Anthon R. Hulsmann

Autonomic Innervation of Human Airways: Structure, Function, and Pathophysiology in Asthma

The human airways are innervated via efferent and afferent autonomic nerves, which regulate many aspects of airway function. It has been suggested that neural control of the airways may be abnormal in asthmatic patients, and that neurogenic mechanisms may contribute to the pathogenesis and pathophysiology of asthma. In this review, the autonomic innervation of the human airways and possible abnormalities in asthma are discussed. The parasympathetic nervous system is the dominant neuronal pathway in the control of airway smooth muscle tone. Stimulation of cholinergic nerves causes bronchoconstriction, mucus secretion, and bronchial vasodilation. Although abnormalities of the cholinergic innervation have been suggested in asthma, thus far the evidence for cholinergic dysfunction in asthmatic subjects is not convincing. Sympathetic nerves may control tracheobronchial blood vessels, but no innervation of human airway smooth muscle has been demonstrated. β-Adrenergic receptors, however, are abundantly expressed on human airway smooth muscle and activation of these receptors causes bronchodilation. The physiological role of β-adrenergic receptors is unclear and their function seems normal in asthmatic patients. Inhibitory nonadrenergic noncholinergic (NANC) nerves, containing vasoactive intestinal peptide and nitric oxide, may be the only neural bronchodilator pathways in human airways. Although a dysfunction of inhibitory NANC nerves has been proposed in asthma, thus far no differences in inhibitory NANC responses have been found between asthmatics and healthy subjects. Excitatory NANC nerves, extensively studied in animal airways, have also been detected in human airways. In animal studies, stimulation of excitatory NANC nerves causes bronchoconstriction, mucus secretion, vascular hyperpermeability, cough, and vasodilation, a process called ‘neurogenic inflammation’. Recent studies have demonstrated an interaction between the excitatory NANC nervous system and inflammatory cells. Neuropeptides may influence the recruitment, proliferation, and activation of leukocytes. On the other hand, inflammatory cells may modulate the neuronal phenotype and function. The functional relevance of the excitatory NANC nervous system and its interaction with the immune system in asthma still remains to be elucidated.

Peptidases: structure, function and modulation of peptide‐mediated effects in the human lung

Peptidases are enzymes capable of cleaving, and thereby often inactivating, small peptides. They are widely distributed on the surface of many different cell types, with the catalytic site exposed only at the external surface. Peptidases are involved in a variety of processes, including peptide-mediated inflammatory responses, stromal celldependent B lymphopoiesis, and T-cell activation. In addition, some peptidases may have functions that are not based on their enzymatic activity. Peptidases are classified according to the location of the cleavage site in the putative substrate (Table 1). Endopeptidases recognize specific amino acids in the middle of the peptide, whereas exopeptidases recognize one or two terminal amino acids. Exopeptidases that attack peptides from the N-terminus (removing either single amino acids or a dipeptide) are termed (dipeptidyl) aminopeptidases, whereas peptidases attacking the C-terminus are termed carboxypeptidases.

Airway dimensions in bronchopulmonary dysplasia: Implications for airflow obstruction

The cause of lung function abnormalities in bronchopulmonary dysplasia (BPD) is incompletely understood, even in the “new era” of this disease. Altered airway wall dimensions are important in the pathogenesis of airflow obstruction in diseases such as asthma and chronic obstructive pulmonary disease. Whether airway wall dimensions contribute to lung function abnormalities in BPD is unknown. The purpose of this study was to investigate airway wall dimensions in relation to airway size in BPD. Lung tissue of patients with BPD was obtained at autopsy, and lung tissue from children who died from sudden infant death syndrome (SIDS) served as control. Airway wall dimensions and epithelial loss were measured in 75 airways from 5 BPD patients and 176 airways from 11 SIDS patients. Repeated measures analysis of variance was used to assess the relationships between airway wall dimensions and airway size for BPD and SIDS patients. Little epithelial loss was present in the BPD patients while extensive loss was observed in some of the SIDS patients. The inner wall area, outer wall area, epithelium area and smooth muscle area were all substantially larger (all P < 0.001) in BPD than in SIDS patients. It is likely that the increased thickness of the airway wall components contributes to airflow obstruction in BPD patients. Pediatr. Pulmonol. 2008; 43:1206–1213.

Studies of human airways in vitro: A review of the methodology

The pathophysiology of human airway narrowing is only partly understood. In order to gain more insight in the mechanisms of human lung diseases and potential beneficial therapeutic agents, adequate models are needed. Animal airway models are of limited value since lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are unique to humans and because the mechanisms of airway narrowing differ between species. Therefore, it is important to perform studies on human isolated airways. We describe the models that have been developed to study airway function in vitro, emphasizing human airway preparations. The easily prepared airway strip and ring preparations are described first. The potential damage during preparation and the interference with airway structure are important drawbacks in these preparations. Lung parenchymal strips, described next, were designed in order to study responsiveness of small airways. However, parenchymal strips are anatomically complex, and responsiveness is determined by the relative amounts of airway and vascular smooth muscle. The lack of reproducibility between species and even within one animal limits their usefulness. Airway tube preparations, in which luminal and serosal stimulation can be separated, enable us to study the modulatory role of the airways epithelium in vitro. Furthermore, airway compliance can be measured. In the isolated perfused lung preparation, relationships between the airways and the vascular system are preserved and the interaction between these two systems can be studied. Weight gain due to fluid extravasation is a problem in this model which has not been used yet to study human lungs in vitro. Next, methodological aspects such as tissue handling and storage, recording of responses, removal of the epithelium, and electrical field stimulation are discussed in some detail. Although animal airways tissue can be studied immediately after removal, human tissue is often obtained with some delay. However, this seems tenable since electron microscopy of lung tissue obtained at autopsy showed that recovery of the preparation occurs during incubation of carbogenated Krebs-Henseleit (K-H) buffer. Dissected airways can be stored overnight in cooled K-H buffer until up to 55 hr after resection without losing viability. Commonly used physiological salt solutions which bath the tissue contain osmotic molecules, ions important for contractility, glucose as a substrate, and a bicarbonate-carbon dioxide buffer.(ABSTRACT TRUNCATED AT 400 WORDS)

The perfused human bronchiolar tube characteristics of a new model.

