Nontypeable Haemophilus influenzae in chronic obstructive pulmonary disease and lung cancer

Chronic obstructive pulmonary disease (COPD) is predicted to become the third leading cause of death in the world by 2020. It is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases, most commonly cigarette smoke. Among smokers with COPD, even following withdrawal of cigarette smoke, inflammation persists and lung function continues to deteriorate. One possible explanation is that bacterial colonization of smoke-damaged airways, most commonly with nontypeable Haemophilus influenzae (NTHi), perpetuates airway injury and inflammation. Furthermore, COPD has also been identified as an independent risk factor for lung cancer irrespective of concomitant cigarette smoke exposure. In this article, we review the role of NTHi in airway inflammation that may lead to COPD progression and lung cancer promotion

The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFNγ-induced cell death

IFNγ induces cell death in epithelial cells, but the mediator for this death pathway has not been identified. In this study, we find that expression of Bik/Blk/Nbk is increased in human airway epithelial cells (AECs [HAECs]) in response to IFNγ. Expression of Bik but not mutant BikL61G induces and loss of Bik suppresses IFNγ-induced cell death in HAECs. IFNγ treatment and Bik expression increase cathepsin B and D messenger RNA levels and reduce levels of phospho–extracellular regulated kinase 1/2 (ERK1/2) in the nuclei of bik+/+ compared with bik−/− murine AECs. Bik but not BikL61G interacts with and suppresses nuclear translocation of phospho-ERK1/2, and suppression of ERK1/2 activation inhibits IFNγ- and Bik-induced cell death. Furthermore, after prolonged exposure to allergen, hyperplastic epithelial cells persist longer, and nuclear phospho-ERK is more prevalent in airways of IFNγ−/− or bik−/− compared with wild-type mice. These results demonstrate that IFNγ requires Bik to suppress nuclear localization of phospho-ERK1/2 to channel cell death in AECs

Golgi Apparatus in Airway Secretory Cells

https://openworks.mdanderson.org/sumexp22/1068/thumbnail.jp

Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation

<p>Abstract</p> <p>Background</p> <p>Although cigarette smoking is the principal cause of lung carcinogenesis, chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, has been identified as an independent risk factor for lung cancer. Bacterial colonization, particularly with non-typeable <it>Haemophilus influenzae </it>(NTHi), has been implicated as a cause of airway inflammation in COPD besides cigarette smoke. Accordingly, we hypothesized that lung cancer promotion may occur in a chronic inflammatory environment in the absence of concurrent carcinogen exposure.</p> <p>Results</p> <p>Herein, we investigated the effects of bacterial-induced COPD-like inflammation and tobacco carcinogen-enhanced tumorigenesis/inflammation in the retinoic acid inducible G protein coupled receptor knock out mouse model (Gprc5a-/- mouse) characterized by late-onset, low multiplicity tumor formation. Three-month-old Gprc5a-/- mice received 4 intraperitoneal injections of the tobacco-specific carcinogen, NNK, followed by weekly exposure to aerosolized NTHi lysate for 6 months. The numbers of inflammatory cells in the lungs and levels of several inflammatory mediators were increased in Gprc5a-/- mice treated with NTHi alone, and even more so in mice pretreated with NNK followed by NTHi. The incidence of spontaneous lung lesions in the Gprc5a-/- mice was low, but NTHi exposure led to enhanced development of hyperplastic lesions. Gprc5a-/- mice exposed to NNK alone developed multiple lung tumors, while NTHi exposure increased the number of hyperplastic foci 6-fold and the tumor multiplicity 2-fold. This was associated with increased microvessel density and HIF-1α expression.</p> <p>Conclusion</p> <p>We conclude that chronic extrinsic lung inflammation induced by bacteria alone or in combination with NNK enhances lung tumorigenesis in Gprc5a-/- mice.</p

Airway Epithelial Innate Immunity

Besides providing an essential protective barrier, airway epithelial cells directly sense pathogens and respond defensively. This is a frontline component of the innate immune system with specificity for different pathogen classes. It occurs in the context of numerous interactions with leukocytes, but here we focus on intrinsic epithelial mechanisms. Type 1 immune responses are directed primarily at intracellular pathogens, particularly viruses. Prominent stimuli include microbial nucleic acids and interferons released from neighboring epithelial cells. Epithelial responses revolve around changes in the expression of interferon-sensitive genes (ISGs) that interfere with viral replication, as well as the further induction of interferons that signal in autocrine and paracrine manners. Type 2 immune responses are directed primarily at helminths and fungi. Prominent pathogen stimuli include proteases and chitin, and important responses include mucin hypersecretion and chitinase release. Type 3 immune responses are directed primarily at extracellular microbial pathogens, including bacteria and fungi, as well as viruses during their extracellular phase of infection. Prominent microbial stimuli include bacterial wall components, such as lipopeptides and endotoxin, as well as microbial nucleic acids. Key responses are the release of reactive oxygen species (ROS) and antimicrobial peptides (AMPs). For all three types of response, paracrine signaling to neighboring epithelial cells induces resistance to infection over a wide field. Often, the epithelial effector molecules themselves also have signaling properties, in addition to the release of inflammatory cytokines that boost local innate immunity. Together, these epithelial mechanisms provide a powerful first line of pathogen defense, recruit leukocytes, and instruct adaptive immune responses

