Proliferation during early phases of bronchiolar repair in neonatal rabbits following lung injury by 4-ipomeanol

Nonciliated bronchiolar (Clara cells) are progenitor cells during development. During differentiation, they are more susceptible to injury by environmental toxicants metabolized by the cytochrome P450 monooxygenase system, and injury results in altered bronchiolar repair and development. Squamous cells and abnormal cuboidal epithelium persist into early adulthood. The hypothesis tested in this study was that the failure of bronchiolar epithelium to repair normally in neonates following injury is due to an inhibition of proliferation. A model of differential repair in rabbit kits was used. Proliferation was followed for 1 week post injury in rabbit kits treated with a single dose of the P450-mediated cytotoxicant 4-ipomeanol (IPO) at 7 days old (repair abnormal) and compared to rabbits treated with a single dose of IPO at 21 days old (repair normal). Proliferation was measured by the nuclear incorporation of 5-chloro-2'-deoxyuridine (CldU) within epithelium at the target site (terminal bronchiole). The repair pattern between the two age groups was histologically defined. There was no difference in the CldU labeling index during the week of repair between the two age groups, even though the bronchiolar epithelium did not return to normal in the animals treated at 7 days old. In summary, proliferation (through S-phase) is not inhibited during repair in neonatal rabbits treated with IPO at 7 days old compared to animals treated at 21 days old, and we conclude that other factors may be responsible for the altered repair in the young neonates injured by a P450-mediated cytotoxicant.     

喉罩与气管插管复合硬膜外麻醉对手术患者心血管循环及口腔分泌物量的影响

目的 探讨全麻合并连硬外手术中置喉罩和气管内插管对患者心血管反应及口腔分泌物量的影响.方法 选择无心血管疾病、无重要脏器疾患、ASA Ⅰ～Ⅱ级、择期全麻合并连硬外手术患者40例,随机分成两组:喉罩组和插管组,每组20例.记录各组患者置喉罩或气管插管前(T1)、诱导后(T2)、1 min(T3)、3 min(T4)、术中(T5)、拔罩(管)时(T6)、拔罩(管)后1 min( T7)、拔罩(管)后3 min(T8)的SBP、DBP、HR、SpO2.结果 喉罩或气管插管前的SBP、DBP、HR差别不大;拔管T6、T7、T8的SBP、DBP、HR组间比较差异有统计学意义(P＜0.05),插管组T6 SBP( 138±35) mm Hg,DBP(92±16)mm Hg,HR(96±19)次/min高于喉罩组T6(P＜0.05).结论 喉罩对患者心血管系统影响小,可以达到与气管插管一样满意的通气效果,具有血流动力学平稳、操作方便、简单、咽部不适、声嘶发生低而且口腔分泌物量少等优点.     

Prostanoid receptors of the EP3 subtype mediate inhibition of evoked [3H]acetylcholine release from isolated human bronchi

1. The release of neuronal [³H]acetylcholine (ACh) from isolated human bronchi after labelling with [³H]choline was measured to investigate the effects of prostanoids.
2. A first period of electrical field stimulation (S₁) caused a [³H]ACh release of 320±70 and 200±40 Becquerel (Bq) g⁻¹ in epithelium-denuded and epithelium-containing bronchi respectively (P>0.05). Subsequent periods of electrical stimulation (S_n, n=2, 3, and 4) released less [³H]ACh, i.e. decreasing S_n/S₁ values were obtained (0.76±0.09, 0.68±0.07 and 0.40±0.04, respectively).
3. Cumulative concentrations (1–1000 nM) of EP-receptor agonists like prostaglandin E₂, nocloprost, and sulprostone (EP₁ and EP₃ selective) inhibited evoked [³H]ACh release in a concentration dependent manner with IC₅₀ values between 4–14 nM and maximal inhibition of about 70%.
4. The inhibition of evoked [³H]ACh release by prostaglandin E₂, nocloprost and sulprostone was not affected by the DP-, EP₁- and EP₂-receptor antagonist AH6809 at a concentration of 3 μM, i.e. a 3–30 times greater concentration than its affinity (pA₂ values) at the respective receptors.
5. Circaprost (IP-receptor agonist; 1–100 nM), iloprost (IP- and EP₁-receptor agonist; 10-1000 nM) and U-46619 (TP-receptor agonist; 100–1000 nM) did not significantly affect [³H]ACh release.
6. Blockade of cyclooxygenase by 3 μM indomethacin did not significantly modulate evoked [³H]ACh release in epithelium-containing and epithelium-denuded bronchi. Likewise, the combined cyclo- and lipoxygenase inhibitor BW-755C (20 μM) did not affect evoked [³H]ACh release.
7. In conclusion, applied prostanoids appear to inhibit [³H]ACh release in epithelium-denuded human bronchi under the present in vitro conditions, most likely via prejunctional prostanoid receptors of the EP₃ subtype.

