Meconium aspiration results in mechanical obstruction, inflammatory injury, altered capillary permeability, and surfactant inhibition, all of which can alter pulmonary function and cause respiratory distress. Meconium removal from the lung and surfactant replenishment may blunt surfactant inhibition, inflammatory changes, and preserve lung mechanics. Therapeutic strategies in meconium injury have included perfluorochemical (PFC) ventilation to provide gas exchange while helping to cleanse the lung and, more recently, lung lavage with KL4 surfactant (a mixture of phospholipids and synthetic peptide) to remove meconium debris and replenish surfactant. Using an adult rat model of meconium injury (Pediatrics, 100:998,1997), we have now evaluated whether lung lavage would help to preserve lung mechanics and limit inflammatory response. Adult rats were intubated, and given 0.3 ml meconium (13.5 mg dry wt) or saline (NS) endotracheally. Ten minutes later, meconium instilled rats (Mec) were lavaged (x3) with 6 ml/kg aliquots of saline (NSL) or PFC (PFCL). Another group of Mec rats was lavaged twice with KL4 (a gift of Acute Therapeutics Inc., Doylestown, Pa) at 2.5 mg/ml, and once at 10 mg/ml (KL4L). A final group of Mec rats was lavaged twice with saline, followed by once with KL4 at 10mg/ml, in order to replenish surfactant that may be washed out with saline lavages. After recovery from anesthesia (1-2 hours), animals were extubated to spontaneously breathe room air for 18 hours, a period previously shown to correlate with maximal lung injury. Therafter, dynamic pulmonary compliance was measured (Cdyn, ml/cmH2O/kg), and bronchoalveolar lavage (BAL) was performed on excised lungs. The cell free BAL fluid was analyzed by SDS-PAGE for the presence of serum proteins. Compared to NS, Cdyn was decreased in Mec group (0.95±.06, n=4, vs 2.04±0.43, n=3 p<0.01). Cdyn was further decreased in NSL group (0.66±.12, n=5, p<0.05, vs Mec), and was unchanged in PFCL group (0.71±.09, n=5). In comparison, KL4L group improved Cdyn (1.37±.2, n=5, p<0.02, vs Mec). In the NSKL group, Cdyn tended to improve (1.56±.4, n=5, p=0.54). KL4 lavage also decreased the cell count in BAL fluid when compared with Mec group(p<0.009). While increased levels of serum proteins were found in the Mec compared to NS group, these were further increased in all other groups except KL4L. These studies show that in spontaneously breathing animals, KL4 lavage diminishes inflammatory response to meconium and improves lung compliance, without compromising alveolar permeability.