Pulmonary macrophages migrate to the sites where inhaled chrysotile fibers initially are deposited (i.e., surfaces of alveolar duct bifucations) and form a major component of an early asbestos-induced interstitial lesion in rats. To establish the basic cellular mechanisms of asbestos-induced lung disease, it is essential to determine the chemical mediators which attract macrophages to these sites of fiber deposition. Fluids lavaged from the lungs of exposed rats contain substantial chemotactic activity for macrophages compared to fluids from sham-exposed animals. This chemotactic activity is derived from complement activated by inhaled asbestos on alveolar surfaces. This contention is supported by observing: 1) Production in vitro of chemotactic activity by asbestos in serum or in lung lavageates was blocked by complement inhibitors, and 2) Fractionation, by molecular sieve chromatography, of serum proteins and concentrated proteins lavaged from the lungs of asbestos-exposed rats showed chemotactic activity in the 14-18,000 MW range. This fractionation profile is identical to C5a, the chemotactic product of complement activation. Rats treated with cobra venom factor (CVF) to deplete circulating complement as well as complement-deficient mice demonstrated significantly depressed macrophage accumulation at sites of asbestos deposition. Most recently time course studies have shown that the complement-dependent chemotactic factor is rapidly activated during a 3-hr exposure to asbestos, peak activity is maintained through 48 hrs post-exposure, and the chemotactic activity is no longer detectable by 8 days after exposure. In addition, once the C5a is activated, no detectable C5 is present in the lungs until 2 wks post-exposure. Now we have learned that complement-deficient asbestos-exposed mice fail to develop significant interstitial lung diseae, suggesting that the complement-dependent macrophage response may play an essential role in mediating disease progression.
