Aspergillus fumigatus-Induced Allergic Airway Inflammation Alters Surfactant Homeostasis and Lung Function in BALB/c Mice

Abstract

The differential regulation of pulmonary surfactant proteins (SPs) is demonstrated in a murine model of Aspergillus fumigatus (Af )-induced allergic airway inflammation and hyperresponsiveness. BALB/c mice were sensitized intraperitoneally and challenged intranasally with Af extract. Enzyme-linked immunosorbent assay analysis of serum immunoglobulin (Ig) levels in these mice showed markedly increased total IgE and Af-specific IgE and IgG1. This was associated with peribronchial/perivascular tissue inflammation, airway eosinophilia, and secretion of interleukin (IL)-4 and IL-5 into the bronchoalveolar lavage fluid (BALF). Functional analysis revealed that in comparison with nonsensitized mice, allergic sensitization and challenge resulted in significant increases in acetylcholine responsiveness. To analyze levels of SPs, the cell-free supernate of the BALF was further fractionated by high-speed (20,000 x g) centrifugation. After sensitization and challenges, the pellet (large-aggregate fraction) showed a selective downregulation of hydrophobic SPs SP-B and SP-C by 50%. This reduction was reflected by commensurate decreases in SP-B and SP-C messenger RNA (mRNA) expression of the lung tissue of these animals. In contrast, there was a 9-fold increase in SP-D protein levels in the 20,000 x g supernate without changes in SP-D mRNA. The increased levels of SP-D showed a significant positive correlation with serum IgE (r = 0.85, P < 0.001). Tissue mRNA and protein levels of SP-A in either the large- or the small-aggregate fractions were unaffected. Our data indicate that allergic airway inflammation induces selective inhibition of hydrophobic SP synthesis accompanied by marked increases in the lung collectin SP-D protein content of BALF. These changes may contribute significantly to the pathophysiology of Af-induced allergic airway hyperresponsiveness.

Major House Dust Mite Allergens Dermatophagoides pteronyssinus 1 and Dermatophagoides farinae 1 Degrade and Inactivate Lung Surfactant Proteins A and D

“…There is no doubt that chronic exposure, which is so characteristic of HDM sensitivity, would result in the cumulative build up and continuous replenishment of very high concentrations of allergens in lung tissues. Despite some reported increases in SP-A and SP-D levels 24 h after allergen challenge, which may well represent an innate immune defense mechanism (11,12,15,59), given our findings, we believe that as well as very short-term exposure, which has been discussed above, long-term exposure to HDM allergens would disrupt the physiological levels and functions of SP-D in the lungs, and this could have profound consequences. Consistent with this, decreased levels of SP-A and SP-D in BALF are seen in the chronic phase of allergen exposure in murine models of allergic hypersensitivity to HDM allergens (58).…”

“…SP-A and SP-D levels increase severalfold in allergic asthma (11)(12)(13), and furthermore, the kinetics of the increase in SP-D levels after allergen challenge have been reported to coincide with the resolution of inflammation (14). Mouse models of house dust mite (Dermatophagoides pteronyssinus (Der p)) allergy have clearly demonstrated a protective role for SP-D during secondary allergen exposure.…”

IL-4 and IL-13 Form a Negative Feedback Circuit with Surfactant Protein-D in the Allergic Airway Response

“…We previously described that SP-D is selectively increased among the SPs following allergen challenge of sensitized mice (24,25). In this study, we hypothesize that SP-D production is induced by mechanisms underlying the allergic immune response and that it contributes to regulation of the inflammatory changes.…”

“…Sensitization with Af and with OVA was performed as described previously (24,27,34). STAT-6-deficient mice were sensitized and challenged using either Af extract or glycerol (as negative control).…”

“…In this study, we hypothesize that SP-D production is induced by mechanisms underlying the allergic immune response and that it contributes to regulation of the inflammatory changes. SP-D-deficient mice and the function of rSP-D was studied in models of T cell-driven allergic responses against Aspergillus fumigatus (Af) (24,26,27), an airborne fungal pathogen, that has been shown to bind to this lung collectin (28,29).…”