Immediate and Short-Term Cellular and Biochemical Responses to Pulmonary Single-Dose Studies of Insulin and H-MAP

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Abstract
Purpose. It was previously reported that co-administration of H-MAP to the airways of the lungs significantly influenced the absorption, disposition, and effect of insulin in a dose-dependent fashion. Doses of H-MAP (16 mg/kg) and insulin (1.3 U/kg) required to achieve maximum pharmacokinetic and pharmacodynamic responses were determined. The purpose of the present study was to evaluate the effects of insulin and H-MAP spray-instilled (SI) to rats on the physiology of the lung. A short-term, single-dose study of insulin alone and combined with H-MAP was performed. Methods. Solutions of either insulin (INS), H-MAP, or insulin plus H-MAP (INMA) were SI to the lungs of rats. Lipopolysaccharide solution (LPS) and sodium dodecyl sulfate solution (SDS) were used as positive controls, and normal saline (SAL) was used as negative control. Animals were sacrificed at various time points and bronchoalveolar lavage (BAL) was conducted. BAL fluid was analyzed for local markers of lung injury, such as total cell numbers, differential cell count, total protein content and enzyme activities of lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and N-acetyl glucosaminidase (NAG). Results. SI of any solution, including normal saline, seems to have a minor but detectable effect on the normal physiology of the lung. SI of positive control solutions resulted in most markers of immunity and lung injury being significantly elevated, notably enzyme activity and white cell infiltrate. In contrast, SI of INS produced a response similar to that of SAL. SI of INMA resulted in a small transient response characterized by a slight increase in the proportion of neutrophils at 24 h, which decreased with time and was comparable to that of SAL at 72 h. SI of H-MAP resulted in a response similar to that from INMA; however an additional transient increase in LDH activity was noted which may be related to the mechanism of action of H-MAP. Conclusion. SI of INS, H-MAP, and INMA caused no apparent toxicity at the doses studied. A small, transient effect of H-MAP was noted which did not elicit the full complement of inflammatory markers and which was substantially smaller than the effect of either LPS or SDS.

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