This study examines the relationships between inflammation, surfactant protein (SP) expression, surfactant function, and lung physiology in a murine model of acute lung injury (ALI). 129/J mice received aerosolized endotoxin lipopolysaccharide [LPS] daily for up to 96 h to simulate the cytokine release and acute inflammation of ALI. Lung elastance (E(L)) and resistance, lavage fluid cell counts, cytokine levels, phospholipid and protein content, and surfactant function were measured. Lavage and lung tissue SP content were determined by Western blot and immunohistochemistry, and tissue messenger RNA (mRNA) levels were assessed by Northern blot and in situ hybridization. Tumor necrosis factor-alpha and neutrophil counts in bronchoalveolar lavage fluid increased within 2 h of LPS exposure, followed by increases in total protein, interleukin (IL)-1beta, IL-6, and interferon-gamma. E(L) increased within 24 h of LPS exposure and remained abnormal up to 96 h. SP-B protein and mRNA levels were decreased at 24, 48, and 96 h. By contrast, SP-A protein and mRNA levels and SP-C mRNA levels were not reduced. Surfactant dysfunction occurred coincident with changes in SP-B levels. This study demonstrates that lung dysfunction in mice with LPS-ALI corresponds closely with abnormal surfactant function and reduced SP-B expression.

Relationships between lung function and surfactant function and composition were examined during the evolution of acute lung injury in guinea pigs. Lung mechanics and gas exchange were assessed 12, 24, or 48 h after exposure to nebulized lipopolysaccharide (LPS). Bronchoalveolar lavage (BAL) fluid was processed for phospholipid and protein contents and surfactant protein (SP) A and SP-B levels; surfactant function was measured by pulsating bubble surfactometry. Lung elastance, tissue resistance, and arterial-alveolar gradient were moderately elevated by 12 h after LPS exposure and continued to increase over the first 24 h but began to recover between 24 and 48 h. Similarly, the absolute amount of 30,000 g pelleted SP-A and SP-B, the phospholipid content of BAL fluid, and surfactant function declined over the first 24 h after exposure, with recovery between 24 and 48 h. BAL fluid total protein content increased steadily over the first 48 h after LPS nebulization. In this model of acute lung injury, the intra-alveolar repletion of surfactant components in early recovery led to improved surfactant function despite the presence of potentially inhibitory plasma proteins.

Free radicals (FRs) and serum proteins have both been implicated in the pathophysiology of surfactant dysfunction during acute lung injury (ALI). This study examines how these 2 distinct mechanisms interact to contribute to altered surfactant function in this setting. Calf lung surfactant (2 mg/mL) was incubated with no additives (C = control), and with low = (LD = 125 microM FeCl2; 250 microM H2O2) and high-dose (HD = 250 microM FeCl2, 500 microM H2O2) Fenton reaction reagents to generate hydroxyl radical. Each condition was studied with (1) no protein (N); and with 25%, 200%, and 800% (weight protein/weight phospholipid) protein added as (2) bovine albumin, (3) bovine fibrinogen, (4) hemoglobin, or (5) calf serum. Lipid (LFR) and protein (PFR) free-radical products, and modifications in the tertiary structure of Surfactant Protein A (SPA) on Western blot, were observed in N LD and N HD samples. Added proteins reduced LFR and PFR changes as well as SPA structural changes. Protection was greatest for fibrinogen, hemoglobin, and serum, and least for albumin. Minimal to no dysfunction, assayed by pulsating surfactometry, was observed in all samples. These findings indicate that addition of serum proteins to surfactant at 2 mg/mL protects against, rather than promotes, FR-mediated chemical changes in surfactant lipid and protein constituents.