Sputum

1961 Chernick WS, Barbero GJ, Eichel HJ. In vitro evaluation of the effect of enzymes on tracheobronchial secretions from patients with cystic fibrosis. Pediatrics 1961; 27:589-596.[PubMed]
Effect of various enzymes on the viscosity of CF sputum showed that pancreatic dornase had the most marked effect showing complete dissolution of the fibrous structure of the sputum. This finding supported the theory that the excessive viscosity of CF sputum (figure 1) was related to a fibrous network observed in the sputum which was primarily of deoxyribonucleoproteins as had been shown by this group (Chernick et al, 1959 above).

The effect of enzymes on the sputum had been reported in other chronic pulmonary conditions (Sherry S et al. Proc Soc Exp Biol Med 1948; 68:179) and also on CF sputum (Shwachman & Leubner, 1955 above). These and other early studies eventually led to the introduction of rhDNase (Pulmozyme) as an effective mucolytic but only after the side effects of the biological product were circumvented by producing this genetically engineered product rhDNase (Pulmozyme) (Shak et al, 1990 below). Armstrong JB and White JC (Lancet 1950; 2:739 above) had shown that deoxyribonuclease would liquefy viscous purulent exudate; later Elmes PC & Armstrong JB (Thorax 1953; 8:295-300) reported its use in chronic bronchitis, but the side effects of the bovine preparation precluded its use and further development (Raskin P. Am Rev Respir Dis 1968; 98:697-698). Shwachman (1955 above) mentions that May and Lowe used a pancreatic preparation by inhalation in one patient and that at autopsy widespread granulomatous lesions were found in the lung, a lesion not seen in any other patient. However, eventually Shak et al (1990 below) cloned, sequenced, and expressed rhDNase which later became one of the major advances in treatment of the Nineties (Fuchs et al. 1994 below).

1961 Reid L. The composition of tracheobronchial secretions in cystic fibrosis. Postgrad Med J 1961; 37:599-600. [PubMed]
Professor Lynne Reid (figure 2) was a prominent CF researcher at the Brompton Hospital in London before she moved to the USA. Her first academic appointment was as a research assistant at the Institute of Diseases of the Chest at London University. She was appointed a professor of experimental pathology at London University in 1967, and was made Dean of the Cardiothoracic Institute at London University in 1973. She accepted a position on the faculty of Harvard Medical School in 1976, as one of the school's few women faculty members. Most of her publications concerned the bronchial secretions and the characteristics of bronchial mucous glands. These were popular areas for research for the few researchers involved in CF at the time, so copious and so very viscid was the sputum of people with cystic fibrosis. As it eventually turned out there were no intrinsic structural abnormalities of the mucus. During her time in the UK she was a good friend to and closely involved with the UK Cystic Fibrosis Research Trust. Lynne Reid reviewed much of her research in 1981 at the Minnesota Meeting (1000 Years of Cystic Fibrosis. University of Minnesota, 1981).

1962 Lieberman J. Enzymatic dissolution of pulmonary secretions. An in vitro study of sputum from patients with cystic fibrosis of the pancreas. Am J Dis Child 1962; 104: 342-348.[PubMed]
Dr Jack Lieberman of Los Angeles observed that a favourable effect on sputum viscosity by the addition of enzymes had been reported both in vitro (Chernick et al, Pediatrics 1961; 27:589 above) and in vivo (Shwachman et al. Pediatrics 1960; 25:155). This present study confirmed the liquefaction which occurred in the presence of various enzymes in order of effect – trypsin, ficin, chymotrypsin, deoxyribonuclease and elastase.
There was an interesting editorial comment to this article as follows – “Now if someone can find a way to bring a sufficient quantity of a non-irritating mixture of enzymes to bear on the bronchiolar mucus he can see if it works in the patient”. This did eventually occur with rhDNase (Pulmozyme) but it was some 30 years before this was achieved (Shack et al. 1990; Fuchs et al, 1994 below). (Also Lieberman J. JAMA 1968; 205:312-313 below).

