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. 2010 Jul;116(1):313-22.
doi: 10.1093/toxsci/kfq119. Epub 2010 Apr 19.

Airway mast cells in a rhesus model of childhood allergic airways disease

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Airway mast cells in a rhesus model of childhood allergic airways disease

Laura S Van Winkle et al. Toxicol Sci. 2010 Jul.

Abstract

Asthma is a leading cause of morbidity in children. Risk factors include chronic exposure to allergens and air pollution. While chronically activated mast cells contribute to the pathophysiology of asthma in part through their proteases such as chymase and tryptase, previous studies of airway mast cell abundance and distribution in asthmatics have been inconsistent. To determine whether repeated episodic exposures to environmental pollutants during postnatal lung development alter airway mast cell abundance and distribution, we exposed infant rhesus monkeys to a known human allergen, house dust mite antigen (HDMA), and/or a known environmental pollutant, ozone (O(3)), and quantitatively compared the abundance of tryptase- or chymase-positive mast cells in three airway levels. Mast cells are resident in multiple compartments of the airway wall in infant rhesus monkeys raised from birth in filtered air. Tryptase- and chymase-positive cells were most abundant in trachea and least in terminal bronchioles. The majority of tryptase-positive and almost all chymase-positive cells were in extracellular matrix and smooth muscle bundles. Chronic exposure to HDMA elevated the abundance of both tryptase- and chymase-positive cells in the trachea and intrapulmonary bronchi. Neither exposure to O(3) nor HDMA + O(3) increased mast cell accumulations in the airway wall. We conclude that during postnatal airway development (1) mast cells are a resident airway cell population even in the absence of toxic air contaminants; (2) aeroallergen exposure alters large airway mast cell distribution and abundance, increasing chymase-positive mast cells; and (3) this response is attenuated by exposure to oxidant air pollutants.

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Figures

FIG. 1.
FIG. 1.
Exposure time line of the experiment. Arrows indicate specific events within the 6-month exposure protocol. (A) Thirty-day-old rhesus monkeys were exposed to eleven 14-day cycles of either (1) FA or (2) 0.5 ppm O3. (B) Rhesus monkeys were sensitized through subcutaneous and intramuscular injections at 2 and 4 weeks of age. Thirty-day-old postnatal monkeys sensitized to HDMA were exposed to 11 rounds of 14-day aerosol exposure cycles of either (3) HDMA allergen or (4) a combination of HDMA allergen + 0.5 ppm O3. Exposure cycles are continuous within all groups, terminating at 6 months of age.
FIG. 2.
FIG. 2.
Representative micrographs of mast cell stains in the intrapulmonary airway level from the rhesus monkey. (A) Arrows indicate immunohistochemically positive tryptase-positive mast cells (MCT) and (B) histochemically positive chymase mast cells (MCTC). Scale bar is 100 μm.
FIG. 3.
FIG. 3.
Abundance and distribution of MCT- and MCTC-positive cell (Vs) mass in specific regions in the airway wall. (A) The lung was microdissected open along the axial pathway, and airway branch points were marked. Trachea, intrapulmonary (generations 1–5), and terminal bronchioles (defined as proximal to the first alveolar outpocketings) were measured and compared. (B) MCT- and MCTC-positive cells were most abundant in the trachea and declined in the intrapulmonary and terminal airways. The trend is similar but exaggerated following HDMA exposure; both MCT- and MCTC-positive cell mass within the trachea was significantly greater than either intrapulmonary or terminal airway groups. Compared to FA controls, MCT cell mass was significantly increased in the trachea following the HDMA exposure regimen. (C) MCTC cell mass was significantly increased in both the trachea and the intrapulmonary airways. Terminal bronchiolar mast cells were not increased in response to HDMA exposure. Data are means ± SEM (n = 5–6 monkeys per group). *p < 0.05, as compared with FA controls in the same airway region.
FIG. 4.
FIG. 4.
Distribution of MCT- and MCTC-positive cells within compartments in the trachea and intrapulmonary regions. Mast cells were quantified in FA and house dust mite antigen (HDMA)-exposed animals within the epithelium, blood vessel, glands, smooth muscle, and extracellular matrix compartments. (A) Within tracheas of FA animals, MCT cells were predominantly observed within the extracellular matrix followed by an approximately equal distribution within the glands and smooth muscle. MCT cells were rarely detected within the epithelium. MCT cell distribution was not changed significantly following HDMA sensitization and aerosol exposure. (B) The majority of MCTC cells in the trachea were distributed in the extracellular matrix and smooth muscle. Cells were rarely detected within blood vessels and undetected in the epithelium and glands. Upon HDMA exposure, distribution of MCTC cells changed significantly in the smooth muscle and the extracellular matrix. (C) Intrapulmonary MCT cells were predominantly observed in the smooth muscle and extracellular matrix. Following HDMA exposure, MCT cells were significantly decreased in the smooth muscle and increased in the extracellular matrix. (D) Similar to the trachea, a majority of intrapulmonary MCTC cells were distributed within the smooth muscle and extracellular matrix. Mast cells were undetected within the epithelial, blood vessel, and glandular compartments. Distribution between compartments did not change significantly following HDMA treatment. Data are plotted as means ± SEM (n = 5–6 monkeys per group). *p < 0.05, as compared with FA controls in the same compartment.
FIG. 5.
FIG. 5.
MCT and MCTC cell mass (Vs) in the trachea and intrapulmonary conducting airways. (A) HDMA allergen–exposed animals had both significantly greater MCT and MCTC cell mass compared to FA controls. Interestingly, HDMA MCTC cells are also significantly greater compared to all other aerosol exposures in the trachea. (B) Individual MCTC Vs plotted as a percentage of total mast cells in the trachea. A trend showing increased percentage of MCTC/MCT can be seen following all aerosol treatments compared to FA controls. A large increase in the MCTC/MCT ratio is seen between O3-treated (55%) compared to FA animals (15%). But due to a large variance within the data, the comparison was insignificant (p = 0.06). (C) Within the intrapulmonary component, MCTC Vs increased significantly following HDMA exposure compared with both FA controls and O3 aerosol treatments. Surprisingly, MCT Vs was not significantly increased following HDMA exposure, as compared to FA controls. (D) Comparable to the trachea, the percentage of intrapulmonary MCTC/MCT also trended in an increasing fashion following aerosol exposures compared to FA controls. The combined HDMA + O3–exposed group had the greatest MCTC/MCT ratio compared to FA controls (38 vs. 9%) but failed to reach significance (p = 0.07). Data are shown as means ± SEM (n = 5–6 monkeys per group). *p < 0.05, MCTC Vs as compared with FA controls in the same airway region. †p < 0.05, as compared with HDMA treatment in the trachea. §p < 0.05, MCT Vs as compare with FA treatment in the trachea. ‡p < 0.05, as compared with HDMA treatment in the intrapulmonary region.

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