Breathing Dysfunction Research Articles

Transgenic Mice Lacking Serotonin Neurons Have Severe Apnea and High Mortality during Development

Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically on 5-HT neurons, or whether their influence is excitatory or inhibitory, remains controversial. Here we show that neonatal Lmx1b(flox/flox;ePet-Cre/+) mice (also called Lmx1b(f/f/p) mice), which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 s. This was associated with a marked decrease in ventilation to less than one-half of normal. These respiratory abnormalities were most severe during the postnatal period, markedly improving by the time the pups were 2-4 weeks old. Despite the severe breathing dysfunction, many of these mice survived, but there was a high perinatal mortality, and those that survived had a decrease in growth rate until the age at which the respiratory defects resolved. Consistent with these in vivo observations, respiratory output was markedly reduced in isolated brainstem-spinal cord preparations from neonatal Lmx1b(f/f/p) mice and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT(2A) and neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatal Lmx1b(f/f/p) mice were reversed in vitro and in vivo with agonists of 5-HT(2A) and/or NK-1 receptors. These results demonstrate that ventilatory output in the neonatal period is critically dependent on serotonin neurons, which provide excitatory drive to the respiratory network via 5-HT(2A) and NK-1 receptor activation. These findings provide insight into the mechanisms of sudden infant death syndrome, which has been associated with abnormalities of 5-HT neurons and of cardiorespiratory control.

Obstructive sleep apnoea syndrome: the first picture?

The obstructive sleep apnoea syndrome is a form of disordered breathing in which the upper airways close repeatedly during sleep.1 It is characterized by snoring, witnessed apnoeas and daytime sleepiness.1,2 A large neck and obesity are common, while other risk factors include ageing, the male sex and alcohol intake.1,2 The condition may carry an independent risk of stroke and death.3 The first modern description of obstructive sleep apnoea syndrome is credited to Burwell and colleagues just over half a century ago.4 However, Lavie5 and Bray6 have documented much earlier accounts, for example by Russell (1866), Broadbent (1877), and both Morison and Caton (1889). Following Caton's case report, Heath7 made reference to the sleepy fat boy in The Pickwick Papers by Charles Dickens, published in 1837.8 The eponymous description the Pickwickian Syndrome was proposed by Burwell et al.4 Francis Grose (1731–1791) was a well-known English antiquary and raconteur. He was a prolific illustrator of architectural remains and was among the earliest lexicographers to compile a dictionary of English slang.9,10 Grose was aptly named, being hugely obese. His father came from German-speaking Berne, in Switzerland. The family was also known as Grosse, which translates as big or large, suggesting a family background of adiposity. Short as well as corpulent, he was said to be only five feet tall, while weighing 22 stone.11 These figures, though most likely inaccurate, would give a prodigious BMI of 60. Robert Burns called him ‘a fine, fat, fodgel wight, o'stature short, but genius bright’.12 He was described in the first edition of The National Biography as ‘a sort of antiquarian Falstaff’. A satirical portrait, probably by a friend the Rev James Douglas, shows a corpulent thick-necked man asleep in a chair (Figure 1). The mouth is partially open, suggesting mouth breathing and possibly snoring. It is clear from an inscription underneath that he had dozed off at a gathering of the Society of Antiquaries. It seems he fell asleep often and was ‘a great eater and drinker and fond of sleep’.13 Gandon observed that Grose was subject to ‘salutary periods of repose’, but was cheerful and witty after these.14 Another friend, the Rev Mark Noble, compared him to Sancho Panza in his love of sleep.9 Figure 1 Portrait of Francis Grose. Etching attributed to Rev James Douglas, c. 1785. The British Museum Francis Grose died suddenly in Dublin, at the age of 60 years. It is thought that he suffered a stroke.11,15 It seems credible that Francis Grose had the obstructive sleep apnoea syndrome. Nowadays the diagnosis is confirmed by overnight polysomnography or other sleep-related tests.1 Such investigations were not available in the past and hence the diagnosis must remain tentative. In support, his great obesity and somnolence are well established, while a hugely thick neck is confirmed in another portrait of Grose by Nathaniel Dance (National Portrait Gallery, London). Other supporting although non-specific features are his age, gender and fondness for alcohol. It is not possible now to obtain a history of witnessed apnoea, while the idea that he may be snoring in Douglas's sketch is of course conjecture. The obstructive sleep apnoea syndrome may be an independent risk factor for hypertension16 and cardiovascular disease.17 Grose's putative obstructive sleep apnoea and obesity both would have increased his risk of hypertension, while the breathing dysfunction as well as raised blood pressure would enhance his chance of suffering a stroke.3,17 If the diagnosis is correct, it did not impair greatly his formidable intellect. Sleepiness seems more marked than cognitive dysfunction in obstructive sleep apnoea syndrome:18 the condition may have little impact on intelligence and verbal ability, although it adversely affects sustained attention.19 Despite his fondness for alcohol, his frequent lapses into sleep but absence of post sleep torpor would mitigate against sleepiness induced by alcohol alone. There are no reported episodes in his younger days to suggest a background of narcolepsy. Artists often depicted medical conditions long before the particular entities were described clinically. It is plausible to suggest that, by chance, the etching is the first picture of the obstructive sleep apnoea syndrome. It precedes by a half century or more illustrations of the fat boy in various editions of The Pickwick Papers. It is remarkable that what was in all likelihood an informal sketch of Grose by a colleague and friend, remains such an elegant and medically interesting work.