     

Capsaicin and neurokinin A-induced bronchoconstriction in the anaesthetised guinea-pig: evidence for a direct action of menthol on isolated bronchial smooth muscle

1. For many years menthol has been used in the treatment of respiratory disorders although, a bronchodilator effect of menthol has yet to be described. Using the bronchoconstrictors capsaicin (acting via stimulating the release of neuropeptides from sensory afferents) and neurokinin A (NKA) we have raised airways resistance in the guinea-pig (GP) and studied the effect of menthol on both capsaicin and NKA-induced bronchoconstriction in vivo. In vitro the effect of menthol on acetylcholine (ACh) and KCl precontracted GP bronchi was also studied.
2. GP (n=13) were anaesthetized (urethane 1.5 g kg⁻¹, i.p.) and a bolus injection of capsaicin (7.5 μg ml⁻¹, i.v.) or infusion of NKA (1 μg min⁻¹, i.v.) was given either in the presence of air (0.81 min⁻¹) or air impregnated with menthol vapour (7.5 μg l⁻¹) freely breathed from a tracheal cannula via a T-piece. Airways resistance (R_aw) and ventilation were measured throughout. Bronchi of mean internal diameter (1029+73.6 μm; n=24) were removed from GP (n=16) and mounted in the Cambustion myograph. Bronchial rings were maximally precontracted with 80 mM KC1 or 2 mM ACh. Relaxation due to a cumulative dose of menthol (1–3000 μM) was measured.
3. Menthol produced a significant (P<0.05) 51.3% reversal of the capsaicin-induced increase in R_aw, and also inhibited the significant (P<0.05) reduction in minute ventilation (V_e) associated with the capsaicin-induced increased in R_aw. Menthol also caused a significant (P<0.05) 41% reversal of the NKA-induced increase in R_aw. The NKA-induced decrease in V_e was again significantly (P<0.05) reversed with menthol inhalation. Menthol caused a significant (P<0.001) dose-dependent relaxation of KCl and ACh precontracted bronchi.
4. We have shown that menthol attenuates both capsaicin and NKA-induced bronchoconstriction in vivo and relaxes KCl and ACh preconstricted bronchi in vitro. Menthol inhibition of NKA and capsaicin-induced bronchoconstriction could be, in part, explained by a direct action of menthol on bronchial smooth muscle.

     

The mouse trap

Mouse models of asthma are now being used extensively in drug research. However, the successful unravelling of combinatorial interplays of cells and molecules in the murine airways may not be matched by equally successful demonstrations of an asthma-like pathophysiology. Here, Carl Persson, Jonas Erjefält, Magnus Korsgren and Frank Sundler discuss the fact that major features of asthma may still need to be demonstrated in the airways of allergic mice.     

Resveratrol rescues cAMP-dependent anionic transport in the cystic fibrosis pancreatic cell line CFPAC1

BACKGROUND AND PURPOSE

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride channel in the plasma membrane of epithelia whose mutation is the cause of the genetic disease cystic fibrosis (CF). The most frequent CFTR mutation is deletion of Phe⁵⁰⁸ and this mutant protein (delF508CFTR) does not readily translocate to the plasma membrane and is rapidly degraded within the cell. We hypothesized that treating epithelial cells with resveratrol, a natural polyphenolic, phyto-ooestrogenic compound from grapes, could modulate both the expression and localization of CFTR.

EXPERIMENTAL APPROACH

Cells endogenously expressing CFTR (MDCK1 and CAPAN1 cells) or delF508CFTR (CFPAC1 and airway epithelial cells, deriving from human bronchial biopsies) were treated with resveratrol for 2 or 18 h. The effect of this treatment on CFTR and delF508CFTR expression and localization was evaluated using RT-PCR, Western blot and immunocytochemistry. Halide efflux was measured with a fluorescent dye and with halide-sensitive electrodes. Production of interleukin-8 by these cells was assayed by ELISA.

