Early bacterial clearance from murine lungs. Species-dependent phagocyte response.

Two sets of phagocytic cells are available to defend the lung against inhaled bacteria. Both resident alveolar macrophages and granulocytes from the circulation have been observed in pulmonary air spaces after the deposition of bacteria; their functional roles, however, have been defined. We rendered mice selectively granulocytopenic with heterologous antiserum in order to ascertain the relative contributions of these two groups of cells in intrapulmonary bacterial killing. The clearance of Staphylococcus aureus was unimpaired in granulocytopenic animals, confirming the primary role of the alveolar macrophages in the killing of these organisms. In contrast, granulocytopenic animals cleared only 10.0+/-7.0% of an inoculum of Klebsiella pneumoniae compared with 33.0+/-4.0% clearance in normal animals (P < 0.02), and Pseudomonas aeruginosa proliferated to 513% of baseline levels in granulocytopenic animals, whereas normal mice cleared 26.8+/-10.6% of the inoculum. These findings indicate that circulating granulocytes play a major role in the clearance of the latter two organisms. This variation in cellular response to different bacterial species suggests that the defense of the lung against pathogenic bacteria is more complex than has been previously assumed.

The effect of complement depletion on lung clearance of bacteria.

We have investigated the effect of hypocomplementemia on early pulmonary clearance of four species of bacteria. The experiments were performed in an inbred animal model to minimize immunologic variability. Complement was depleted by cobra venom factor, and activity in serum was monitored with a phagocytic assay. Bacterial specific antibodies were examined by an indirect radioimmunoassay, and animals with high levels of activity were excluded from anaysis. 4 h after aerosolization with Streptococcus pneumoniae, complement-depleted animals had cleared only 75% of the initial number of organisms, whereas saline-treated controls cleared 91% (P less than 0.01). Aerosolization with Pseudomonas aeruginosa was followed at 4 h by a twofold greater growth of organisms in the complement-depleted animals (446% of original deposition) as compared to the saline-treated controls (211% of original deposition) (P less than 0.02). Clearance of Klebsiella pneumoniae and Staphylococcus aureus were similar in complement-depleted animals and saline-treated controls. These experiments suggest that hypocomplementemia predisposes to bacterial pneumonia and may explain the high incidence of pulmonary infections in patients having impaired complement activity. Our results further indicate that varying defense mechanisms may be involved with clearing the lung of differing bacterial species.

Increased plasma concentrations of C9, C1-inhibitor and alpha 1-protease inhibitor associated with cigarette smoking.

The association between various parameters of acute and chronic smoking status and plasma levels of three proteins, C9, C1-inhibitor (C1-INH) and alpha 1-protease inhibitor (alpha 1-PI) were determined for 49 male cigarette smokers and 49 age-matched nonsmokers (mean age = 32.2 years). The mean number of cigarettes smoked was 28.7 per day while the cumulative consumption was only 18.1 pack-years. Plasma levels of all three proteins were significantly higher in the smokers than nonsmokers. Plasma C9 and alpha 1-PI concentrations correlated with cumulative cigarette consumption and plasma nicotine concentrations. While C1-INH concentration did not correlate with either cumulative cigarette consumption or plasma nicotine concentration, it correlated significantly with serum thiocyanate concentration. No consistent correlation was found between plasma concentration of these proteins and parameters of pulmonary function.

Population characteristics and cigarette yield as determinants of smoke exposure.

Relationships of population characteristics, smoking history, and cigarette yield with smoke exposure as measured by peripheral blood concentrations of thiocyanate, carboxyhemoglobin, nicotine and cotinine were sought in 170 male smokers. This population of smokers had significant elevations of serum thiocyanate, blood carboxyhemoglobin and plasma nicotine and cotinine concentrations as compared with an equal number of age- and sex-matched nonsmokers and these concentrations correlated significantly with past 24-hour cigarette consumption. Although the nicotine yield of the cigarette correlated significantly with plasma cotinine and marginally with plasma nicotine, the reduction in plasma nicotine and cotinine was not proportionate to the reduced yield of the cigarettes, suggesting that smokers partially compensate for the lower yields of their cigarettes. Blood levels of carboxyhemoglobin, nicotine and cotinine were also significantly associated with the weight of the subjects, presumably due to the relationship between weight and the volume of distribution. Univariate and multiple regression analyses provided evidence that coffee and alcohol consumption and years smoked also may be important determinants of smoke exposure.