Metabolic Consequences of Sleep-Disordered Breathing

There is increasing evidence of a causal relationship between sleep-disordered breathing and metabolic dysfunction. Metabolic syndrome (MetS), a cluster of risk factors that promote atherosclerotic cardiovascular disease, comprises central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, manifestations of altered total body energy regulation. Excess caloric intake is indisputably the key driver of MetS, but other environmental and genetic factors likely play a role; in particular, obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may induce or exacerbate various aspects of MetS. Clinical studies show that OSA can affect glucose metabolism, cholesterol, inflammatory markers, and nonalcoholic fatty liver disease. Animal models of OSA enable scientists to circumvent confounders such as obesity in clinical studies. In the most widely used model, which involves exposing rodents to IH during their sleep phase, the IH alters circadian glucose homeostasis, impairs muscle carbohydrate uptake, induces hyperlipidemia, and upregulates cholesterol synthesis enzymes. Complicating factors such as obesity or a high-fat diet lead to progressive insulin resistance and liver inflammation, respectively. Mechanisms for these effects are not yet fully understood, but are likely related to energy-conserving adaptations to hypoxia, which is a strong catabolic stressor. Finally, IH may contribute to the morbidity of MetS by inducing inflammation and oxidative stress. Identification of OSA as a potential causative factor in MetS would have immense clinical impact and could improve the management and understanding of both disorders.

Tuberculose pulmonar: associação entre extensão de lesão pulmonar residual e alteração da função pulmonar

To describe alterations in spirometric variables and its disturbances and to study the existence of a relationship between extent of the residual lung lesion at the end of treatment for tuberculosis and alteration of the lung function measured by spirometry. Analyzed were 96 patients with diagnosis of pulmonary tuberculosis, treated in three health centers in the metropolitan area of Recife, from January, 2003 to November, 2005. Patients of both genders, 15 years of age or older were included, whose chest x-rays at end of the treatment were classified according to criteria of the National Tuberculosis Association (NTA) for extent of lung lesion. Patients replied to a questionnaire at the beginning of the survey, and were submitted to spirometry after conclusion of treatment. Of the 96 patients, 89.6% presented with radiographic sequels. About 54% had moderate to severe sequels. These radiographic alterations correspond to 24.6% and 73.8% respectively of alterations in the pulmonary function. The large number of residual radiographic lesionss (89.6%) and breathing dysfunction (66,7%) identified in this survey call attention to the fact that treatment of a patient with pulmonary tuberculosis must not be restricted to bacteriological healing of the disease. Identification of the residual lung lesions and of the breathing dysfunction in patients who conclude treatment will promote early actions to treat these sequels, improving the quality of life of these patients.