KEY RESULTS

Resveratrol treatment increased CFTR expression or maturation in immunoblotting experiments in MDCK1 cells or in CFPAC1 cells. Indirect immunofluorescence experiments showed a shift of delF508CFTR localization towards the (peri)-membrane area in CFPAC1 cells and in human airway epithelial cells. A cAMP-dependent increase in membrane permeability to halide was detected in resveratrol-treated CFPAC1 cells, and was inhibited by a selective inhibitor of CFTR.

CONCLUSION AND IMPLICATIONS

These results show that resveratrol modulated CFTR expression and localization and could rescue cAMP-dependent chloride transport in delF508CFTR cells.     

Upper airway collapsibility evaluated by a negative expiratory pressure test in severe obstructive sleep apnea

OBJECTIVES:

To investigate the usefulness of measuring upper airway collapsibility with a negative expiratory pressure application as a screening test for severe obstructive sleep apnea (OSA).

INTRODUCTION:

OSA is a risk factor for cardiovascular disease, and it may have serious consequences. Its recognition may have important implications during the perioperative period. Increased upper airway collapsibility is one of the main determinants of OSA, and its evaluation could be useful for identifying this condition.

METHODS:

Severe OSA and normal subjects (24 in each group) were matched by body mass index and referred to our sleep laboratory. The subjects were enrolled in an overnight sleep study, and a diurnal negative expiratory pressure test was performed. Flow drop (ΔV̇) and expiratory volume were measured in the first 0.2 s (V_0.2) of the negative expiratory pressure test.

RESULTS:

ΔV̇ and V_0.2 (%) values were statistically different between normal and OSA subjects. OSA patients showed a greater decrease in flow than normal subjects. In addition, severely OSA patients exhaled during the first 0.2 s of the negative expiratory pressure application was an average of only 11.2% of the inspired volume compared to 34.2% for the normal subjects. Analysis of the receiver operating characteristics showed that V_0.2 (%) and ΔV̇ could accurately identify severe OSA in subjects with sensitivities of 95.8% and 91.7%, respectively, and specificities of 95.8% and 91.7%, respectively.

CONCLUSIONS:

V_0.2 (%) and ΔV̇ are highly accurate parameters for detecting severe OSA. The pharyngeal collapsibility measurement, which uses negative expiratory pressure during wakefulness, is predictive of collapsibility during sleep.     

The sleep apnea cardiovascular endpoints (SAVE) trial: Rationale and start-up phase

THE SLEEP APNEA CARDIOVASCULAR ENDPOINTS (SAVE) STUDY (CLINICAL TRIALS REGISTRATION NUMBER: NCT00738170) is an academic initiated and conducted, multinational, open, blinded endpoint, randomised controlled trial designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the incidence of serious cardiovascular events in patients with established cardiovascular disease. The answer to this question is of major importance to populations undergoing ageing and lifestyle changes all over the world. The SAVE study brings together respiratory, sleep and cardiovascular clinician-scientists in a unique interdisciplinary collaborative effort with industry sponsors to conduct the largest and most ambitious clinical trial yet conducted in the field of sleep apnea, with a global recruitment target of 5000 patients. Following its launch in Australia and China in late 2008, SAVE has now entered a phase of international expansion with new recruitment networks being established in New Zealand, India and Latin America. This article describes the rationale for the SAVE study, the considerations behind its design, and progress thus far in establishing the recruitment network. The report emphasises the important role that Chinese sleep and cardiovascular investigators have played in the start-up phase of this landmark international project.     

Amyloidosis of the heart and respiratory system

Since the incidence of amyloidosis is increasing, the purpose of this article is to review the imaging features of intrathoracic amyloidosis. Amyloidosis forms a heterogeneous group of disorders characterised by the extracellular deposition of a homologous protein complex. The heart is the most commonly involved organ in the chest. Respiratory amyloidal deposition is much less common and may be generalised, when it occurs as a part of a systemic disease, or it may be restricted only to the respiratory system. Although, the abnormalities are considered non-specific, recent literature suggests—especially for cardiac amyloidosis—specific patterns of abnormalities.