Puffing topography as a determinant of smoke exposure.

Puffing topography variables were measured in a well-characterized, male population smoking their own brand of cigarette. Of the puffing topography variables, interpuff interval appeared to be the primary determinant of blood concentrations of smoke constituents: however, preliminary data in a homogeneous population according to the nicotine yield of their cigarette suggest that total puff volume per cigarette may also be a significant determinant of blood levels of smoke constituents. Smokers of low nicotine yield cigarettes partially compensated for these lower yields by increasing the total volume puffed per cigarette. Observed differences in puffing topography associated with increased daily cigarette consumption and cumulative smoking history were consistent with a higher smoke exposure per cigarette. Further, although both alcohol and coffee consumption are associated with present and cumulative smoking history, coffee consumption is uniquely associated with differences in puffing topography consistent with a higher smoke exposure per cigarette. However, by multiple regression analyses, neither coffee nor alcohol consumption histories added significantly to the prediction of blood concentrations of smoke constituents over that obtained by smoking history and puffing topography.

Congenital tracheobronchomegaly (Mounier-Kuhn syndrome): a report of 10 cases and review of the literature.

Mounier-Kuhn syndrome is a congenital abnormality of the trachea and main bronchi characterized by atrophy or absence of elastic fibers and thinning of muscle, which allows the trachea and main bronchi to become flaccid and markedly dilated on inspiration with narrowing or collapse on expiration or cough. The abnormal airway dynamics and pooling of secretions in broad outpouchings of redundant musculomembranous tissue between the cartilaginous rings predispose to the development of chronic pulmonary suppuration, bronchiectasis, emphysema, and pulmonary fibrosis. A broad spectrum of clinical abnormalities has been documented in Mounier-Kuhn syndrome, ranging from minimal disease with good preservation of pulmonary function to progressive disease leading to respiratory failure and death. In the appropriate clinical setting, Mounier-Kuhn syndrome is diagnosed in women from chest radiographs when the transverse and sagittal diameters of the trachea exceed 21 mm and 23 mm, respectively, and when the transverse diameters of the right and left main bronchi exceed 19.8 mm and 17.4 mm, respectively. In men it is diagnosed when the transverse and sagittal diameters of the trachea exceed 25 mm and 27 mm, respectively, and when the transverse diameters of the right and left main bronchi exceed 21.1 mm and 18.4 mm, respectively. The diagnosis can be confirmed easily by computed tomography.

Lung uptake of Tc-99m HMPAO in cigarette smokers expressed by lung/liver activity ratio.

Tc-99m HMPAO, a lipophilic radiopharmaceutical used for brain imaging, has been reported to localize in smokers' lungs. To quantitate this uptake in the lung, 55 patients, who were referred for brain imaging for dementias or strokes, also underwent lung imaging (anterior lung imaging includes a large part of the liver) after IV injection of the radiopharmaceutical. Regions of interest over the liver and the lung were calculated. Of the 55 patients (ages 13-79), 30 were smokers and 25 were nonsmokers. The smokers had been smoking from 6-59 years, and daily cigarette consumption ranged from 8-50 cigarettes. The mean lung/liver ratio for smoking patients were 0.792 +/- 0.042 (SE); the mean lung/liver ratio for nonsmoking patients was 0.408 +/- 0.019 (SE). Lung/liver ratio uptake was significantly higher in the smoking patients (P < 0.01) than in the nonsmokers. Thus, lung/liver uptake of Tc-99m HMPAO may be used as an indicator of cigarette smoking.

The effect of heating on the functional activity of iota carrageenan.

Iota carrageenan is toxic to cells of the reticuloendothelial system. If carrageenan is dissolved at 40 degrees C and injected intraperitoneally, it will induce a significant reduction of alveolar macrophages. Heating the carrageenan preparation to 121 degrees C, however, results in a marked diminution of this in vivo cytotoxicity. This observation offers an explanation for the variability of effects previously attributed to carrageenan, and suggests that preparation methods should be standardized and carefully monitored.

