We measured bronchial reactivity to inhaled histamine and prepared electron micrographs from bronchial biopsies from 8 asthmatic patients who never smoked (2 females, 6 males, 18 to 62 yr of age). Judging from their clinical histories and the need for medication and long-term follow-up of PEF values, 2 of them had mild asthma, 3 moderately severe, and 3 severe asthma. They had not experienced respiratory infections for at least 2 months prior to the study. The result, obtained from the cumulative dose-response curve, was expressed as the provocative dose (PD20) of histamine producing a 20% fall in forced expiratory volume in one second (FEV1). In 5 patients, the PD20 varied from 0.049 mg to 2.234 mg. In the sixth patient, only PD15 could be measured (5.187 mg). In 2 patients, the low initial FEV1 values, because of severe, partly irreversible obstruction, prevented the measurement of bronchial reactivity. Bronchial biopsies were taken with rigid tube bronchoscopy from 3 levels: (1) at the carina of the right upper lobe, (2) at the opening of the right middle or lower lobe, and (3) inside the right lower lobe. The specimens were prepared for both light and electron microscopy. Fresh biopsies showed that asthma patients can have epithelial destruction at all levels of the airways. The ciliated cells appeared to be the most destroyed cell type in the epithelium. Intraepithelial nerves and mast cells were seen. Epithelial destruction in the respiratory tract of the asthma patients with mild to severe bronchial hyperresponsiveness was prominent enough to expose the epithelial nerves for specific or nonspecific stimuli.

Damage of the airway epithelium and bronchial reactivity in patients with asthma.

Four subjects who produced immotile sperm were studied. In three of the subjects, who had frequent bronchitis and sinusitis, there was no mucociliary transport, as measured by tracheobronchial clearance. Electron microscopy indicated that cilia from cells of these patients lack dynein arms.

http://science.sciencemag.org/content/sci/193/4250/317.full.pdf

A human syndrome caused by immotile cilia

1. Damage of the Airway Epithelium and Bronchial : Reactivity in Patients with Asthma

The Wnt family of secreted ligands act through many receptors to stimulate distinct intracellular signalling pathways in embryonic development, in adults and in disease processes. Binding of Wnt to the Frizzled family of receptors and to low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptors stimulates the intracellular Wnt-beta-catenin signalling pathway, which regulates beta-cateninstability and context-dependent transcription. This signalling pathway controls many processes, such as cell fate determination, cell proliferation and self-renewal of stem and progenitor cells. Intriguingly, the transmembrane receptor Tyr kinases Ror2 and Ryk, as well as Frizzledreceptors that act independently of LRP5 or LRP6, function as receptors for Wnt and activate beta-catenin-independent pathways. This leads to changes in cell movement and polarity and to the antagonism of the beta-catenin pathway.

Proximal events in Wnt signal transduction

Axis Development and Early Asymmetry in Mammals

We investigated six men and a woman suspected of suffering from congenital immotility of cilia. All had chronic airway infections, and the men had immotile spermatozoa. The woman and three men had Kartagener's syndrome. The investigations included measurements of the mucociliary transport in the lower airways and ultrastructural studies of the sperm tails or respiratory cilia (or both). Mucociliary transport was significantly delayed. Sperm tails lacked dynein arms in five patients. Respiratory cilia from the women and two men lacked dynein arms and were irregularly oriented. The results support the hypothesis that a congenital defect in the cilia and sperm tails will cause chronic respiratory-tract infections and male sterility--the immotile-cilia syndrome. In about half these patients there will also be a situs inversus--i.e., Kartagener's syndrome.

The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility.

Mucociliary transport in the tracheobronchial tract was studies in 2 subjects by having them inhale a radioactively tagged test aerosol and by taking external measurements of the radioacitivity in the lungs for 2 hours. Both subjects had living, yet immotile seprmatozoa; the sperm tails lacked normal dynein arms, which are essential for the bending movements of sperm tails as well as of other cilia. The subjects were classified as suffering from Kartagener's syndrome (situs inversus, chronic sinusitis, and bronchiectasis) and were shown to have an extremely slow, probably absent transport. The results of the study were in agreement with a recent hypothesis explaining Kartagener's syndrome as due to a genetic lack of dynein arms. An estimate of the importance of mucociliary transport as a protective mechanism of the lung may be possible by examining patients suffering from Kartagener's syndrome.

Evidence of congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects.

On the Function of Cilia in the Female Reproductive Tract

Nineteen men with viable spermatozoa of a reduced motility were divided into two groups according to the morphology as seen in light microscopy; one with less (group A) and one with more (group B) than 50 % abnormal sperm tails. These men were eamined with regard to history and symptoms of respiratory tract diseases. Spermatozoa and cilia from the respiratory tract were examined with electron microscopy. Tracheobronchial clearance was evaluated with labelled teflon particles. Five men (group C) with the “immotile-cilia syndrome”, primarily selected because of respiratory tract symptoms, were also studied with regard to sperm motility and morphology.



There was a close correlation between immotility or very poor motility of the spermatozoa and ciliary dysfunction only when the spermatozoa had a normal configuration. Poor sperm motility coupled with abnormalities in the sperm tails, as evaluated with light microscopy, was rarely associated with ciliary dysfunction. The reason for this could be that the spermatozoa from these men (in group B) all had abnormal fibrous sheath and/or mitochondria: structures not present in cilia from the respiratory tract.



Nine of the 12 men with immotile sperm tails (group A, B, and C) had the immotile-cilia syndrome and a complete or partial lack of dynein arms in the sperm tails. Two other men with the immotile-cilia syndrome had spermatozoa with some motility; spermatozoa from one had both inner and outer dynein arms and spermatozoa from the other lacked the outer arms.



Respiratory tract cilia were studied in four men with the immotile-cilia syndrome (from groups A and C). Inner and outer dynein arms were missing in the spermatozoa and cilia from three men, but in the same cells from the fourth man only the inner arms were absent.

Relation between Abnormalities of Human Sperm Flagella and Respiratory Tract Disease

Smokers with chronic bronchitis and/or chronic obstructive pulmonary disease (COPD) have been reported to have an increased bronchial reactivity (BR). It has been discussed whether increased BR is a risk factor for the development of COPD in smokers. We studied 10 monozygotic twin pairs who were discordant for tobacco smoking by means of histamine provocation tests, lung function tests, and serum samples for total IgE. The smokers had a mild obstructive ventilatory impairment, with FEV1 significantly lower than that of the partner both when it was determined from the flow-volume loops (3.2 ± 1.0 L for smokers and 3.4 ± 0.8 L for nonsmokers) and by the Vitalograph spirometer (3.5 ± 1.0 L for smokers and 3.8 ± 0.8 L for nonsmokers). Forced midexpiratory flow (FEF25–75%) and forced expiratory flow at 75 to 85% of vital capacity (FEF75–85%) were both significantly lower in the smokers (p < 0.05). The alveolar plateau phase N2-delta test and lung clearing index in the multibreath nitrogen washout test were bot...

Björn Mossberg

Papers

The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility.

Evidence of congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects.

On the Function of Cilia in the Female Reproductive Tract

Relation between Abnormalities of Human Sperm Flagella and Respiratory Tract Disease

Bronchial reactivity, lung function, and serum immunoglobulin E in smoking-discordant monozygotic twins.