Effect of Diabetes Mellitus on Endotoxin-Induced Lung Injury

Abstract

Objective: To examine the effects of diabetes mellitus on lipopolysaccharide (LPS)-induced pulmonary edema and alveolar neutrophil recruitment and activation.Hypothesis: Zucker diabetic fatty rats are resistant to the effects of intratracheal LPS on the extravasation of plasma proteins into the lungs.Design: Zucker diabetic fatty (ZDF) rats (genotype fa/fa) were used as a model of diabetes mellitus, while their normoglycemic heterozygous littermates served as controls. Lipopolysaccharide (Escherichia coli 0111: B4; 100-200 µg) or vehicle (0.25 mL of isotonic sodium chloride solution) was instilled into the airways of ZDF and control rats. Four hours later, pulmonary microvascular dysfunction was assessed by measuring the extravasation of Evans blue dye into the lung. Lipopolysaccharide-induced neutrophil recruitment was assessed by counting the number of neutrophils within the bronchoalveolar lavage fluid and measuring their expression of CD11b/CD18 by fluorescence-activated cell analysis sorting.Results: The LPS (200 µg) induced a 32% increase in Evans blue dye extravasation into the lungs of controls (P = .008) but had no such effect in diabetic animals. Pulmonary extravasation of Evans blue dye in controls was greater than that of ZDF rats both at baseline (P = .002) and in response to 200 µg of LPS (PϽ.001). The LPS upregulated neutrophil CD11b/CD18 expression in diabetic and nondiabetic groups and induced a greater than 50-fold increase in the number of neutrophils within the airways of both control and diabetic groups (PϽ.001). Conclusion:Despite the recruitment of a large number of neutrophils into the lung, the LPS-induced change in pulmonary microvascular permeability in diabetic animals is substantially less than that of nondiabetic controls.

Diabetes mellitus does not adversely affect outcomes from a critical illness*

“…Although we were unable to identify any single protective factor in our analysis, putative mechanisms include the anti-inflammatory effects of insulin (20), prevention of acute lung injury (22)(23)(24), adaptation to previous oxidant stress (39), or an improved nutritional or caloric substrate in obese patients with type 2 DM (30). Animal models have suggested DM may offer protection from acute renal injury (21), although this theory is opposed by the observation of increased incidence of renal injury in diabetic patients admitted with sepsis (16).…”

“…DM is suggested to be an independent risk factor for intensive care unit bloodstream infections (without increasing mortality) (19). However, DM may be associated with anti-inflammatory effects of exogenous insulin used for treating hyperglycemia, (20) offer renal protection against acute kidney injury, (21) decrease the incidence of acute lung injury, (22)(23)(24) and increase overall provider vigilance.…”

Increased Reabsorption of Alveolar Edema Fluid in the Obese Zucker Rat

“…Since diabetic patients have a decreased incidence of acute respiratory distress syndrome (Moss et al 2000), the mechanism responsible for the lower incidence has been studied in obese Zucker rats (Wright et al 1999) and in leptin resistant mice (Bellmeyer et al 2007) in association with an experimental model of diabetic mellitus. Interestingly, alveolar fluid clearance decreased in leptin resistant mice, but it was not studied in obese Zucker rats.…”

Obesity and Nutrition in Acute Respiratory Distress Syndrome

“…Most animal studies examining obesity-associated effects on pulmonary immunity and inflammation have focused on models of asthma and pneumonia, and although some forms of airway inflammation appear to be amplified by obesity 50 , the response to pneumonia is blunted 51–53 , suggesting that the inflammatory response in the alveoli (the site of ARDS) is impaired. In the published reports examining obesity’s effects on ARDS models, obese mice and rats demonstrate reduced inflammation, lung injury, and mortality from LPS-, hyperoxia-, and ozone-induced ARDS 54–58 , although in the case of ozone exposure, findings are mixed and appear to vary with the acuity of exposure 57,59–60 .…”