Complement receptors of rat macrophages.

Some species, including rabbits, guinea pigs, and humans, have complement receptors on resident alveolar macrophages, whereas Swiss mice lack detectable receptors on these macrophages. Using complement-coated sheep erythrocytes or bacteria, we were unable to detect complement receptors (CR1, CR2, or CR3) on resident alveolar macrophages of male Sprague-Dawley rats. Nonelicited peritoneal macrophages from Sprague-Dawley rats had CR1 and CR3 receptors and were able to bind bacteria opsonized with complement. Resident alveolar macrophages of Long-Evans and Fisher rats lacked detectable complement receptors, but CR1 and CR3 receptors were detected on the alveolar macrophages of Lewis-Wistar rats. The reason for the lack of complement receptors on murine macrophages is not known, but studies of this phenomenon may prove useful in elucidating the role of macrophage complement receptors in the pulmonary inflammatory response.

Early clearance of pneumococci from the lungs of decomplemented rats.

Pneumococcal types which exhibited varying degrees of interaction with the complement system in vitro wee aerosolized into normal and decomplemented rats, and the rate of killing of pneumococci was monitored by serial cultures of whole lung homogenates. The clearance of pneumococci from the alveoli did not correlate with the ability of the pneumococci to be opsonized by complement in vitro. Similarly, rats depleted of complement in the serum and the bronchoalveolar lavage fluid maintained their ability to rapidly inactivate aerosolized pneumococci. These results indicate that the early phase of pneumococcal killing in the alveoli does not require complement and suggest that in the nonimmune host, phagocytosis by alveolar macrophages can be achieved without complement-dependent opsonization or, alternatively, that extracellular factors rapidly inactivate inhaled pneumococci.

Effects of smoking on inflammatory mediators and their relationship to pulmonary dysfunction.

Study populations of 170 male smokers and 170 age- and sex-matched nonsmokers were used to determine the effects of cigarette smoking on pulmonary function, peripheral blood leukocytes and phase reactive proteins. Further, the interrelationships between these parameters were sought. Consistent with their young age (mean 37 years) and relatively brief smoking history (mean 24 pack-years), the smokers had a significant, yet modest, impairment of pulmonary function as measured by both forced expiratory spirometry and the single breath nitrogen/closing volume test. Smokers exhibited a significant elevation in total peripheral blood leukocytes which was attributable to increases in neutrophils, lymphocytes, monocytes and eosinophils. Similarly, significant increases in the "phase reactive" proteins [i.e., the ninth component of complement (C9), ceruloplasmin and alpha 1-protease inhibitor (alpha 1-PI)] were also observed in smokers. Increases in total leukocytes, neutrophils, C9 and alpha 1-PI were significantly associated with present and cumulative cigarette consumption, blood levels of smoke constituents/metabolites (i.e., carboxyhemoglobin, nicotine and cotinine) and impaired pulmonary function (i.e., FEV1 and FVC). However, duration of smoking (years smoked) and pack-years smoking history were the best predictors of elevations in inflammatory mediators and pulmonary dysfunction. These data support the hypotheses that: a low grade inflammatory reaction is induced in smokers and is dependent upon a dose-related exposure to smoke; and the smoking-induced changes in inflammatory mediators are associated with the observed pulmonary dysfunction.

Increased neutrophil myeloperoxidase activity associated with cigarette smoking.

Neutrophils from 49 young male smokers contained significantly higher myeloperoxidase (MPO) activity than those from 49 age-matched, nonsmoking controls, while the elastase-like activity was not different in the two populations. MPO activity was increased in some smokers, but did not correlate significantly with the increased number of peripheral blood neutrophils, cigarette usage (present or cumulative), or the mild pulmonary dysfunction detected by forced expiratory spirometry and the single breath nitrogen test. This increased MPO activity in smokers' neutrophils may contribute to the greater risk of obstructive pulmonary disease in some smokers by an exacerbation of the protease-antiprotease imbalance in the lung. This hypothesis is supported by the prior observations that neutrophils are recruited in greater numbers into the lungs of smokers and that MPO (in the presence of H2O2 and chloride ion) oxidatively inactivates antiproteases of both the alveoli and the mucus-lined airways.