Strips or rings of airway tissue are often used to study contractile responses of human airways in vitro. These preparations have the disadvantage that it is impossible to deliver stimuli selectively to the mucosal or serosal surface. Hence, they allow only for a limited evaluation of the modulatory role of the airway epithelium. We developed an in vitro model that allows independent stimulation from either the serosal or the mucosal side of human peripheral airways. Segments of human peripheral airways were perfused with a Krebs solution at a constant pressure, and responsiveness was measured as a change in flow rate. Pressure/flow relationships indicated laminar flow over a wide pressure range, and a working pressure of 6 cm H2O was chosen because this is a physiological transpulmonary pressure. When stepwise stretching the airway to 180% of its length, we noted an increase in baseline flow and a decrease in flow reduction after methacholine 10(-5) M. At 140% of the length, accurate and reproducible measurements of the sensitivity (EC50) to methacholine were obtained, and airway closure did not occur. A one-way analysis of variance (ANOVA) revealed that the between-patients differences accounted for 91% of the total variability for -log EC50. We conclude that this in vitro model offers interesting possibilities for evaluating the modulatory effects of the human airway epithelium. In addition, the model provides the opportunity to study human small-airway mechanical properties and secretory functions.

Modulation of airway responsiveness by the airway epithelium in humans: Putative mechanisms

The airway epithelium forms the interface between the respiratory system and the external environment and consists of ciliated and non-ciliated ceils tightly attached to each other and to the basement membrane [1]. In bronchial asthma, areas of airway epithelium become damaged and the degree of epithelial damage correlates with the level of bronchial responsiveness [2,3]. Inflammatory cells present in the asthmatic airway mucosa may contribute to the epithelial damage by the production of oxidants. proteases and cationic proteins [1,3-5]. In addition, airway epithelium may be disrupted by an increased subepithelial hydrostatic pressure caused by oedema of the inflamed airway wall [6]. Several mechanisms have been proposed to explain the relationship between epithelial damage and airway hyperresponsiveness. These include, firstly, a reduced production of epithelium-derived relaxing factors (EpDRF) [7] and secondly, a decreased metabolization of bronchoconstricting mediators and neurotransmitters by the damaged epithelial cells [8]. Thirdly, loss of epithelial integrity may increase airway permeability and provide easy access of bronchoactive mediators to the airway smooth muscle [9]. Finally, epithelial damage may expose intra-epithehal sensory (peptidergic) nerves. Excitation of these sensory nerves by inflammatory mediators may lead to a local reflex bronchoconstriction via release of neuropeptides or tachykinins [10]. The above-mentioned hypothetical mechanisms are schematically shown in Figure I and will be discussed in some detail in the present review.

Hamartomas of the oro- and nasopharyngeal cavity in infancy: two cases and a short review

IntroductionOro- and nasopharyngeal masses are rare in infancy and consist of developmental anomalies and, mostly benign, neoplasms.Case reportWe report two infants with a tumour in the ear–nose–throat region.DiscussionAs shown by our cases, the clinical presentation of an oropharyngeal mass in infancy varies from respiratory insufficiency at birth to incidental finding by the parents a few months after birth.

Educational paper: neonatal skin lesions

Although most skin lesions in neonates are transient or benign, they may also be the presenting symptom of a life-threatening disease such as herpes neonatorum. In the present review, we present a short overview of neonatal skin lesions and a practical table to guide the general paediatrician in the diagnosis and management of neonatal skin lesions. Recent reviews are cited for further reading.

Electrical field stimulation causes oxidation of exogenous histamine in Krebs-Henseleit buffer: A potential source of error in studies of isolated airways

Electric field stimulation (EFS) relaxes human histamine-precontracted airways in vitro. This relaxation is only partly neurally mediated. Nonneural relaxation has been also shown in blood vessels and is due to the generation of oxygen radicals by EFS. In isolated airways the origin of the nonneural component of the relaxation is not clear. Because exogenous catecholamines are oxidized during EFS of carbogenated Krebs-Henseleit (K-H) buffer, we questioned whether this is also the case for exogenous histamine. Human airways precontracted with histamine or methacholine were exposed to either EFS-stimulated carbogenated K-H buffer that also contained histamine or methacholine or unstimulated buffer. Airways exposed to EFS-stimulated buffer that contained histamine relaxed, whereas airways exposed to buffer containing methacholine or exposed to unstimulated buffer did not. It appeared that the histamine concentrations in the organ baths decreased during 30 min of EFS. This decrease was significantly reduced in the presence of ascorbic acid. We conclude that EFS causes oxidation of histamine in carbogenated K-H buffer, and this may at least partly explain the nonneural component of EFS-induced relaxations of precontracted human isolated airways. Therefore, histamine should not be used to induce precontraction in EFS experiments.