1-7. However, the effect of meconium on ACE-2 has never been studied before. Objective To study the effect of meconium on ACE-2, and whether inhibition of proteolytic enzymes present in the meconium reverses its effects on ACE-2. Methods Alveolar epithelial A549 cells were exposed to F-12 medium, 2.5% meconium, meconium + a protease inhibitor cocktail (PIc) and PIc alone for 16 h. At the end of incubation, apoptosis was measured with a nuclear fragmentation assay and cell lysates were collected for ACE-2 immunoblotting and enzyme activity. Results Meconium caused a fourfold increase in apoptotic nuclei (p < 0.001). The pro-apoptotic effect of meconium can be reversed by PIc. Meconium reduced ACE-2 enzyme activity by cleaving ACE-2 into a fragment detected at ~ 37 kDa by immunoblot. PIc prevented the degradation of ACE-2 and restored 50% of ACE-2 activity (p < 0.05). Conclusion These data suggest that meconium causes degradation of lung protective ACE-2 by proteolytic enzymes present in meconium, since the effects of meconium can be reversed by PIc., Author(s): Chintan K. Gandhi [sup.1] [sup.2] , Romel Holmes [sup.3] , Ira H. Gewolb [sup.1] , Bruce D. Uhal [sup.4] Author Affiliations: (1) 0000 0001 2150 1785, grid.17088.36, Division of [...]

Hypercapnia (elevated [CO.sub.2] levels) occurs as a consequence of poor alveolar ventilation and impairs alveolar fluid reabsorption (AFR) by promoting Na,K-ATPase endocytosis. We studied the mechanisms regulating [CO.sub.2]-induced Na,K-ATPase endocytosis in alveolar epithelial cells (AECs) and alveolar epithelial dysfunction in rats. Elevated [CO.sub.2] levels caused a rapid activation of AMP-activated protein kinase (AMPK) in AECs, a key regulator of metabolic homeostasis. Activation of AMPK was mediated by a [CO.sub.2]-triggered increase in intracellular [Ca.sup.2+] concentration and [Ca.sup.2+]/calmodulin-dependent kinase kinase-[beta] (CaMKK-[beta]). Chelating intracellular [Ca.sup.2+] or abrogating CaMKK-[beta] function by gene silencing or chemical inhibition prevented the [CO.sub.2]-induced AMPK activation in AECs. Activation of AMPK or overexpression of constitutively active AMPK was sufficient to activate PKC-[zeta] and promote Na,K-ATPase endocytosis. Inhibition or downregulation of AMPK via adenoviral delivery of dominant-negative AMPK-[[alpha].sub.1] prevented [CO.sub.2]-induced Na,K-ATPase endocytosis. The hypercapnia effects were independent of intracellular ROS. Exposure of rats to hypercapnia for up to 7 days caused a sustained decrease in AFR. Pretreatment with a [beta]-adrenergic agonist, isoproterenol, or a cAMP analog ameliorated the hypercapnia-induced impairment of AFR. Accordingly, we provide evidence that elevated [CO.sub.2] levels are sensed by AECs and that AMPK mediates [CO.sub.2]-induced Na,K-ATPase endocytosis and alveolar epithelial dysfunction, which can be prevented with [beta]-adrenergic agonists and cAMP., Introduction Regulation of [CO.sub.2] elimination is essential for the maintenance of cellular homeostasis (1). In mammals, the lung disposes of the excess [CO.sub.2] produced by the body, and in several [...]

Low Reynolds number flows (Re < 1) in the human pulmonary acinus are often difficult to assess due to the submillimeter dimensions and accessibility of the region. In the present computational study, we simulated three-dimensional alveolar flows in an alveolated duct at each generation of the pulmonary acinar tree using recent morphometric data. Rhythmic lung expansion and contraction motion was modeled using moving wall boundary conditions to simulate realistic sedentary tidal breathing. The resulting alveolar flow patterns are largely time independent and governed by the ratio of the alveolar to ductal flow rates, [Q.sub.a]/[Q.sub.d]. This ratio depends uniquely on geometrical configuration such that alveolar flow patterns may be entirely determined by the location of the alveoli along the acinar tree. Although flows within alveoli travel very slowly relative to those in acinar ducts, 0.021% [less than or equal to] [U.sub.a]/[U.sub.d] [less than or equal to] 9.1%, they may exhibit complex patterns linked to the three-dimensional nature of the flow and confirm findings from earlier three-dimensional simulations. Such patterns are largely determined by the interplay between recirculation in the cavity induced by ductal shear flow over the alveolar opening and radial flows induced by wall displacement. Furthermore, alveolar flow patterns under rhythmic wall motion contrast sharply with results obtained in a rigid alveolus, further confirming the importance of including inherent wall motion to understand realistic acinar flow phenomena. The present findings may give further insight into the role of convective alveolar flows in determining aerosol kinematics and deposition in the pulmonary acinus. [DOI: 10.1115/1.2768109]

