Ex vivo adult stem cell characterization from multiple muscles in ambulatory children with cerebral palsy during early development of contractures.

Cerebral palsy (CP) is one of the most common conditions leading to lifelong childhood physical disability. Literature reported previously altered muscle properties such as lower number of satellite cells (SCs), with altered fusion capacity. However, these observations highly vary among studies, possibly due to heterogeneity in patient population, lack of appropriate control data, methodology and different assessed muscle. In this study we aimed to strengthen previous observations and to understand the heterogeneity of CP muscle pathology. Myogenic differentiation of SCs from the Medial Gastrocnemius (MG) muscle of patients with CP (n = 16, 3-9 years old) showed higher fusion capacity compared to age-matched typically developing children (TD, n = 13). Furthermore, we uniquely assessed cells of two different lower limb muscles and showed a decreased myogenic potency in cells from the Semitendinosus (ST) compared to the MG (TD: n = 3, CP: n = 6). Longitudinal assessments, one year after the first botulinum toxin treatment, showed slightly reduced SC representations and lower fusion capacity (n = 4). Finally, we proved the robustness of our data, by assessing in parallel the myogenic capacity of two samples from the same TD muscle. In conclusion, these data confirmed previous findings of increased SC fusion capacity from MG muscle of young patients with CP compared to age-matched TD. Further elaboration is reported on potential factors contributing to heterogeneity, such as assessed muscle, CP progression and reliability of primary outcome parameters.

Acute liver injury following acetaminophen administration does not activate atrophic pathways in the mouse diaphragm.

N-acetyl-para-amino phenol (APAP, usually named paracetamol), which is commonly used for its analgesic and antipyretic properties may lead to hepatotoxicity and acute liver damage in case of overdoses. Released cytokines and oxidative stress following acute liver damage may affect other organs' function notably the diaphragm, which is particularly sensitive to oxidative stress and circulating cytokines. We addressed this issue in a mouse model of acute liver injury induced by administration of APAP. C57BL/6J mice (each n = 8) were treated with N-acetyl-para-amino phenol (APAP) to induce acute drug caused liver injury and sacrificed 12 or 24 h afterwards. An untreated group served as controls. Key markers of inflammation, proteolysis, autophagy and oxidative stress were measured in diaphragm samples. In APAP treated animals, liver damage was proven by the enhanced serum levels of alanine aminotransferase and aspartate aminotransferase. In the diaphragm, besides a significant increase in IL 6 and lipid peroxidation, no changes were observed in key markers of the proteolytic, and autophagy signaling pathways, other inflammatory markers and fiber dimensions. The first 24 h of acute liver damage did not impair diaphragm atrophic pathways although it slightly enhanced IL-6 and lipid peroxidation. Whether longer exposure might affect the diaphragm needs to be addressed in future experiments.

COPD awareness survey: do Belgian pulmonary physicians comply with the GOLD guidelines 2010?

Chronic Obstructive Pulmonary Disease (COPD) is underestimated, underdiagnosed and often under-treated in the general population. A survey of 17 structured questions, delivered to all Belgian pulmonary physicians (PPs) (116 responses), evaluated diagnosis and treatment strategies in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 2010 and assessed opinions about the importance of diurnal variation of COPD symptoms. All COPD diagnoses (37% new cases) were spirometry confirmed. Main diagnostic parameters were symptoms (99%), external risk factors (99%), clinical examination (97%), exacerbations (96%) and patient mobility (96%). FEV1 (forced expiratory volume in 1s) (97%) or FEV1/FVC (ratio of FEV1 to forced vital capacity) (93%) were used most to assess diagnosis and severity. The 3 most important therapeutic objectives were symptom relief, preventing exacerbations, and improving quality of life; if these were not reached, the preferred strategy (60% of PPs) was adding another medication. Treatment strategies varied with COPD stage: short-acting beta2-agonists (90%) and short-acting anti-cholinergics (59%) were used for GOLD I disease, whereas for higher stages long-acting beta2-agonists (36-48%) and long-acting anti-cholinergics (79%) were given with inhaled corticosteroids (21-67%). Symptoms were perceived to vary throughout the day, affecting quality of life (97%) and mobility (89%). In particular, respiratory symptoms were more severe in the morning (51-92%), leading PPs to adapt treatment (69%). This survey demonstrated that management of COPD by PPs in Belgium is generally in line with the GOLD guidelines 2010 and that they perceive morning symptoms as being frequent and having an impact on patient's life.

