Sevoflurane and desflurane protect cholinergic-induced bronchoconstriction of hyperreactive airways in rabbits

Purpose: The potential of desflurane to alter respiratory mechanics in the presence of bronchial hyperresponsiveness (BHR) is still a subject of debate. Accordingly, we evaluated the bronchoprotective potential of desflurane compared with sevoflurane following cholinergic lung constriction in rabbits with normal and hyperreactive airways. Methods: The input impedance of the respiratory system (Zrs) was measured during midazolam-based anesthesia before and during intravenous infusions of increasing doses of methacholine (MCh). The rabbits in the control group (Group C) were then randomized to receive either sevoflurane 1 MAC followed by desflurane 1 MAC or vice versa, whereas ovalbumin-sensitized rabbits received sevoflurane followed by desflurane (Group S-SD) or vice versa (Group S-DS). Baseline Zrs measurements and the MCh provocations were repeated under the maintenance of each volatile agent. Airway resistance (Raw), tissue damping (G), and elastance data were obtained from Zrs by model fitting. Results: Similar bronchoprotective effects of sevoflurane and desflurane against MCh-induced bronchoconstriction were observed independently of the severity of the bronchospasm and the presence of BHR. With sevoflurane, the decreases in Raw ranged from 22 (8.8)% to 44 (12)%, and with desflurane, they ranged from 22 (8.7)% to 50 (12)%. The increases in G reflecting the enhanced ventilation heterogeneities in the lung periphery were not affected by the volatile agents. Conclusions: If the contractile stimulus is cholinergic in origin, sevoflurane and desflurane exert similar bronchoprotective potentials to act against lung constriction independent of the presence of BHR. These volatile anesthetics otherwise lack a potential to improve the enhanced ventilation heterogeneities that develop particularly in the presence of BH

The Cutaneous Lesions of Dioxin Exposure: Lessons from the Poisoning of Victor Yushchenko

Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne” are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotic

Effects of volatile anaesthetic agents on enhanced airway tone in sensitized guinea pigs

Although volatile anaesthetics afford protection against bronchospasm, their potential to reverse a sustained constriction of hyperreactive airways has not been characterized. Accordingly, we investigated the ability of halothane, isoflurane, sevoflurane and desflurane to reverse lung constriction induced by prolonged stimulation of the muscarinic receptors in guinea pigs sensitized to ovalbumin

From the Cover: High Susceptibility of Lrig1 Sebaceous Stem Cells to TCDD in Mice

We have previously shown that cytochrome P450 1A1 (CYP1A1) was highly induced for a long period of time in a patient who had been poisoned by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound known to activate the aryl hydrocarbon receptor (AhR). During that period of time, no sebaceous glands could be observed in the skin of this patient. In this study, starting from observations in the patient exposed to TCDD, we analyzed the seboatrophy induced by dioxins in mice. We observed a very different pattern of AhR and CYP1A1 immunostaining in skin biopsies of the patient. When applying TCDD and beta-naphthoflavone, another AhR agonist, on the ears of C57BL/6J mice, we reproduced (1) an atrophy of sebaceous glands, (2) a strong induction of CYP1A1 within the glands, and (3) a dramatic repression of the genes encoding the sebogenic enzymes AWAT1, ELOVL3, and SCD1. These effects were reversible. Leucine-rich repeats and immunoglobulin- like domains protein 1 (LRIG1) expressing progenitor cells, found in the vicinity of sebaceous glands, were shown to be the initial skin cellular targets of AhR agonists. These cells retained the DNA label BrdU and colocalized with the CYP1A1 protein for at least 30 days. A downregulation of LRIG1 by siRNA in cultured sebocytes significantly decreased the CYP1A1 response to TCDD, indicating that LRIG1 contributes to a higher susceptibility of AhR agonists. In conclusion, these observations provide for the first time a strong experimental support to the concept that dioxin-induced skin pathology may be driven by a molecular switch in progenitor cells involved in the physiological turnover of sebaceous glands

The contribution of the pulmonary microvascular pressure in the maintenance of an open lung during mechanical ventilation