Systematic review of health-related quality of life measures for children with respiratory conditions

Patient-reported outcomes (PROs) are increasingly used in both clinical trials and clinical care to evaluate patient benefits. The purpose of this review was to identify currently available PROs for children with pulmonary conditions and to make recommendations regarding future development and application of these measures. Systematic searches were conducted and disease-specific health-related quality of life (HRQOL) measures, a type of PRO, were identified for asthma, cystic fibrosis (CF), vocal cord dysfunction and sleep-related breathing disorders. Psychometric properties, age-appropriateness, respondent burden and minimal clinically importance difference scores were evaluated in accordance with the Food and Drug Administration guidelines. For both asthma and CF there are several psychometrically sound, well-established measures; however, for vocal cord dysfunction and sleep-related breathing disorders there are no measures children can complete for themselves. In summary, this review indicated that although significant progress has been made, there are still a number of pulmonary conditions for which there is no disease-specific HRQOL measure.

Breathing dysfunction in Rett syndrome: Understanding epigenetic regulation of the respiratory network

Severely arrhythmic breathing is a hallmark of Rett syndrome (RTT) and profoundly affects quality of life for patients and their families. The last decade has seen the identification of the disease-causing gene, methyl-CpG-binding protein 2 (Mecp2) and the development of mouse models that phenocopy many aspects of the human syndrome, including breathing dysfunction. Recent studies have begun to characterize the breathing phenotype of Mecp2 mutant mice and to define underlying electrophysiological and neurochemical deficits. The picture that is emerging is one of defects in synaptic transmission throughout the brainstem respiratory network associated with abnormal expression in several neurochemical signaling systems, including brain-derived neurotrophic factor (BDNF), biogenic amines and gamma-amino-butyric acid (GABA). Based on such findings, potential therapeutic strategies aimed at improving breathing by targeting deficits in neurochemical signaling are being explored. This review details our current understanding of respiratory dysfunction and underlying mechanisms in RTT with a particular focus on insights gained from mouse models.

Insight into pathophysiology of sudden infant death syndrome

Physiological studies that have been undertaken in children with apparent life-threatening events point to disturbances of the autonomic nervous system and brain stem abnormalities. These abnormalities are manifested as breathing dysfunctions and sleeping patterns, as well as heart rate variability. The diminished arousal response in infants who are exposed to intermittent hypoxia can be fatal during conditions when oxygen availability is limited. This inference well explains well the success of campaigns for supine sleeping position, which associated with the decrease in the rate of sudden infant syndrome deaths.

Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2−/y knockout mice

Rett syndrome (RTT) is an inborn neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 gene (MECP2). Besides mental retardation, most patients suffer from potentially life-threatening breathing arrhythmia. To study its pathophysiology, we performed comparative analyses of the breathing phenotype of Mecp2-/y knockout (KO) and C57BL/6J wild-type mice using the perfused working heart-brainstem preparation (WHBP). We simultaneously recorded phrenic and efferent vagal nerve activities to analyse the motor pattern of respiration, discriminating between inspiration, postinspiration and late expiration. Our results revealed respiratory disturbances in KO preparations that were similar to those reported from in vivo measurements in KO mice and also to those seen in RTT patients. The main finding was a highly variable postinspiratory activity in KO mice that correlated closely with breathing arrhythmias leading to repetitive apnoeas even under undisturbed control conditions. Analysis of the pontine and peripheral sensory regulation of postinspiratory activity in KO preparations revealed: (i) prolonged apnoeas associated with enhanced postinspiratory activity after glutamate-induced activation of the pontine Kölliker-Fuse nucleus; and (ii) prolonged apnoeas and lack of reflex desensitization in response to repetitive vagal stimulations. We conclude that impaired network and sensory mediated synaptic control of postinspiration induces severe breathing dysfunctions in Mecp2-/y KO preparations. As postinspiration is particularly important for the control of laryngeal adductors, the finding might explain the upper airway-related clinical problems of patients with RTT such as apnoeas, loss of speech and weak coordination of breathing and swallowing.

Comparative studies on the respiratory dysfunction in Rett syndrome patients and the corresponding mouse model

Rett syndrome (RTT) is a severe neurodevelopmental disorder. Mutations as primary cause of RTT have been identified in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. Most patients suffer from potentially life-threatening breathing disturbances. In spite of the clinical impact of the respiratory dysfunction in RTT little is known about the underlying mechanisms. To study the pathomechanisms of the respiratory disorder in RTT we performed comparative analysis of the breathing dysfunction in RTT patients and the corresponding mouse model. Therefore, we investigated the breathing activity in ambulatory RTT patients by long-term plethysmographic recordings using a mobile sleep laboratory recorder. In addition, we characterised the breathing phenotype of MeCP2-/y knockout (KO) mice using the working heart-brainstem preparation (WHBP).