Atrophy and hypertrophy signalling in the diaphragm of patients with COPD.

We investigated whether atrophy and hypertrophy signalling were altered in the diaphragm of chronic obstructive pulmonary disease (COPD) patients. We studied diaphragm fibre dimensions and proportion, expression of markers of the ubiquitin-proteasome pathway, nuclear factor (NF)-kappaB pathways, muscle regulatory factors and myostatin in diaphragm biopsies from 19 patients with severe COPD and 13 patients without COPD. Type I proportion was significantly increased in the diaphragm of COPD patients while type II proportion was decreased. The cross-sectional area of all fibre types was reduced in the COPD patients. In addition, MAFbx mRNA was higher in the diaphragm of COPD patients while Nedd4 mRNA decreased. Cytoplasmatic levels of inhibitor protein IkappaBalpha and IkappaBbeta were decreased in the COPD patients as was NF-kappaB p50 DNA-binding activity. MyoD mRNA and its nuclear protein content were decreased in the diaphragm of COPD patients and myogenin mRNA and protein levels remained unchanged. Myostatin mRNA was decreased but its protein levels in the nuclear and cytoplasmic fraction were significantly increased in the COPD patients. These data show that the ubiquitin-proteasome pathway, the NF-kappaB pathway and myostatin protein were up-regulated in the diaphragm of COPD patients while MyoD expression was reduced. These alterations may contribute to diaphragm remodeling in COPD.

Markers of inflammation and disuse in vastus lateralis of chronic obstructive pulmonary disease patients.

BACKGROUND: Disuse and/or local inflammation in the muscle cannot be excluded as potential influences for the decreased muscle force in patients hospitalised due to an acute chronic obstructive pulmonary disease (COPD) exacerbation. This study aims to compare expression levels of markers of disuse (insulin-like growth factor-1 (IGF-I), MyoD and myogenin) and inflammation [interleukin-6 (IL-6), IL-8 and tumour necrosis factor-alpha (TNF-alpha)] in the muscle of hospitalised and stable COPD patients and healthy elderly. MATERIAL AND METHODS: Muscle biopsies (m. vastus lateralis) were taken in 14 hospitalised COPD patients (aged 68 +/- 8), 11 clinically stable COPD patients (aged 68 +/- 9) and seven healthy subjects (aged 70 +/- 7) to analyse local mRNA expression levels of IL-6, IL-8, TNF-alpha, IGF-I and protein expression levels of IGF-I, MyoD and myogenin. Relationships of these expression levels with lung and skeletal muscle function were investigated. RESULTS: IGF-I mRNA and MyoD protein levels were significantly lower in hospitalised patients compared to healthy subjects. MyoD protein levels were positively related to quadriceps force. Muscle IL-6 and IL-8 expression in hospitalised patients was similar compared to stable patients and healthy subjects and was not related to expression levels of muscle markers of disuse or quadriceps force. Muscle TNF-alpha and myogenin were not detected. CONCLUSION: Decreased expression levels of muscle IGF-I and MyoD in hospitalised patients suggest a potential influence of disuse in the increased muscle weakness during an acute COPD exacerbation. This study did not find any evidence supporting local inflammation via IL-6, IL-8 and/or TNF-alpha in the vastus lateralis muscle of COPD patients.

[Exercise effort training for COPD: physiological basis and results]. / Le réentraînement à l'effort des BPCO: bases physiologiques et résultats.

INTRODUCTION: In the last decade pulmonary rehabilitation has become a well accepted treatment for patients with chronic obstructive pulmonary disease (COPD) suffering from persistent dyspnea and fatigue, despite appropriate medical treatment. STATE OF ART: Patients with COPD frequently have muscular dysfunction that can be corrected by appropriate exercise training programmes. Muscle function as measured by strength and endurance tests exercise capacity and also the health status and quality of life are improved by exercise and endurance training. However, integration of exercise training in a multidisciplinary management programme is necessary to take account of all aspects of the illness. PERSPECTIVES: Methods of exercise training need to be adapted for patients with severe COPD who are unable to undertake endurance training and for patients who obtain little benefit. CONCLUSIONS: Pulmonary rehabilitation, thanks to its multidisciplinary nature, seems to be an effective modality of management for patients with COPD. However, the improvements in physical ability, quality of life and general health require an exercise training programme that is adapted for the individual patient.

