Low-dose adrenomedullin-2/intermedin(8-47) reduces pulmonary ischemia/reperfusion injury.

Adrenomedullin-2/intermedin stabilizes the pulmonary microvascular barrier challenged by application of thrombin ex vivo and by experimental ventilation in vivo. Here, we test the hypothesis that adrenomedullin-2/intermedin(8-47) protects mouse lungs from ischemia/reperfusion injury in vivo. C57BL/6 mice were anesthetized, intubated, ventilated, and heparinized. Blood vessels and the main bronchus of the left lung were clamped for 90min. Thereafter, lungs were reperfused for 120min. Five min before clamping and before reperfusion, mice obtained intravenous injections of adrenomedullin-2/intermedin(8-47). After reperfusion, mice were sacrificed and bronchoalveolar lavage of the left and the right lung was performed separately. The integrity of the blood-air barrier was investigated by electron microscopy using stereological methods. In response to ischemia/reperfusion injury, intraalveolar leukocytes accumulated in the ischemic lung. Two applications of 10ng/kg body weight adrenomedullin-2/intermedin(8-47) dramatically reduced leukocyte infiltration to about 15% (p≤0.001). Also the proportion of the subpopulation of neutrophil granulocytes decreased (12% vs 5%, p=0.013). Electron microscopy revealed a protection of the blood-air barrier by adrenomedullin-2/intermedin(8-47). Adrenomedullin-2/intermedin(8-47) ameliorates early ischemia/reperfusion injury in mouse lungs by protecting the integrity of the blood-air barrier and by potently reducing leukocyte influx into the alveolar space. Adrenomedullin-2/intermedin(8-47) might be of therapeutic interest in lung transplantation and cardiopulmonary bypass.

Controlled lung reperfusion to reduce pulmonary ischaemia/reperfusion injury after cardiopulmonary bypass in a porcine model.

OBJECTIVES: Ischaemia/reperfusion (I/R) injury of the lungs contributes to pulmonary dysfunction after cardiac surgery with cardiopulmonary bypass (CPB), leading to increased morbidity and mortality of patients. This study investigated the value of controlled lung reperfusion strategies on lung ischaemia-reperfusion injury in a porcine CPB model. METHODS: Pigs were subjected to routine CPB for 120 min with 60 min of blood cardioplegic cardiac arrest (CCA). Following CCA, the uncontrolled reperfusion (UR, n = 6) group was conventionally weaned from CPB. Two groups underwent controlled lung reperfusion strategies (CR group: controlled reperfusion conditions, n = 6; MR group: controlled reperfusion conditions and modified reperfusate, n = 6) via the pulmonary artery before CPB weaning. Sham-operated pigs (n = 7) served as controls. Animals were followed up until 4 h after CPB. Pulmonary function, haemodynamics, markers of inflammation, endothelial injury and oxidative stress as well as morphological lung alterations were analysed. RESULTS: CPB (UR group) induced deterioration of pulmonary function (lung mechanics, oxygenation index and lung oedema). Also, controlled lung reperfusion groups (CR and MR) presented with pulmonary dysfunction after CPB. However, compared with UR, controlled lung reperfusion strategies (CR and MR) improved lung mechanics and reduced markers of oxidative stress, but without alteration of haemodynamics, oxygenation, inflammation, endothelial injury and lung morphology. Both controlled reperfusion groups were similar without relevant differences. CONCLUSION: Controlled lung reperfusion strategies attenuated a decrease in lung mechanics and an increase in oxidative stress, indicating an influence on CPB-related pulmonary injury. However, they failed to avoid completely CPB-related lung injury, implying the need for additional strategies given the multifactorial pathophysiology of postoperative pulmonary dysfunction.

Reduced speech perceptual acuity for stop consonants in individuals who stutter.