This study used electropalatography to identify articulatory drift in alveolar stops (/t/ and /d/) produced by 10 children with functional articulation and phonological disorders. Drift involves an abnormal change in place of articulation that occurs during stop closure. An index was used to measure drift, with higher values indicating greater drift. The results showed that drift was higher for children who produced undifferentiated gestures (articulations with increased tongue-palate contact). Drift is an important characteristic of articulation because it is believed to reflect impaired speech motor control. In addition, drift could explain some perceptually based speech errors that are frequently reported in functional disorders.

Pneumonectomy results in rapid compensatory growth of the remaining lung and also leads to increased flow and shear stress, which are known to stimulate endothelial nitric oxide synthase (eNOS). Nitric oxide is an essential mediator of vascular endothelial growth factor-induced angiogenesis, which should necessarily occur during compensatory lung growth. Thus our hypothesis is that eNOS is critical for compensatory lung growth. To test this, left pneumonectomy was performed in eNOS-deficient mice (eNOS-/-), and compensatory growth of the right lung was characterized throughout 14 days postpneumonectomy and compared with wild-type pneumonectomy and sham controls. Compensatory lung growth was severely impaired in eNOS-/- mice, as demonstrated by significant reductions in lung weight index, lung volume index, and volume of respiratory region. Also, pneumonectomy-induced increases in alveolar surface density and cell proliferation were prevented in eNOS-/- mice, indicating that eNOS plays a role in alveolar hyperplasia. Compensatory lung growth was also impaired in wild-type mice treated with the nitric oxide synthase inhibitor [N.sup.G]-nitro-L-arginine methyl ester. Together, these results indicate that eNOS is critical for compensatory lung growth. angiogenesis; pulmonary regeneration; pneumocytes; alveolar proliferation

Wang, P. M., Y. Ashino, H. Ichimura, and J. Bhatta-charya. Rapid alveolar liquid removal by a novel convective mechanism. Am J Physiol Lung Cell Mol Physiol 281: L1327-L1334, 2001.--Although alveoli clear liquid by active transport, the presence of surface-active material on the alveolar surface suggests that convective mechanisms for rapid liquid removal may exist. To determine such mechanisms, we held the isolated blood-perfused rat lung at a constant alveolar pressure (PA). Under videomicroscopy, we micropunctured a single alveolus to infuse saline or Ringer solution in ~10 adjacent alveoli. Infused alveoli were lost from view. However, as the infused liquid cleared, the alveoli reappeared and their diameters could be quantified. Hence the time-dependent determination of alveolar diameter provided a means for quantifying the time to complete liquid removal ([C.sub.t]) in single alveoli. All determinations were obtained at an PA of 5 cm[H.sub.2]0. [C.sub.t], which related inversely to alveolar diameter, averaged 4.5 s in alveoli with the fastest liquid removal. Injections of dye-stained liquid revealed that the liquid flowed from the injected alveoli to adjacent airfilled alveoli. Lung hyperinfiations instituted by cycling PA between 5 and 15 cm[H.sub.2]0 decreased [C.sub.t] by 50%. Chelation of intracellular [Ca.sup.2+] prolonged [C.sup.t] and abolished the irfliation-induced enhancement of liquid removal. We conclude that when liquid is injected in a few alveoli, it rapidly flows to adjacent air-filled alveoli. The removal mechanisms are dependent on alveolar size, inflation, and intracellular [Ca.sup.2]+. We speculate that removal of liquid from the alveolar surface is determined by the curvature and surface-active properties of the air-liquid interface. surfactant; pulmonary edema; cell calcium; Laplace equation, inflation Received 4 May 2001; accepted in final from 30 July 2001

The phospholipase A2 (PLA2) of rat type II alveolar epithelial cells is studied on the basis of their properties by biochemical and immunologic methods. An enzyme with a high molecular weight is the important PLA2 in the cells. Identical PLA2 is expressed by the human A549 alveolar epithelial-like cell line. The total rat lung cytosol reveals the occurrence of the cell line as a small component. The production of the cellular lipid controller reveals the prominent participation of the enzyme.