[Physiological effects of lung reduction surgery: the contribution of an animal model of emphysema]. / Bases physiologiques des effets de la chirurgie de réduction de volume pulmonaire: apports de son application à un modèle animal d'emphysème.

INTRODUCTION: Lung volume reduction surgery (LVRS) is a technique largely used for palliation of symptoms in selected patients with emphysema. Despite some encouraging early results, it is often still regarded as an experimental technique due to the significant associated mortality and unpredictable results. STATE OF ART: The aim of this study was to explore the pathophysiological basis of benefit from LVRS when applied to a hamster model of emphysema induced by elastase and thus allow better selection criteria of patients being considered for this treatment. PERSPECTIVES: Despite a positive effect on pulmonary elastic recoil pressures, LVRS did not, unlike its effects in humans, improve airway obstruction in the emphysematous hamsters. Differences in chest wall mechanics may explain these contrasting findings. Adaptation of the intrinsic and cellular properties of the diaphragm that are seen in emphysema are preserved after LVRS. CONCLUSIONS: Despite differences with emphysema in humans, this hamster model supports the importance of the residual volume/total lung capacity ratio when selecting patients with emphysema for LVRS. The positive outcome of this intervention on the dynamics of the diaphragm is not compromised by modifications undergone by the diaphragmic myocytes.

Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is often associated with peripheral muscle weakness, which is caused by several factors. Acute exacerbations may contribute, but their impact on muscle force remains unclear. Correlations between peripheral muscle force and inflammatory and anabolic markers have never been studied in COPD. The effect of an acute exacerbation on quadriceps peak torque (QPT) was therefore studied in hospitalised patients, and the aforementioned correlations were examined in hospitalised and in stable patients. METHODS: Lung function, respiratory and peripheral muscle force, and inflammatory and anabolic markers were assessed in hospitalised patients on days 3 and 8 of the hospital admission and 90 days later. The results on day 3 (n=34) were compared with those in clinically stable outpatients (n=13) and sedentary healthy elderly subjects (n=10). RESULTS: Hospitalised patients had lowest mean (SD) QPT (66 (22)% predicted) and highest median (IQR) levels of systemic interleukin-8 (CXCL8, 6.1 (4.5 to 8.3) pg/ml). Insulin-like growth factor I (IGF-I) tended to be higher in healthy elderly subjects (p=0.09). QPT declined between days 3 and 8 in hospital (mean -5% predicted (95% CI -22 to 8)) and partially recovered 90 days after admission to hospital (mean 6% predicted (95% CI -1 to 23)). QPT was negatively correlated with CXCL8 and positively correlated with IGF-I and lung transfer factor in hospitalised and in stable patients. CONCLUSIONS: Peripheral muscle weakness is enhanced during an acute exacerbation of COPD. CXCL8 and IGF-I may be involved in the development of peripheral muscle weakness in hospitalised and in stable patients with COPD.

Effects of mechanical ventilation on diaphragm function and biology.

The pathophysiological mechanisms of weaning from mechanical ventilation are not fully known, but there is accumulating evidence that mechanical ventilation induces inspiratory muscle dysfunction. Recently, several animal models have provided potential mechanisms for mechanical ventilation-induced effects on muscle function. In patients, weaning difficulties are associated with inspiratory muscle weakness and reduced endurance capacity. Animal studies demonstrated that diaphragm force was already decreased after 12 h of controlled mechanical ventilation and this worsened with time spent on the ventilator. Diaphragmatic myofibril damage observed after 3-days controlled mechanical ventilation was inversely correlated with maximal diaphragmatic force. Downregulation of the diaphragm insulin-like growth factor-I and MyoD/myogenin messenger ribonucleic acid occurred after 24 h and diaphragmatic oxidative stress and increased protease activity after 18 h. In keeping with these findings, diaphragm fibre atrophy was shown after 12 h and reduced diaphragm mass was reported after 48 h of controlled mechanical ventilation. These animal studies show that early alterations in diaphragm function develop after short-term mechanical ventilation. These alterations may contribute to the difficulties in weaning from mechanical ventilation seen in patients. Strategies to preserve respiratory muscle mass and function during mechanical ventilation should be developed. These may include: adaptation of medication, training of the diaphragm, stabilisation of the catabolic state and pharmacotherapy.

