Complement Factor 3 Mediates Particulate Matter–Induced Airway Hyperresponsiveness

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Abstract
Epidemiologic studies have suggested that exposure to air- borne particulate matter (PM) can exacerbate allergic airway responses; however, the mechanism(s) are not well under- stood. We and others have recently shown that development of airway hyperresponsiveness (AHR) may be a complement- mediated process. In the present study, we examined the role of complement factor 3 (C3) in the development of PM- induced AHR and airway inflammation by comparing re- sponses between C3-deficient (C3 � / � ) and wild-type mice. Mice were exposed to 0.5 mg of ambient particulate collected in urban Baltimore. Forty-eight hours later, airway responsive- ness to intravenous acetylcholine was assessed and bronchoal- veolar lavage was conducted. PM exposure of wild-type mice resulted in significant increases in AHR, whereas it did not sig- nificantly increase airway reactivity in C3 � / � mice. Interest- ingly, PM induced similar inflammatory responses in both wild- type and C3 � / � mice. Immunohistochemical staining demon- strated marked C3 deposition in the airway epithelium and connective tissue of wild-type mice after PM exposure. These results suggest that exposure to PM may induce AHR through activation of complement factor 3 in the airways. The morbidity and mortality of asthma has increased dra- matically over the last few decades. Although the factors that contribute to this increase are not well understood, epidemiologic studies have suggested that increased expo- sure to air pollutants such as ozone and particulate matter (PM) are clearly associated with increased hospitaliza- tions, increased asthma medication usage, and decrements in pulmonary function (1, 2). Animal studies have sup- ported a role for PM exposure in development of asthma- like parameters, in that exposure of animals to PM surro- gates such as residual oil fly ash (ROFA) and diesel PM induce significant airway inflammation concomitant with increases in airway responsiveness (3-6). To date, the ex- act mechanisms by which PM exposure can induce acute bronchoconstriction and airway hyperresponsiveness (AHR) are unknown. Upon activation of the complement system, cleavage of the third and fifth components of the complement system (C3 and C5, respectively) generates the peptides C3a and C5a, both of which are potent anaphylatoxins. C3a and C5a can trigger contraction of smooth muscle, increase the permeability of small blood vessels, and regulate vasodila- tion (reviewed in Ref. 7). In addition, complement factors are potent chemoattractants for a variety of inflammatory cells including neutrophils, eosinophils, and macrophage/ monocytes. Recent studies suggest that these molecules of the innate immune response are produced by airway epi- thelial cells and macrophages at the airway surface (8, 9). Receptors for both of these anaphylatoxins (C5aR and C3aR) have been shown to be constitutively expressed on bronchial and alveolar epithelial cells, as well as on vas- cular endothelial and smooth muscle cells (10). Recent reports suggest that allergen exposure upregulates C3aR ex- pression (11) on bronchial smooth muscle cells. Further- more, recent studies in C3aR- and C3-deficient mice support a role for C3 in antigen-induced AHR (11, 12). However, the role of complement components in non-anti- body-mediated inflammatory responses has not been ex- plored. We have previously shown that PM collected in urban Baltimore induces AHR concomitant with significant ele- vations in bronchoalveolar lavage (BAL) cellularity (13). In the present study, we examined the role of C3 in AHR and inflammation induced by ambient Baltimore PM by comparing airway reactivity and inflammatory responses in wild-type and C3 � / � mice. We demonstrate that particu- late-induced AHR is C3-dependent, whereas the accom- panying inflammatory response is independent of C3 acti- vation.