Breathing Generation and Potential Pharmacotherapeutic Approaches to Central Respiratory Disorders

Breathing is generated and controlled by a brainstem neuronal network. Both intrinsic and synaptic interactions are involved in respiratory rhythm generation and their contribution is state-dependent, changing with hypoxia and the neuromodulatory state. Cellular mechanisms involved in acute or chronic pathological conditions are still unknown. A dysfunction in the neuronal network that controls breathing may be involved in several respiratory disorders such as central sleep apnea, sudden infant death syndrome, congenital hypoventilation, and in some clinical conditions that produce breathing dysfunction such as drug-induced respiratory depression, obesity hypoventilation syndrome, etc. Despite the fact that several drugs are currently used to treat these diseases, the probable effects of this pharmacotherapy on the central rhythm generator and on other neuronal networks related with breathing control is poorly understood. Here, we review the current pharmacological approaches in the treatment of respiratory disorders, such as acetazolamide, theophylline, aminophylline, progesterone, nitric oxide. Possible effects of these drugs on the central respiratory network are discussed and putative therapeutic targets for the development of future pharmacological therapies suggested.

Assessment of the measurement tools of dysfunctional breathing

Introduction Prevalence of dysfunctional breathing (DB) has been claimed to range from 10% 5 to 90%. 1 Currently the clinical assessment of dysfunctional breathing is problematic and there is controversy about the role of hypocapnia and the proposed relationship between symptoms and signs of dysfunctional breathing with CO 2 levels. 3,4 Dysfunctional breathing is being implicated in many conditions commonly seen by osteopaths including fibromyalgia and chronic pain 2 and work related musculo-skeletal problems. 6 In this study we aimed to determine how measurement tools used to predict dysfunctional breathing reflect CO 2 levels and how they correlate with each other. Methods Breathing assessment was performed on 120 adults. Assessment include carbon dioxide measurement via capnometry, breath holding time according to the Buteyko Method protocol, a manual assessment of respiratory motion (MARM), Nijmegen Questionnaire, self-assessment of breathing questionnaire, and Heart Rate Variability coherence with respiration. Various anthropometrical, health outcome and emotional status evaluations were also performed. Results Preliminary results indicate that none of the measures of dysfunctional breathing correlate significantly with CO 2 levels. Claims that breath holding time could accurately predict PCO 2 were not supported. D.B. measures that did show a correlation with each other include respiratory motion balance as tested by MARM and ability to achieve high levels of coherence between respiration and heart rate variability. The self-evaluation of breathing questionnaire showed good correlation with the validated Nijmegen Questionnaire in scores for breathlessness, breathing restriction and breathing pattern disturbance. Conclusions Signs and symptoms of dysfunctional breathing appear to exist even when PCO 2 levels appear normal. Breathing may reflect the function of many systems of the body and a purely biochemical view of breathing dysfunction may be limited. For a complete picture of patients' breathing it is necessary to evaluate the biomechanical aspects of breathing pattern and symptom patterns in addition to the assessment of carbon dioxide.

Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction

Pre-eclamptic toxaemia (PET) may be associated with both endothelial dysfunction (ED) and sleep-disordered breathing (SDB). It was hypothesised that females with PET would demonstrate both SDB and ED, and that a correlation between these two would suggest a potential causative association. A total of 17 females with PET and 25 matched females with uncomplicated pregnancy were studied. They underwent a nocturnal ambulatory sleep study (using Watch_PAT100) and noninvasive evaluation of endothelial function utilising the reactive hyperaemia test (using Endo_PAT 2000). A higher ratio of post- to pre-occlusion pulse-wave amplitude (endothelial function index (EFI)) indicated better endothelial function. Females with PET had a significantly higher respiratory disturbance index (RDI) and lower EFI than controls (18.4+/-8.4 versus 8.3+/-1.3.h(-1), and 1.5+/-0.1 versus 1.8+/-0.1, respectively). Blood pressure significantly correlated with RDI and with EFI. EFI tended to correlate with RDI. In conclusion, these results suggest that both sleep-disordered breathing and endothelial dysfunction are more likely to occur in females with pre-eclamptic toxaemia than in females with uncomplicated pregnancies. The current authors speculate that respiratory disturbances contribute to the functional abnormality of the blood vessels seen in females with pre-eclamptic toxaemia, although causality cannot be determined based on this study.