Changes in pulmonary hemodynamics modify the mechanical properties of the lungs. The effects of alterations in pulmonary capillary pressure (Pc) were investigated on the airway and lung tissue mechanics during positive-pressure ventilation and following lung recruitment maneuvers. Isolated, mechanically normoventilated (PEEP 2.5 cmH(2)O) rat lungs were perfused with Pc set to 0 (unperfused), 5, 10 or 15 mmHg, in random sequence. The pulmonary input impedance (ZL) was measured at end-expiration before and after a 10-min long ventilation. After inflation of the lung to 30 cmH(2)O during P-V curve recordings, another set of ZL was measured to evaluate the degree of recruitment. The PEEP was then decreased to 0.5 cmH(2)O and the sequence was repeated. Airway resistance and parenchymal damping and elastance (H) were estimated from ZL by model fitting. From the P-V curves, elastance (E) and hysteresis indices were determined. Mechanical ventilation at both PEEP levels resulted primarily in elevations in the tissue parameters, with the greatest increases at the 0 Pc level (H changes of 27.8+/-4.2 and 61.3+/-3.7% at 2.5 and 0.5 cmH(2)O PEEP, respectively). The maintenance of physiological Pc (10 mmHg) led to a significantly lower elevation in H (11.6+/-1.5% versus 31.4+/-3.6%). The changes in the oscillatory mechanics were also reflected in E and the hysteresis of the P-V curves. These findings indicate that pulmonary hypoperfusion during mechanical ventilation forecasts a parenchymal mechanical deterioration. Physiological pressure in the pulmonary capillaries is therefore an important mechanical factor promoting maintenance of the stability of the alveolar architecture during positive-pressure mechanical ventilation

Impact of elevated pulmonary blood flow and capillary pressure on lung responsiveness

Since alterations in pulmonary hemodynamics may lead to airway hyperreactivity, the consequences of individual changes in pulmonary blood flow (Qp) and capillary pressure (Pc) on lung responsiveness were investigated. During maintenance of a steady-state Pc of 5, 10, or 15 mmHg (groups 1-3), acute increases of Qp were generated in isolated, perfused rat lungs by simultaneous pulmonary arterial pressure elevation and venous pressure lowering. Conversely, at constant low (groups 4 and 5) or high Qp (groups 6 and 7), Pc was lowered or elevated by changing, in parallel, the pulmonary arterial and venous pressures. Pulmonary input impedance was measured under baseline conditions and during methacholine provocation (2-18 microg*kg(-1)*min(-1)), whereas the pulmonary hemodynamics were altered in accordance with the group allocation. The airway resistance and constant-phase parenchymal model parameters were identified from the pulmonary input impedance spectra. Increases of Qp at constant Pc had no effect on the basal lung mechanics, whereas they enhanced the lung reactivity to methacholine, particularly when high Pc was maintained [peak airway resistance increases of 299 +/- 99% (SE) vs. 609 +/- 217% at Qp levels of 5 and 10 ml/min, respectively, P < 0.05]. In contrast, the change of Pc at constant Qp slightly deteriorated the basal parenchymal mechanics without affecting the lung responsiveness. These findings suggest that increases in Qp per se may lead to the development of airway hyperreactivity. This phenomenon may contribute to the airway susceptibility under conditions associated with simultaneous elevations in pulmonary vascular pressures and Qp, such as exercise-induced asthma and the situation in children with congenital heart diseases

From the Cover: High Susceptibility of Lrig1 Sebaceous Stem Cells to TCDD in Mice

We have previously shown that cytochrome P450 1A1 (CYP1A1) was highly induced for a long period of time in a patient who had been poisoned by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound known to activate the aryl hydrocarbon receptor (AhR). During that period of time, no sebaceous glands could be observed in the skin of this patient. In this study, starting from observations in the patient exposed to TCDD, we analyzed the seboatrophy induced by dioxins in mice. We observed a very different pattern of AhR and CYP1A1 immunostaining in skin biopsies of the patient. When applying TCDD and beta-naphthoflavone, another AhR agonist, on the ears of C57BL/6J mice, we reproduced (1) an atrophy of sebaceous glands, (2) a strong induction of CYP1A1 within the glands, and (3) a dramatic repression of the genes encoding the sebogenic enzymes AWAT1, ELOVL3, and SCD1. These effects were reversible. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) expressing progenitor cells, found in the vicinity of sebaceous glands, were shown to be the initial skin cellular targets of AhR agonists. These cells retained the DNA label BrdU and colocalized with the CYP1A1 protein for at least 30 days. A downregulation of LRIG1 by siRNA in cultured sebocytes significantly decreased the CYP1A1 response to TCDD, indicating that LRIG1 contributes to a higher susceptibility of AhR agonists. In conclusion, these observations provide for the first time a strong experimental support to the concept that dioxin-induced skin pathology may be driven by a molecular switch in progenitor cells involved in the physiological turnover of sebaceous glands

Differential roles of endothelin-1 ETA and ETB receptors and vasoactive intestinal polypeptide in regulation of the airways and the pulmonary vasculature in isolated rat lung

The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR