Jerome Kleinerman

Pathologic Changes in the Peripheral Airways of Young Cigarette Smokers

Abstract The lungs of young smokers and controls of comparable age from a population of sudden non-hospital deaths were systematically studied to determine the relation between cigarette smoking and pathologic changes in peripheral airways. The characteristic lesion observed was a respiratory bronchiolitis associated with clusters of pigmented alveolar macrophages and was present in the lungs of all smokers studied but rarely seen in nonsmokers (p<0.002). The lungs of smokers also showed small but significant increases in mural inflammatory cells and denuded epithelium in the membranous bronchioles as compared to controls (p<0.05). We postulate that this respiratory bronchiolitis is a precursor of centriacinar emphysema and may be responsible for the subtle functional abnormalities observed in young smokers. (N Engl J Med 291: 755–758, 1974)

Effects of Hypoxia on the Myocardial Metabolism of Intact Dogs

Coronary blood flow and myocardial oxygen and carbohydrate metabolism were studied in normal intact dogs subjected to different Degreess of hypoxia. Total left ventricular oxygen consumption was maintained during administration of 10 per cent and 5 per cent oxygen owing to increase in coronary flow and myocardial oxygen extraction. Ten per cent oxygen administration had little effect on carbohydrate uptake by the heart. Five per cent oxygen resulted in decreased coefficients of extraction for glucose, lactate and pyruvate, but total utilization was maintained. Complete anoxia resulted in negative arteriovenous differences for lactate and markedly decreased or negative values for pyruvate.

Hyperreactivity to cow milk in young children with pulmonary hemosiderosis and cor pulmonale secondary to nasopharyngeal obstruction

Six black infants and young children with high titers of milk precipitins were identified by screening the sera of 160 children with idiopathic chronic lung disease. None of the six had immunoglobulin deficiency, elevation of sweat chlorides, SS hemoglobin, or recurrent aspiration. All six children had typical manifestations of milk-induced pulmonary hemosiderosis: recurrent pulmonary infiltrates (6/6), hemosiderin-laden pulmonary macrophages (5/6), intermittent wheezing (5/6), eosinophilia (4/6), anemia (4/6), iron deficiency (4/4), failure to thrive (4/6), and elevated levels of serum IgE (4/4). Three children also had chronic rhinitis and eventually developed large adenoids, hypercapnia and acidosis during sleep, and right heart failure. Elimination of cow milk from the diet, symptomatic therapy, and adenoidectomy when indicated resulted in improvement of all six patients. Pulmonary hemosiderosis and some cases of upper airway obstruction with pulmonary hypertension appear to be two stages, early and delayed, of the same immunophysiologic process. Early dietary intervention may prevent the cardiovascular complications of this process.

Toxic Effects of Oxygen on Cultured Human Neonatal Respiratory Epithelium

Extract: Explants of tracheal epithelium from each of six human neonates were exposed to both 80% and 20% oxygen under otherwise identical culture conditions. Cessation of ciliary movement and carbon particle transport occurred after 48–96 hr of exposure to 80% oxygen, but not after 168 hr of exposure to 20% oxygen.This alteration of ciliary function was related temporally to squamous metaplasia, or to degeneration and sloughing of cells from the surface epithelium. Explants secreted more mucin and lysozyme during the first 24–72 hr of culture in 80% oxygen. Thereafter, diminished secretion was observed, apparently related to loss of goblet cells from the surface epithelium and failure to discharge the secretory products of submucosal glands. These findings indicate that high oxygen concentrations at atmospheric pressure alone can cause marked alterations of structure and function in neonatal large airways epithelium. Onset of these changes corresponds to the time when the earliest clinical and cytologic evidence of bronchopulmonary dysplasia has been detected, suggests that similar oxygen-induced changes are produced in vivo. Loss of mucociliary function may be an important pathogenetic component of bronchopulmonary dysplasia.Speculation: Organ culture of human large airways epithelium appears to be a useful model for study of pulmonary oxygen toxicity. Studies of oxygen concentrations and duration of exposure tolerated by human respiratory epithelium, the cellular mechanisms of oxygen-induced alteration, and the use of pharmacologic agents to prevent or delay onset of toxic changes may be facilitated by using this in vitro technique.

Effect of Hypotension due to Spinal Anesthesia on Coronary Blood Flow and Myocardial Metabolism in Man

The induction of spinal anesthesia resulted in hypotension and decreased coronary blood flow and myocardial oxygen consumption. At the same time the myocardial extraction coefficient of oxygen was not increased, indicating myocardial oxygenation to be adequate for the lower work load. This does not imply that local ischemia might not occur in the presence of coronary artery sclerosis. The coronary arteriovenous differences of glucose, lactate and pyruvate were not changed during the period of hypotension.

Stochastic model of metastases formation.

A mathematical model is developed to describe the dynamics of the hematogenous metastatic process to the lung from a solid tumor growing in a peripheral body site. The accumulation of tumor cell clumps of various sizes in the pulmonary circulation and the formation of metastatic foci are described by a non-homogeneous, two-dimensional Markov process. An analytical solution is found for the special case of metastases produced by the intravenous injection of tumor cell clumps. The system is decoupled experimentally to determine the time-varying entrance rate of tumor cell clumps into the circulation from a growing fibrosarcoma and the number of metastatic foci produced by the intravenous injection of tumor clumps. Model validation is based on comparisons of model simulations with data for the development of metastatic foci and the probability of cure following tumor excision. The model is used to simulate hypothetical therapy to prevent tumor metastases.

System dynamics of a metastatic process from an implanted tumor

A lumped-parameter, deterministic model of the hematogenous metastatic process from a solid tumor is developed to provide a general theoretical framework for analysis and simulation. The model consists of a series of population compartments: tumor cells in the tumor mass, tumor vessels, tumor cells penetrating the vessels, tumor cells arrested in the target organ, and metastatic foci in the target organ. Model simulations are compared with experimental results from a group of mice implanted with a fibrosarcoma which leads to pulmonary metastases. The model is found to provide good agreement with the general process dynamics. In addition, the experimental consequences of tumor trauma and tumor amputation are compared with model simulations of these perturbations to validate the model behaviour. Finally, the effects of inhibited tumor vessel growth, retarded vessel penetration by tumor cells, and pulmonary vessel damage are simulated, which suggest future experiments.

Identification of functional tumor vessels by resorcin-crystal violet stain infusion.

A resorcin-crystal violet solution of low viscosity injected into the circulatory plexus supplying a tumor is used to identify and characterize functional tumor vessels. Unstained sections of tumor tissue demonstrate heavily stained vascular endothelium with no leakage of stain to extravascular tissue for intact vessels, and little or no background staining. The method is simple to apply for tumor vessel morphology and morphometry.

1679 PHYSIOLOGIC SEQUELAE OF NO 2 -INDUCED BRONCHIOLITIS

To test the hypothesis that injury in the developing lung may lead to chronic obstructive lung disease, we studied the effects of NO2-induced bronchiolitis in newborn hamsters. Three day (d) Syrian hamsters were exposed continuously to 30-35 ppm NO2 23 hrs daily for 7 d. Pressure-volume and flow-volume curves during forced expiration at -50 cm H2O and minimal volumes (MV) were determined on excised lungs at 3 and 9 weeks (wk) of age. In NO2 animals studied at 3 wk (n=5), maximal expiratory flow at 40% total lung capacity (TLC) and elastic recoil pressure at 40% TLC were significantly lower than in control group (c) (n=4) (p<.02 and p<.04, respectively), while MV was significantly increased (p<.02). The upstream resistance (mean ± SEM) in the 3 wk NO2 group (.275 ± .058 cm H2O/ml/sec) was greater than in (c) (.209 ± .010) (p=NS). All measurements in 9 wk NO2 animals (n=4) were not significantly different from (c) (n=6). The decreased flow rates and increased MV in the NO2 group suggest small airways obstruction which may be related to decreased elastic recoil, increased airways resistance or both factors. The reversibility after 8 wk may result from 1) lung growth producing an increase in airways diameter, 2) alteration of the elastic properties of the lung associated with an increase in alveolar number during growth, or 3) physiologic accommodation to the effects of NO2. These data do not support the concept that acute lung injury is a progenitor of chronic lung disease. (Supp. by Amer. Lung Assn.)