Communication and eating proficiency in 125 females with Rett syndrome: The Swedish Rett center survey

Purpose. To describe communication and eating proficiency and related factors in Swedish females with Rett syndrome, from a parental/caregiver view.Method. Data from a questionnaire were used and approached descriptively, qualitatively and comparatively. Parents/caregivers of 125 females with Rett syndrome completed the survey. The mean age of the females was 19.6 years.Results. Communication: expressive language was limited and the most common way of expressing will was by producing motor acts, 50% of which were higher level of language (eye- and finger-pointing and gestures). Results also showed communicative behaviour was demonstrated during social activities. Eating proficiency: For eight specific types of eating difficulties, the majority of the females suffered from none, one or two of them. There were significant associations of some specific eating difficulties with breathing dysfunctions and food consistency, but not with dental or oral problems.Conclusions. Results from this study have confirmed that verbal communication in Rett syndrome is limited. Despite a lack of verbal communication the females in this study were reported to need and enjoy social interplay. Outcomes concerning eating were generally good. For optimal intervention, it is recommended that family and professionals work together to evaluate eating situations and communication ability for females with Rett syndrome.

Avaliação anamnésica de sintomas de disfunçâo temporomandibular em crianças asmáticas

Mechanical respiratory dysfunction in asthmatic children, contributing to overuse the secondary respiratory muscles related to cervical spine and allergic sinunasal alterations, leading to development of mouth breathing (MB), might induce craniocervical disorders and predispose asthmatic patients to Temporomandibular Disorders (TMD). The purpose of this study was to assess the presence and features of TMD symptoms in asthmatic children by using the Fonseca anamnestic index (1994). The sample consisted of 30 asthmatic children (7.97± 2.58 years old) who were submitted to TMD evaluation by the use of Fonseca index, and were classified as mouth-breathing children in accordance to Emerson and Cordeiro (1993). Statistical analysis was performed using Chi-square test and Z-test (Mann Whitney U-test, p£0,05). Results show that more than 93% of the patients presented TMD symptoms and a great number of patients were classified as showing mild TMD. Temporomandibular joint pain as well as difficulty during mouth opening were significantly more frequently in asthmatic girls than in boys. Mouth breathing was observed in 90% of the patients and M B degree was proportional to TMD severity. Such results suggest that asthma features, like mechanical respiratory dysfunction and mouth breathing, could be related to the development of TMD symptoms in asthmatic children. Hence a TMD evaluation must be part of the physical therapy program designed for asthmatic children.

Development of chemoreceptor responses in infants

This paper is devoted to the field of chemoreception and its role in the control of breathing in infants. We use "chemoreception" to refer to the capacity to sense and process changes in P(O2) and P(CO2), and also to react to these changes by adjusting ventilation in order to maintain homeostasis. Functional chemoreceptors are not essential to commence or even to sustain breathing efforts immediately at or after birth; the intense brain activation, which occurs at birth, is sufficient. Over subsequent days to weeks, however, this "neurogenic" drive weakens and drive from the chemoreceptors becomes critical for generating and maintaining a normal breathing rhythm. Failure of the chemoreceptors to develop normally, consequently, becomes an important underlying cause of breathing dysfunction, particularly during sleep. The paper deals with the methods available to study chemoreception in newborn infants and provide an overview of the early postnatal changes and interactions, which influence breathing at rest and under stress. The latter may be described in terms of the threshold and strength as well as the delay/speed with which ventilation changes in response to chemical stimulation. We conclude with a survey of disorders associated with chemoreceptor deficits in infancy.

