Squamous Metaplasia of the Bronchial Mucosa and its Relationship to Smoking

doi:10.1378/chest.103.5.1429

Chest

Volume 103, Issue 5, May 1993, Pages 1429-1432

https://doi.org/10.1378/chest.103.5.1429 Get rights and content

We performed flexible fiberoptic bronchoscopy (FFB) on 106 heavy cigarette smokers. Six bronchial biopsy specimens, obtained from the carina and five major bronchi, were screened for squamous metaplasia. Individual biopsy specimens were sectioned into 4-μm sections, and a metaplasia index (MI), or percentage of sections containing squamous metaplasia, was determined. Metaplasia was noted at one or more biopsy sites in 66 of 99 subjects (seven were excluded from the analysis). Twenty-five percent of the subjects showed metaplasia at three or more biopsy sites, and one subject had metaplasia on all six biopsy specimens. The presence of squamous metaplasia varied from 40.4 percent in the right lower lobe to 15.3 percent in the left upper lobe. The subjects were grouped into simple categories based on the number of packs smoked per day and the pack-year history of smoking. Subjects who smoked more than two packs per day (n = 11) had the highest MI (37.4 ±4.9 percent, mean ± SEM). Fifty-seven subjects smoked more than one pack per day but fewer than or equal to two packs per day, and they had a mean MI of 22.3 ± 2.9 percent. Subjects who smoked one pack per day or less (n = 31) had a mean MI of only 12.9±2.8 percent. The MI of those who smoked more than two packs per day was significantly greater than the MI of those who smoked one pack per day or less (p≤0.003). While the MI varied from 12.9±3.5 percent in subjects who had smoked less than 20 pack-years to a maximum of 29.1 ±4.5 percent in those who had smoked greater than 60 pack-years, no statistically significant difference was detected between these two groups. Thus, we conclude that heavy tobacco use is associated with important alterations of bronchial mucosa. Furthermore, the intensity of tobacco use (packs per day) rather than the number of pack-years appears to be the more important factor in promoting squamous metaplasia of the bronchial mucosa.

Section snippets

METHODS

One hundred six subjects were enrolled into the study under a protocol approved by the committee for protocol research at M.D. Anderson Cancer Center, Houston. All subjects were recruited on the basis of having a history of smoking more than 15 pack-years. One pack-year was defined as the equivalent of smoking one pack per day for one year (eg, one pack per day for 30 years was equivalent to smoking two packs per day for 15 years). Subjects were volunteers from a variety of backgrounds, but

RESULTS

One hundred six patients underwent a bronchoscopy and no significant morbidity related to the procedure occurred. Seven subjects were excluded from the analysis for the following reasons: four had inadequate specimens at four or more biopsy sites, two subjects' biopsy specimens were not available for review when the analysis was done, and one subject smoked only cigars. Sixty-two men and 37 women enrolled in the study. The median age was 44 years (range, 19 to 70 years). The group smoked

DISCUSSION

While squamous metaplasia of the bronchial mucosa has been recognized for many years as a common sequela of tobacco use,1, 2, 5 we performed our study to examine this relationship more closely. Tobacco smoke is not the only condition associated with squamous metaplasia. Various activities such as uranium mining, marijuana smoking, and a variety of chronic pulmonary diseases will also produce squamous metaplasia of the bronchial mucosa,3, 7, 8 but tobacco use is probably the most studied.

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Cadmium (Cd) is found at high concentrations in tobacco smoke due to its volatility when tobacco is burned. Inhaled Cd is linked to smoking-related respiratory diseases, such as chronic obstructive pulmonary disease and lung cancer. Alterations in mucociliary clearance, squamous metaplasia, and carcinoma are commonly observed in the respiratory tract of animals exposed to Cd. In vitro cell models widely used to study mechanisms underlying Cd toxicity are not suitable for studying its effects on mucociliary clearance and airway tissue remodeling. Herein we assess Cd-induced functional and structural changes in a well-differentiated human air-liquid-interface (ALI) airway tissue model. Acute treatments with Cd induced aberrant expression and secretion of mucins, impaired cilia functions, and squamous differentiation, and produced persistent oxidative stress and enhanced release of pro-inflammatory cytokines and matrix metalloproteinases. Accumulation of intracellular Cd was associated with sustained oxidative stress and inflammation, which, in turn, may have initiated squamous differentiation in ALI cultures. These observations demonstrate that ALI airway tissue models can recapitulate the functional and structural alterations in Cd-exposed animals, suggesting their potential application for studying tissue responses related to respiratory toxicants like those present in tobacco smoke.
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3D constructs composed of primary normal differentiated human bronchiolar epithelial (NHBE) cells as mono- or co-culture in combination with normal human lung fibroblasts were exposed repeatedly at the air-liquid interface with non-lethal concentrations of mainstream cigarette smoke (4 cigarettes a day, 5 days/week, 13 times repetition in total) to build up a permanent burden on the cells. Samples were taken after 4, 8 and 13 times of repeated smoke exposure and the cultures were analyzed by histopathological methods In comparison with the clean air exposure (process control) and incubator control cells the cigarette smoke exposed cultures showed a reduction of cilia bearing as well as mucus producing cells. In both mono- as well as co-cultures, hyperplasia was induced showing different histological cell types (undifferentiated secretory and squamous cell types). At the end of the exposure phase, we observed the development of non-hyperplastic areas strongly positive to CK13 antibody, commonly seen in squamous cells as a marker for non-cornified squamous epithelium, thus suggesting a transition of the normal bronchial epithelial cells towards metaplastic cells. The control cultures (clean air exposed and incubator cells) showed no comparable phenotypic changes. In conclusion, our in vitro model presents a valuable tool to study the induction of metaplastic alterations after exposure to airborne material.

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Supported in part by grant CA-48369 from The National Cancer Institute.

Presented in part at the 57th Annual Meeting, American College of Chest Physicians, San Francisco, November 4-8, 1991.

Manuscript received May 19; revision accepted September 22.

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Chest

Clinical InvestigationsSquamous Metaplasia of the Bronchial Mucosa and its Relationship to Smoking

Section snippets

METHODS

RESULTS

DISCUSSION

Histiologic changes in bronchial tubes of cigarette-smoking dogs

Cancer

Changes in bronchial epithelium in relation to cigarette smoking, 1955–1960 vs 1970–1977

N Engl J Med

Cancer of the lung: the cytology of sputum prior to the development of carcinoma

Acta Cytol

Smoking and lung cancer: an overview

Cancer Res

Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer

N Engl J Med

Clinical Investigations
Squamous Metaplasia of the Bronchial Mucosa and its Relationship to Smoking