PURPOSE: In individuals who stutter (IWS), speech fluency can be enhanced by altered auditory feedback, although it has adverse effects in control speakers. This indicates abnormalities in the auditory feedback loop in stuttering. Current motor control theories on stuttering propose an impaired processing of internal forward models that might be related to a blurred auditory-to-motor translation. Although speech sound perception is an essential skill to form internal models, perceptual acuity has not been studied in IWS so far. The authors tested the stability of phoneme percepts by analyzing participants' ability to identify voiced and voiceless stop consonants. METHOD: Two syllable continua were generated by systematic modification of the voice onset time. The authors determined speech perceptual acuity by means of discriminatory power in 25 IWS and 24 matched control participants by determining the phoneme boundaries and by quantifying the interval of voice onset times for which phonemes were perceived ambiguously. RESULTS: In IWS, discriminatory performance was weaker and less stable over time when compared with control participants. In addition, phoneme boundaries were located at longer voice onset times in IWS. CONCLUSION: Persistent developmental stuttering is associated with less reliable phonological percepts, supporting current theories regarding the sensory-motor interaction in human speech.

Alveolar epithelial type II cells and their microenvironment in the caveolin-1-deficient mouse.

Caveolin-1 (Cav-1) is highly expressed in alveolar epithelial type I (AE1) and endothelial cells of the alveolar region of the lung. Interestingly, alveolar epithelial type II (AE2) cells that are progenitors of the AE1 cells do not express Cav-1. We investigated whether genetic Cav-1 deficiency alters the phenotype of AE2 cells and their microenvironment using stereology. Total number, mean volume, and subcellular composition of the AE2 cells were not altered in Cav-1(-/-) when compared with wild-type mice. The alveolar septa were thickened and contained a significantly greater volume of extracellular matrix. Thus, AE2 cells as progenitors of AE1 cells are not critically involved in the severe pulmonary phenotype in Cav-1-deficient mice.

Right-shift for non-speech motor processing in adults who stutter.

INTRODUCTION: In adults who do not stutter (AWNS), the control of hand movement timing is assumed to be lateralized to the left dorsolateral premotor cortex (PMd). In adults who stutter (AWS), the network of speech motor control is abnormally shifted to the right hemisphere. Motor impairments in AWS are not restricted to speech, but extend to non-speech orofacial and finger movements. We here investigated the lateralization of finger movement timing control in AWS. METHODS: We explored PMd function in 14 right-handed AWS and 15 age matched AWNS. In separate sessions, they received subthreshold repetitive transcranial magnetic stimulation (rTMS) for 20 min at 1Hz over the left or right PMd, respectively. Pre- and post-stimulation participants were instructed to synchronize their index finger taps of either hand with an isochronous sequence of clicks presented binaurally via earphones. Synchronization accuracy was measured to quantify the effect of the PMd stimulation. RESULTS: In AWNS inhibition of left PMd affected synchronization accuracy of the left hand. Conversely, in AWS TMS over the right PMd increased the asynchrony of the left hand. CONCLUSIONS: The present data indicate an altered functional connectivity in AWS in which the right PMd seems to be important for the control of timed non-speech movements. Moreover, the laterality-shift suggests a compensatory role of the right PMd to successfully perform paced finger tapping.

Allometry of the mammalian intracellular pulmonary surfactant system.

Alveolar epithelial (AE) surface area is closely correlated with body mass (BM) in mammals. The AE is covered by a surfactant layer produced by alveolar epithelial type II (AE2) cells. We hypothesized that the total number of AE2 cells and the volume of intracellular surfactant-storing lamellar bodies (Lb) are correlated with BM with a similar slope as AE surface area. We used light and electron microscopic stereology to estimate the number and mean volume of AE2 cells and the total volume of Lb in 12 mammalian species ranging from 2 to 3 g (Etruscan shrew) to 400-500 kg (horse) BM. The mean size of Lb was evaluated using the volume-weighted mean volume and the volume-to-surface ratio of Lb. The mean volume of AE2 cells was 500-600 µm(3) in most species, but was higher in Etruscan shrew, guinea pig, and human lung. The mean volume of Lb per AE2 cell was 80-100 µm(3) in most species, with the same exceptions as above. However, the total number of AE2 cells and the total volume of Lb were closely correlated with BM and exhibited an allometric relationship similar to the slope of AE surface area. The mean size of Lb was similar in all investigated species. In conclusion, the mean volume of AE2 cells and their Lb are independent of BM but show some interspecific variations. The adaptation of the intracellular surfactant pool size to BM is obtained by the variation of the number of AE2 cells in the lung.