New Research Model Shows That Where Carcinogens Settle May Be A Key Factor In Developing Lung Cancer, The Leading Cause Of Cancer Death

Ridges along the division of the bronchial tree are the most susceptible for collecting toxic particles

(June 10, 2003) Bethesda, MD – Environmental particles the size of those emanating from cigarette smoke and toxic aerosols interact with our pulmonary surfaces and may lead to lung disease.  The location of such cancerous lesions in the bronchial airway may not be a random process, however. Instead, they may be related to a regional pattern of toxic material deposited in selected areas of the lungs.  A new study suggests that a specific site – the ridge separating the two halves of the bronchial airway -- may be a key factor in developing lung cancer.

Background

Earlier studies of cell dynamics indicate that benign and cancerous lesions alike predominate at the division between the central airways.  One study has assessed the likelihood of finding cancer based on the site within the bronchi as ten percent for the main surface and 30 percent each for the lobar, segmental and subsegmental regions. Later research suggests that the accumulation of carcinogenic particles and particles with absorbed carcinogens from cigarette smoke at the airway’s carinas  -- the ridge separating the openings of the right and left main bronchi at their junction with the trachea -- is a potentially important mechanism for human pulmonary carcinogenesis. Animal studies indicate that clearing particles is much slower in the airway carinas than in the tubular airway segments.

The methods currently used to calculate exposure to particles do not take into consideration the inhomogeneity of either the deposition of the toxin or the clearance patterns of the site. The reported locations of cancer manifestation are therefore at odds with the calculated dose patterns among human bronchial airways. Accordingly, the enhanced deposition along the carinal ridges has been thought to be a more relevant deposition quantity for assessing risk than is the method of using average deposition patterns. In addition to there being increased deposits in the carcina, the streamline curvature offers the largest and diffusional deposition due to the thickness of the cell in this location.

A New Study

A new study uses a fluid dynamics model to compute local deposition patterns in central human airway bifurcations, quantify their inconsistencies at the cellular level, and point to the possible consequences of the inhomogeneity regarding the effects of inhaled aerosols.  The investigators believed that only by including the unique contribution of the bifurcation zone or carinal ridge deposition into the risk assessment protocols would the dose exposure be compatible with clinically observed sites.

The authors of “Local Particle Deposition Patterns May Play a Key Role in the Development of Lung Cancer,” are Imre Bala´sha´zy, from the Radiation and Environmental Physics Department, KFKI Atomic Energy Research Institute, Budapest, Hungary; and Werner Hofmann and Thomas Heistracher, both of the University of Salzburg, Salzburg, Austria.  Their findings appear in the May 2003 edition of the Journal of Applied Physiology.

Methodology

The researchers analyzed local deposition patterns in airway bifurcations using a recently developed numerical particle deposition model. In this study the airflow fields were computed by a volume fluid dynamics program in “physiologically realistic airway bifurcation” geometries. This three-dimensional geometry model was adjusted to ensure smooth transitions between the airways with realistic length, diameter, branching angles, daughter airway, and carina curvatures. Only symmetric branching was applied to characterize the most general relationships of the local deposition patterns.

In the model, aerosol particles were randomly selected at the inlet cross section with a random-number generator, in accordance with the assumed inlet air velocity profile. The inlet number and velocity distributions of particles followed parabolic distributions. Velocity of flow and particle in the same points were equal at the inlet.  Because deposition efficiencies, deposition densities, and number of particles are higher for inhalation than for exhalation, the research team limited the analysis to the inspiratory phase of the breathing cycle.

For the quantification of the inhomogeneity of predicted deposition patterns, the entire surface of the bifurcation was scanned. Local deposition enhancement factors were determined as the ratio of local to average deposition densities.

Results

The findings revealed that:

• a small fraction of epithelial cells located at carinal ridges can receive massive doses that may be as much as several hundred times higher than the average dose for the entire airway.  This lends further credence to the hypothesis that the apparent site selectivity of neoplastic lesions may indeed be caused by the enhanced deposition of toxic particulate matter at bronchial airway bifurcations or location of division. 

• The distribution of deposition enhancement factors revealed that the degree of inhomogeneity of particle deposition in bronchial airway bifurcations was high for all particle sizes.

• The computations refered to the bronchial morphology of a healthy lung only. Deposition enhancement factors may be higher in diseased lungs, where airways can be constricted or completely blocked.

Conclusions

Cells located in the area of the dividing spur may receive doses that may be several hundred times higher than the average dose for the entire airway, and mucociliary clearance -- the major defense mechanism in the bronchial tree -- is impaired at carinal ridges.  Thus, the site selectivity of neoplastic lesions at airway bifurcations in the upper bronchial tree may be the result of both selective deposition and reduced clearance of toxic particulate matter. Because all particle sizes display a similar pattern of preferential deposition at carinal ridges, other ambient particles, which are nontoxic, may enhance the carcinogenic response at airway branching sites. This study offers a new perspective on the pathogenesis of lung cancer and may aid in future diagnostic procedures for the nation’s leading cause of cancer death.

Source: May 2003 edition of the Journal of Applied Physiology

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: A copy of the research article is available in pdf format to the press.

Members of the press are invited to obtain a pdf copy of the study and to interview members of the research team. To do so, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.