1961 Chernick WS, Barbero GJ, Parkins FM. Studies on submaxillary saliva in cystic fibrosis. J Pediatr 1961; 59:890-898. [PubMed]
Chernick published a number of papers on the function of the salivary glands. The submaxillary saliva in CF was abnormal. Normally clear, the secretion in CF was turbid and the levels of calcium, protein and glycoproteins were increased. After injection of guanethidine the turbidity cleared and, with the exception of calcium, the increased levels of the other constituents were reversed.

1963 Denton R. The rheology of human mucus. Ann N Y Acad Sci 1963; 106:746-754.[PubMed]
This is a relevant paper as the work of Robert Denton was important in the introduction of the mist tent (see Denton 1955 above). The paper concludes with the seemingly obvious statement that the degree of flow resistance will show as quantitavely the degree of abnormality and may provide information which can lead to further understanding of the chemical changes within the mucus blanket which are responsible for impaired bronchial drainage.

1963 Chernick WS, Barbero GJ. Studies on human tracheobronchial and submaxillary secretions in normal and pathophysiological conditions. Ann N Y Acad Sc 1963; 106:698-708. [PubMed]

The authors state - “Data relating to the tracheobronchial secretions and submaxillary saliva in cystic fibrosis indicate the high concentrations of various organic constituents which are secreted in this disease and the possible interrelationships of electrolytes on the physical properties of such constituents”.
So, as with most of these studies on the physico-chemical characteristics of the airway secretions, there were no firm conclusions which significantly advanced understanding of the basic defect of the condition. It is interesting that these authors again mentioned the possible role of the electrolyte content of the sputum which eventually turned out to be very relevant.

Professor Giulio Barbero (figure 4) was internationally recognised for his research in CF and patient advocacy. He published extensively on CF and general paediatric topics from 1953 to 2001. He was Head of Pediatrics at the University of Missouri, Columbia from 1972-1989. He gave the third Joseph Levy Memorial Lecture at the European CF Meeting in Jerusalem in 1996 entitled "The Science and Humanity of Cystic fibrosis".

1963 Kwart H, Mosley WW Jr, Katz M. The chemical characterization of human tracheobronchial secretion: a possible clue to the origin of fibrocystic mucus. Ann N Y Acad Sci 1963; 106:709-21.[PubMed]
One of many studies that attempted to show differences between normal and CF mucus. The authors summarise that their findings appear to support the basis for the disease they had advanced earlier i.e. that the extraordinary viscidity of CF mucus was formed as a result of a defect in “membrane chemistry”. They consider that the inference is consistent with the difficulties that CF individuals experience conserving sodium chloride.
So another group whose conclusions were not too far off the mark as it turned out. However, in contrast to the excessive loss of salt via the sweat people with CF had a deficiency of salt in the airway secretions due to the excessive absorption of sodium and reduced passage of chloride into the airways.

1963 Matthews LW, Spector S, Lemm J, Potter JL. Studies on pulmonary secretions I. The over-all chemical composition of pulmonary secretions from patients with Cystic Fibrosis, Bronchiectasis and Laryngectomy. Am Rev Resp Dis 1963; 88:199-204.[PubMed]
Leroy Matthews was one of the leading clinical authorities on CF in the USA at the time. He was developing his Comprehensive Treatment Programme in Cleveland which was to become the model for CF care adopted by the CF Foundation for their Centres programme. In this study they found that total solids, DNA protein, lipid and carbohydrate were highest in CF secretions, intermediate in non-CF bronchiectasis and lowest in normals.
The marked decrease in sodium and chloride in CF sputum which they found they considered was possibly related to the infection – “if this is so it makes untenable the hypothesis that the lowered sodium and chloride content of the cystic fibrosis secretions is etiologically responsible for the disease”.
This is interesting for later the “low salt theory” was to be regarded as the most likely explanation for the alteration in the pulmonary secretions and the persisting pulmonary infection problems.