Alterations in gene expression in hamster diaphragm after emphysema and lung volume reduction surgery.

UNLABELLED: The authors have demonstrated previously that emphysema and lung volume reduction surgery (LVRS) resulted in a significant shift of type IIx/b to type IIa fibres in the diaphragm of hamsters with elastase-induced emphysema. To explore the mechanisms leading to this fibre switching, the mRNA expression of the myogenic regulatory factors, the inhibitors of DNA binding proteins (Id-proteins) and insulin-like growth factor-I were examined. Ribonucleic acid was extracted from the diaphragm of control, emphysematous, emphysematous and sham operated and LVRS hamsters and subjected to reverse transcriptase polymerase chain reaction. Compared to control, the ratio MyoD to myogenin declined with emphysema, sham and even more after LVRS, due to a decrease in MyoD mRNA and an increase in myogenin mRNA. Similarly, compared to control, Id-1 protein mRNA levels decreased significantly in sham and even more in LVRS. Id-2 protein mRNA levels decreased in all groups, but reached statistical significance in LVRS only, compared to control. IN CONCLUSION: 1) the reduced MyoD/myogenin ratio may be the mechanism of the shift to a slower fibre type, 2) the decreased MyoD/myogenin ratio in lung volume reduction surgery animals suggests that lung volume reduction surgery enhances rather than decreases the load placed on the diaphragm and 3) the observed down-regulation of the inhibiting factors may facilitate the diaphragm adaptation to overload.

Effects of lung volume reduction surgery in hamsters with elastase-induced emphysema.

Lung volume reduction surgery (LVRS) has been shown to improve respiratory mechanics in selected patients with severe emphysema. This is thought to be due to an improvement in lung elastic recoil. This study was aimed at gaining further understanding about the effects of LVRS on respiratory mechanics and airway function. Control hamsters instilled with saline (Ctrl; n=8) were compared with emphysematous animals that underwent either a sham operation (Sham; n=7) or an LVRS (LVRS; n=7). As expected, there was a significant increase in the static lung volumes in the Sham as compared to the Ctrl group and a significant decrease of these volumes in LVRS as compared to the Sham group. Surprisingly, emphysema was associated with a significant increase and LVRS with a significant decrease in vital capacity. Despite a tendency toward an increase in lung compliance as compared to Sham, indices of maximal expiratory flows tended to decrease with LVRS. As opposed to humans, there was no change in the distribution of airway diameters in Sham compared to Ctrl. These findings appear to be largely explained by the high compliance of the hamster chest wall. This allows for better matching between the emphysematous lung and the chest-wall sizes than in humans.

Different effects of corticosteroid-induced muscle wasting compared with undernutrition on rat diaphragm energy metabolism.

An important adverse effect of corticosteroid treatment is respiratory muscle weakness with diaphragm muscle wasting, but little is known about the underlying pathophysiological processes involved. In order to differentiate between the effects of nutrition depletion and corticosteroids on diaphragm muscle metabolism, a study was performed to investigate the effects of triamcinolone (TR) for 2 weeks and of chronic undernutrition in a pair-weight (PW) group on the structure and energy metabolism of the diaphragm in male Wistar rats compared with a free-fed (FF) group. Diaphragm mass was reduced in TR and PW rats to a similar degree, but the extent of type-IIx/b atrophy was more pronounced in TR rats than in PW rats. No myopathic features were observed after either treatment. ATP in absolute terms as well as the ATP/ADP ratio, total adenine nucleotides, the phosphocreatine (PCr) level and the ratio between PCr and creatine (PCr/Cr) were decreased in the diaphragm of both TR and PW rats. In contrast to the PW group, the total Cr pool was reduced and pyruvate and lactate levels were elevated in the diaphragm of the TR group compared with the FF group. In conclusion, the results of this study indicate that severe undernutrition causes a decrease in muscle energy status resulting in a new metabolic equilibrium, while chronic low-dose TR treatment (0.25 mg/kg per day i.m.) causes a decrease in muscle energy status together with a mismatch between glycolysis and oxidative metabolism.