Byline: Sanjeev. Deshpande, Vikas. Kumar Ectodermal dysplasia is a rare group of inherited disorders characterized by aplasia or dysplasia of tissues of ectodermal origin, such as hair, nails, teeth and [...]

Inflammation may contribute to lung injury and impaired alveolar development in bronchopulmonary dysplasia. We treated hyperoxia-exposed newborn rats with antibodies to the neutrophil chemokine cytokine-induced neutrophil chemoattractant-1 (CINC-1) during 95% [O.sup.2] exposure to reduce adverse effects of hyperoxia-induced inflammation on lung development. Rats were exposed at birth to air, 95% [O.sup.2], or 95% [O.sup.2] + anti-CINC-1 (injected on days 3 and 4). Bromodeoxyuridine (BrdU) was injected 6 h before death. Anti-CINC-1 treatment improved weight gain but not survival at day 8. Anti-CINC-1 reduced bronchoalveolar lavage neutrophils at day 8 to levels equal to air controls. Total detectable lung CINC-1 was reduced to air control levels. Lung compliance was improved by anti-CINC-1, achieving air control levels in the 10-[micro]g anti-CINC-1 group. Anti-CINC-1 preserved proliferating cell nuclear antigen expression in airway epithelium despite 95% [O.sup.2] exposure. BrdU incorporation was depressed by hyperoxia but preserved by anti-CINC-1 to levels similar to air control. Alveolar volume and surface density were decreased by hyperoxia but preserved by anti-CINC-1 to levels equal to air control. Blockade of neutrophil influx in newborns may avert early lung injury and avoid alveolar developmental arrest that contributes to bronchopulmonary dysplasia. chemotactic factors; proliferation; bromodeoxyuridine; proliferating cell nuclear antigen

Alveolar epithelial barrier functions in ventilated perfused rabbit lungs. Am J Physiol Lung Cell Mol Physiol 280: L896-L904, 2001.--We employed ultrasonic nebulization for homogeneous alveolar tracer deposition into ventilated perfused rabbit lungs. [sup.22]Na and [sup.125]I-albumin transit kinetics were monitored on-line with gamma detectors placed around the lung and the perfusate reservoir. [[sup.3]H]mannitol was measured by repetitive counting of perfusion fluid samples. Volume of the alveolar epithelial lining fluid was estimated with bronchoalveolar lavage with sodium-free isosmolar mannitol solutions. Sodium clearance rate was -2.2 [+ or -] 0.3%/min. This rate was significantly reduced by preadministration of ouabain/amiloride and enhanced by pretreatment with aerosolized terbutaline. The [sup.125]I-albumin clearance rate was -0.40 [+ or -] 0.05%/min. The appearance of [[sup.3]H]mannitol in the perfusate was not influenced by ouabain/amiloride or terbutaline but was markedly enhanced by pretreatment with aerosolized protamine. An epithelial lining fluid volume of 1.22 [+ or -] 0.21 ml was calculated in control lungs. Fluid absorption rate was 1.23 [micro]l [multiplied by] g lung [weight.sup.-1] [multiplied by] [min.sup.-1], which was blunted after pretreatment with ouabain/amiloride. We conclude that alveolar tracer loading by aerosolization is a feasible technique to assess alveolar epithelial barrier properties in aerated lungs. Data on active and passive sodium flux, paracellular solute transit, and net fluid absorption correspond well to those in previous studies in fluid-filled lungs; however, albumin clearance rates were markedly higher in the currently investigated aerated lungs. amiloride; epithelial lining fluid; ion channel; ouabain; protamine; protein clearance

Results of a study to evaluate the efficacy and safety of teriparatide as a form of treatment for osseous regeneration in the oral cavity have revealed that this form of treatment was quite effective in improving clinical outcomes, greater resolution of alveolar bone defects and accelerated osseous wound healing in the oral cavity. The practicality of conducting such trials in the case of patients with cancer, in whom the incidence of osteonecrosis of the jaw is much higher is highlighted.

The internal oblique ridge can be used as an anatomic landmark for anesthetizing the back of the jaw in dental procedures. These procedures often fail because the pain-relieving medication is not injected precisely where necessary to deaden the inferior alveolar nerve. Orienting the syringe parallel to the surface of the lower teeth, a needle can be inserted perpendicular to the internal oblique ridge to a distance of about 12 mm, or until bone is contacted. The anesthetic is then injected at the mandibular foramen to achieve effective local anesthesia.