In vitro testing for lung toxicity

We characterized the pattern of arachidonic acid metabolites released from sensitized isolated guinea pig lungs undergoing anaphylactic reactions after ovalbumin challenge. TXB(2) (the stable hydrolysis product of (TXA(2)) is the most abundant product: it was released at an average of 13.7 +/- 7.0 ng/min (+/-SD, n = 33) during the anaphylactic reaction (i.e. a five- to six-fold increase in comparison with the basal release). Its level correlates with both the bronchoconstrictor response and LTC(4) and LTB(4) release. In non-sensitized lungs the release of basal TXB(2) increased about five-fold during a 10-min exposure to a formaldehyde aerosol at the dose of 10 ppm; this increase was concomitant with an 87.5 +/- 10.0% (+/-SD) reduction of the tracing recording the pressure-volume variations in the lung. No change in the release of lipoxygenase products was observed after exposure to formaldehyde aerosol. Pre-treatment with N-acetylcysteine (10(-3)-10(-4)m) reduced both formaldehyde-induced bronchoconstriction and the increase of TXB(2) release. An acid-water aerosol, resembling the composition of acid rain, strongly increased TXB(2) release in the pH range 4.5 to 2.5, without affecting the lipoxygenase pathway of arachidonic acid metabolism. These data suggest that exposure to toxicants that irritate the respiratory tract selectively enhances TXB(2) release, while an antigen challenge stimulates both the cyclooxygenase and lipoxygenase pathways of lung arachidonate metabolism. Thus, the different pattern of arachidonic acid cascade activation may predict a direct toxic effect or an allergic reaction when the xenobiotic is injected into the pulmonary artery or administered by way of inhalation as an aerosol. More recently vasoactive intestinal polypeptide (VIP) has been proposed as a modulator of lung inflammation and airway constriction. In sensitized lungs the antigen challenge induced a five-fold increase in VIP release, coinciding with the increase of arachidonate metabolites. Pharmacological evidence shows that TXA(2) enhances VIP release, while VIP suppresses TXA(2) formation. This suggests a possible role of TXA(2)/VIP interaction in regulating bronchial smooth muscle reactivity in condition of enhanced arachidonate metabolism. However, the importance of this interaction in evaluating the toxic response is still to be established.