Lung volume reduction surgery does not improve diaphragmatic contractile properties or atrophy in hamsters with elastase-induced emphysema.

It is claimed that lung volume reduction surgery (LVRS) improves inspiratory muscle function. As diaphragm structure and function are not directly appraisable in patients, we studied the effects of LVRS on the diaphragm in vitro contractile properties and morphology in hamsters with elastase-induced emphysema. Four months after intratracheal instillation of elastase (40 U/100 g), hamsters underwent either bilateral LVRS (LVRS, n = 11) or a sham operation (SHAM, n = 8). Four animals died during the perioperative period in LVRS (n = 7). Hamsters instilled with saline served as control (CTL, n = 8). Animals were studied at the age of 9 mo. LVRS was associated with a significant 25% decrease in functional residual capacity compared to SHAM (p < 0.05). Compared with CTL, LVRS and SHAM showed a significant 18% and 14% reduction in diaphragm mass, respectively (p = 0.02). LVRS had a significantly decreased twitch tension compared to CTL and SHAM (p < 0.01). Both LVRS and SHAM showed increased resistance to muscle fatigue compared with CTL. The histochemical analysis revealed a significant shift from type IIx/b toward type IIa fibers in LVRS and SHAM compared with CTL. In conclusion, emphysema is associated with functional adaptations but LVRS does not appear to beneficially alter the diaphragm contractile and morphological characteristics in hamsters with elastase-induced emphysema.

[Clinical relevance of myosin isoforms in the diaphragm]. / Pertinence clinique de la répartition des isoformes de la myosine dans le muscle diaphragmatique.

The diaphragm as a striated muscle is characterized by the repetition of a single element arranged in series: the sarcomere containing two kinds of myofilaments: a thick one constituted by the myosin, and a thin one primarily composed of actin. The myosin molecule consists of two heads where two myosin heavy chains (MHC) are fixed, a flexible hinge with two light (MLC) chains, and long rod-shaped tails. The diaphragm contains 4 MHC isoforms (MHC-slow, MHC-2A, MHC-2B, MHC-2X) and 6 MLC isoforms (MLC-1f, MLC-3f, MLC-1sa, MLC-1sb, MLC-2f, MLC-2s/v). In humans, the diaphragm contains mainly fibers expressing the isoforms MHC-slow, MHC-2A, and MLC-2f, MLC-2s et MLC-1f. For the mechanical properties of the different isoforms, there is a gradient from the MHC-slow to the MHC-2A, MHC-2B and MHC-2X/2B. According to the circumstances, the diaphragm will adapt towards a slow profile (COPD, cardiac failure and in animals: Duchenne muscular dystrophy, denervation-1 week, age-female, corticosteroids, chronic stimulation), or a fast profile (in animals: chronic hypoxia, denervation-2 weeks, age-males) or a more oxidative profile (in animals: cachexia, obesity). The reasons why the diaphragm adapts towards a slower or a faster muscle are not known. In fact, for a given pathological situation, several factors are able to influence the fiber composition of the diaphragm. Therefore, the net result of the influence of these different factors in terms of MHC and MLC diaphragm adaptation is difficult to predict.

Corticosteroids decrease mRNA levels of SERCA pumps, whereas they increase sarcolipin mRNA in the rat diaphragm.