A High Galactic Latitude HI 21cm-line Absorption Survey using the GMRT: I. Observations and Spectra

We have used the Giant Meterwave Radio Telescope (GMRT) to measure the Galactic HI 21-cm line absorption towards 102 extragalactic radio continuum sources, located at high (|b| >15deg.) Galactic latitudes. The Declination coverage of the present survey is Decl. ~ -45deg.. With a mean rms optical depth of ~0.003, this is the most sensitive Galactic HI 21-cm line absorption survey to date. To supplement the absorption data, we have extracted the HI 21-cm line emission profiles towards these 102 lines of sight from the Leiden Dwingeloo Survey of Galactic neutral hydrogen. We have carried out a Gaussian fitting analysis to identify the discrete absorption and emission components in these profiles. In this paper, we present the spectra and the components. A subsequent paper will discuss the interpretation of these results.Comment: 46 pages, Accepted for publication in Journal of Astrophysics & Astronom

The role of intrinsic efficacy in determining response to a β2-agonist in acute severe asthma

SummaryBackgroundCurrent guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma. However, approximately one-third of patients show little or no initial response to this partial β2-agonist.MethodsWe conducted a randomized, double-blind, proof-of-concept study to investigate whether a full β2-agonist, isoproterenol, offers a therapeutic advantage in adults presenting with acute severe asthma (FEV1<50%) who fail to respond to an initial treatment of the partial β2-agonist, albuterol. Study subjects were randomized to receive a 2-h continuous nebulization of either albuterol (7.5mg/h) (n=10, mean FEV1=37% predicted) or isoproterenol (7.5mg/h) (n=9, mean FEV1=33% predicted). Respiratory symptoms, vital signs and pulmonary function measures were collected.ResultsSubjects from both treatment groups had similar baseline characteristics. The percent improvements from baseline FEV1 at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol (44 vs. 17% and 63 vs. 24%, respectively, P<0.05). The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol (P<0.01). Both treatments were well tolerated, though the mean increase in pulse rate at 60 and 120min (21 vs. 1 and 23 vs. 6beats/min, respectively, P<0.05) and the mean change in serum potassium at 120min (−0.52 vs. −0.07meq/L, P<0.05) from baseline were significantly greater in the isoproterenol group.ConclusionsOur data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol, the use of a β2-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms

Synaptotagmin-2 Is Essential for Survival and Contributes to Ca²⁺ Triggering of Neurotransmitter Release in Central and Neuromuscular Synapses

Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca²⁺ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5’ end of the synaptotagmin-2 gene was replaced by lacZ. Using β-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at ~3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2-deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca²⁺-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca²⁺ triggering of neurotransmitter release

Arecibo HI Absorption Measurements of Pulsars and the Electron Density at Intermediate Longitudes in the First Galactic Quadrant

We have used the Arecibo telescope to measure the HI absorption spectra of eight pulsars. We show how kinematic distance measurements depend upon the values of the galactic constants R_o and Theta_o, and we select our preferred current values from the literature. We then derive kinematic distances for the low-latitude pulsars in our sample and electron densities along their lines of sight. We combine these measurements with all others in the inner galactic plane visible from Arecibo to study the electron density in this region. The electron density in the interarm range 48 degrees < l < 70 degrees is [0.017 (-0.007,+0.012) (68% c.l.)] cm^(-3). This is 0.75 (-0.22,+0.49) (68% c.l.) of the value calculated by the Cordes & Lazio (2002) galactic electron density model. The model agrees more closely with electron density measurements toward Arecibo pulsars lying closer to the galactic center, at 30 degrees<l<48 degrees. Our analysis leads to the best current estimate of the distance of the relativistic binary pulsar B1913+16: d=(9.0 +/- 3) kpc. We use the high-latitude pulsars to search for small-scale structure in the interstellar hydrogen observed in absorption over multiple epochs. PSR B0301+19 exhibited significant changes in its absorption spectrum over 22 yr, indicating HI structure on a ~500 AU scale.Comment: Accepted by Astrophysical Journal September 200