Aspects cliniques des syndromes hypothalamiques idiopathiques : étude rétrospective et revue de la littérature

Hypothalamic obesity is usually induced by tumoral or genetic alterations such as craniopharyngioma or Prader-Willi syndrome, respectively. However, few cases have been reported without recognized etiology, this syndrome is also called idiopathic hypothalamic syndrome. Objectives. – To improve definition and frequency of complications associated with this syndrome. Population and Methods. – A retrospective cohort study was performed in French endocrine paediatric departments and was associated with a literature review. Results. – We report five cases of idiopathic hypothalamic syndrome. This syndrome is correlated with a high mortality (one of our five cases, 25% in the literature) by neurovegetative dysfunction (breathing or thermal alteration). Obesity began before six years old because of compulsive eating and resulted in social behaviour disorders. Abnormal endocrine secretions were characterized by early hyperprolactinemia, permanent but later somatotrope deficiency and 80% of thyreotrope deficiency. Puberty abnormalities included hypogonadotropic hypogonadism as well as precocious (one of our cases, three cases including literature) or normal puberty. Neurogenic hypernatremia and water and electrolytic disorders were also responsible of acute neurological alterations. Conclusion. – This largest study ever reported of idiopathic hypothalamic syndrome emphasizes the need of a multidisciplinary coordination to provide the best care of these patients.

Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation

The authors report the unusual clinical and neurophysiologic features of a sporadic case of a boy carrying an 806delG mutation on the MECP2 gene. A 28-month-old boy was examined for severe developmental delay, seizures, microcephaly, breathing dysfunction, and spontaneous and evoked myoclonic jerks of upper limbs. Neurophysiologic study proved the cortical origin of myoclonus; however, it was not associated with signs of cortical hyperexcitability. 3-Methoxy-4-hydroxy-phenylethylene glycol and valine concentrations were low in CSF.

Longitudinal effects of noninvasive positive-pressure ventilation in patients with amyotrophic lateral sclerosis.

To evaluate the duration of benefit on symptoms, quality of life, and survival derived from the use of noninvasive positive-pressure ventilation by patients with amyotrophic lateral sclerosis. In this prospective, cohort study, 30 of 36 consecutively referred symptomatic patients tolerated nightly noninvasive positive-pressure ventilation and undertook pulmonary function testing and 12 symptom and quality-of-life instruments concerning sleep quality, daytime sleepiness, physical fatigue, mental fatigue, and depression that were administered during a 10-mo period. With treatment, there was a significant improvement in the majority of patients in sleep quality, daytime sleepiness, physical fatigue, and depression; however, significant improvements lasted for up to 10 mo only in sleep quality. Partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, and oxyhemoglobin saturation remained stable or even improved for up to 7 mo during use of part-time noninvasive positive-pressure ventilation. A total of 14 patients had survival prolonged by continuous dependence on noninvasive positive-pressure ventilation. Noninvasive positive-pressure ventilation provides a long-lasting benefit on symptoms and quality of life indicators for amyotrophic lateral sclerosis patients and should be offered to all patients with symptoms of sleep disordered breathing or inspiratory muscle dysfunction. It can also prolong tracheostomy-free survival.

A case of effective gastrostomy for severe abdominal distention due to breathing dysfunction of Rett's syndrome: a treatment of autonomic disorder

We report a case of 13-year-old-girl with Rett's syndrome and effectiveness of gastrostomy for severe paradoxical respiration, seizures and abdominal distention. Since the age of 3, she was observed to have typical hand-washing movement and autistic behavior. At the age of 8, she began to have hyperventilation and seizures in awake stage. Her symptoms were worse from year to year. At the age of 13, gastrostomy was done to treat severe abdominal distention. Her symptoms were improve dramatically by the gastric air removal through gastrobutton.

Role of the cholinergic pathway in mediating platelet-activating factor-induced pulmonary dysfunctions in unsedated calves.

The purpose of this study was to investigate the possible role of the cholinergic pathway in mediating platelet-activating factor (PAF)-induced pulmonary dysfunctions in unsedated calves. In a placebo group, PAF infusion challenge induced significant dysfunctions in the pattern of breathing [a significant increase in respiratory rate (RR) and a significant decrease in tidal volume (VT)], the mechanics of breathing [a significant increase in total lung resistance (RL) and a significant decrease in dynamic lung compliance (CLdyn)] and gas exchange, whereas in atropine pre-treated calves, PAF infusion challenge induced a significant increase in RR, VT and HR and a significant decrease in CLdyn. The RL increase was prevented by atropine pre-treatment. On the basis of our findings, we suggest that, in cattle, the PAF-induced pattern of breathing dysfunctions and the diffuse bronchoconstriction and microvascular leakage of small airways are not mediated through the cholinergic pathway. By contrast, our data suggest that PAF-induced bronchoconstriction of upper airways is at least partly mediated through muscarinic receptors.