1. In order to explore the potential role of the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA)-type pumps and of their modulators phospholamban (PLB) and sarcolipin (SLN) in the functional alterations of the diaphragm induced by corticosteroid treatment, expression of SERCA, PLB and SLN was assessed by RT-PCR in the diaphragm of rats treated daily for 5 days either with triamcinolone (80 mg kg-1, n = 8) or with saline (control; 0.6 ml, n = 8). 2. Triamcinolone treatment reduced the normalised overall amount of all SERCA mRNA in diaphragm by 70 % compared to controls (P < 0.05). This reduction was accounted for by a relatively larger decrease in the SERCA1 mRNA (-69 %, P < 0.05) whilst the decrease in SERCA2 mRNA (-49 %, P = 0.09) did not reach statistical significance. As a result the relative proportion of SERCA2 mRNA was increased from 43 +/- 7 % in control diaphragm to 52 +/- 4 % after triamcinolone treatment (P < 0.05). 3. Only the adult isoform of SERCA1 (i.e. SERCA1a) mRNA was found in the diaphragm of the 15-week-old control rats. Furthermore, triamcinolone treatment resulted in reduced levels of SERCA2a (-40 %, P < 0.05) and increased levels of SLN mRNA (+100 %, P < 0.05), while the decrease in PLB mRNA (-31 %, P = 0.277) did not reach statistical significance. SERCA1b, SERCA2b and SERCA3 mRNA levels fell below the detection limit in the diaphragm of both control and triamcinolone-treated rats. 4. Compared to control diaphragm, control rat heart showed a relatively high PLB/(SERCA1 + SERCA2) mRNA ratio of 7.88 while this ratio amounted only to 0.16 in control extensor digitorum longus (EDL) muscle. Remarkably, the SLN/(SERCA1 + SERCA2) mRNA ratio in normal cardiac muscle (0.96) was nearly the same as in diaphragm, but in EDL it amounted to only 0.05 that in diaphragm. This indicates the very low expression of SLN in rat EDL. 5. These data reveal that considerable alterations in SERCA mRNA levels accompany the functional changes seen in diaphragm after corticosteroid treatment. The relatively larger decrease in SERCA1 mRNA is in agreement with the selective type II fibre atrophy previously observed in the diaphragm of triamcinolone-treated rats, but the magnitude of SERCA alterations is more pronounced than expected on the basis of the structural changes in the diaphragm. The increase in SLN mRNA levels may represent a compensatory mechanism.

Nandrolone decanoate does not enhance training effects but increases IGF-I mRNA in rat diaphragm.

To examine whether concomitant anabolic steroid treatment combined with training might enhance previously observed training effects (A. Bisschop, G. Gayan-Ramirez, H. Rollier, R. Gosselink, R. Dom, V. de Bock, and M. Decramer. Am. J. Respir. Crit. Care Med. 155: 1583-1589, 1997) and whether insulin-like growth factor I (IGF-I) was involved in these changes, male and female rats were submitted to inspiratory muscle training (IMT) for 8 wk (30 min/day, 5 times/wk) and were compared with untrained controls. During the last 5 wk of training, trained rats were divided to receive weekly either low-dose (LD; 1.5 mg/kg) or high-dose (HD; 7.5 mg/kg) nandrolone decanoate or saline for the IMT and control rats. In both sexes, diaphragm muscle mass and contractile properties were unchanged with treatment. In males, HD resulted in decreased diaphragm type I cross-sectional area (-15%; P < 0.05, HD vs. IMT), whereas no changes were observed in females. Finally, an increase in IGF-I mRNA levels was present in HD male (+73%; P < 0.05, HD vs. IMT) and female treated rats [LD (+58%) and HD (+96%) vs. IMT; P < 0.001]. We conclude that administration of nandrolone decanoate did not enhance the previously observed training effects in rat diaphragm, although it increased the IGF-I mRNA expression levels.

Effects of drugs on mucus clearance.

Mucociliary clearance (MCC), the process in which airway mucus together with substances trapped within are moved out of the lungs, is an important defence mechanism of the human body. Drugs may alter this process, such that it is necessary to know the effect of the drugs on MCC. Indeed, agents stimulating MCC may be used therapeutically in respiratory medicine, especially in patients suspected of having an impairment of their mucociliary transport system. In contrast, caution should be taken with drugs depressing MCC as an undesired side-effect, independently of their therapeutic indication. Since cough clearance (CC) serves as a back-up system when MCC fails, the influence of drugs must be examined not only on MCC but also on CC. Ultimately, the clinical repercussions of alterations in mucus transport induced by drug administration must be studied. Tertiary ammonium compounds (anticholinergics), aspirin, anaesthetic agents and benzodiazepines have been shown to be capable of depressing the mucociliary transport system. Cholinergics, methylxanthines, sodium cromoglycate, hypertonic saline, saline as well as water aerosol have been shown to increase MCC. Adrenergic antagonists, guaifenesin, S-carboxymethylcysteine, sodium 2-mercapto-ethane sulphonate and frusemide have been reported not to alter the mucociliary transport significantly. Amiloride, uridine 5'-triphosphate (UTP), quaternary ammonium compounds (anticholinergics), adrenergic agonists, corticosteroids, recombinant human deoxyribonuclease (rhDNase), N-acetylcysteine, bromhexine and ambroxol have been reported either not to change or to augment MCC. Indirect data suggest that surfactant as well as antibiotics may improve the mucociliary transport system. As for the influence of drugs on CC, amiloride and rhDNase have been demonstrated to increase the effectiveness of cough. A trend towards an improved CC was noted after treatment with adrenergic agonists. The anticholinergic agent ipratropium bromide, which is a quaternary ammonium compound, has been suggested to decrease CC significantly. Bromhexine, ambroxol and neutral saline seemed not to alter CC, either positively or negatively. Finally, treatment with either amiloride, recombinant human deoxyribonuclease, bromhexine, ambroxol, N-acetylcysteine, S-carboxymethylcysteine or hypertonic saline has been suggested as a possible cause of clinical improvement in patients, such as the experience of dyspnoea, the case of expectoration or the frequency of infective exacerbations. Other agents did not show a clinical benefit.

Regulation of mucociliary clearance in health and disease.

Airway secretions are cleared by mucociliary clearance (MCC), in addition to other mechanisms such as cough, peristalsis, two-phase gas-liquid flow and alveolar clearance. MCC comprises the cephalad movement of mucus caused by the cilia lining the conducting airways until it can be swallowed or expectorated. MCC is a very complex process in which many variables are involved, all of which may modify the final outcome. The structure, number, movement and co-ordination of the cilia present in the airways as well as the amount, composition and rheological properties of the periciliary and mucus layers are determinants of MCC. Physiological factors such as age, sex, posture, sleep and exercise are reported to influence MCC due to a change in the cilia, the mucus or the periciliary layer, or a combination of these. Environmental pollution is suspected to have a depressant effect on MCC dependent on different factors such as pollutant concentration and the duration of exposure. Most studies focus on sulphur dioxide, sulphuric acid, nitrogen dioxide and ozone. Tobacco smoke and hairspray have been noted to have a negative influence on MCC. Some diseases are known to affect MCC, mostly negatively. The underlying mechanism differs from one illness to another. Immotile cilia syndrome, asthma, bronchiectasis, chronic bronchitis, cystic fibrosis and some acute respiratory tract infections are among the most frequently reported. The present paper reviews normal mucociliary clearance and the effects of diseases on this process.

Physiological basis of improvement after lung volume reduction surgery for severe emphysema: where are we?

Lung volume reduction surgery has become an accepted therapeutic option to relieve the symptoms of selected patients with severe emphysema. In a majority of these patients, it causes objective as well as subjective functional improvement. A proper understanding of the physiological determinants underlying these beneficial effects appears very important in order to better select patients for the procedure that is currently largely carried out on an empirical basis. Lung volume reduction surgery has two distinct effects. Firstly, it causes an increased elastic recoil, which at least partially explains the enhanced maximal expiratory flow. Secondly, it is associated with a reduction of hyperinflation which allows for an increase in global inspiratory muscle strength and in diaphragmatic contribution to tidal volume as well as a decrease in the inspiratory elastic load imposed by the chest wall. Taken together, these effects result in a reduced work of breathing and in an enhanced maximal ventilation which both contribute to the increased exercise capacity and reduced dyspnoea after surgery. The improved lung recoil and the reduced hyperinflation after volume reduction surgery were the primary postulates upon which the usual selection criteria for the procedure were based. It is now likely that these are correct. Nevertheless, some patients do not benefit from lung volume reduction surgery and the current literature does not allow for a refinement of the selection process from a physiological point of view. The exact mechanisms underlying the improvement in lung recoil, lung mechanics, and respiratory muscle function remain incompletely understood. Moreover, the effects of lung volume reduction surgery on gas exchange and pulmonary haemodynamics still need to be more fully investigated. An analysis of the characteristics of patients who do not benefit from the procedure and the development of an animal model for lung volume reduction surgery would probably help address these important issues.