Mechanisms of asthma and allergic inflammation
Inhaled LPS induces blood release of Clara cell specific protein (CC16) in human beings

https://doi.org/10.1016/j.jaci.2005.01.067Get rights and content

Background

Animal models of lung inflammation have validated the plasma 16-kd Clara cell protein (CC16) as a peripheral marker of the permeability of the alveolocapillary barrier.

Objective

We investigated in human beings whether inhaled LPS induced a rise in airways permeability measured by the plasma changes in CC16.

Methods

The CC16 was measured in plasma from 15 subjects exposed to LPS by inhalation, during which the kinetics and the dose-response relationship of LPS-induced CC16 were evaluated. Because LPS-induced response involves macrophages activation, the protective effect of oral methylprednisolone was also evaluated.

Results

An inhalation of 50 μg LPS induced a significant (P < .001) rise in CC16 after 6 hours (from 7.24 [±0.68] μg/L to 10.69 [±0.99] μg/L) that normalized at 24 hours (6.65 [±0.33] μg/L). The CC16 response was dose-related, with the no-response threshold 0.5 μg LPS. A 6-day treatment with 20 mg/d methylprednisolone inhibited significantly (P < .001) the CC16 response to 50 μg LPS.

Conclusion

Exposure to LPS by inhalation in healthy subjects induces an intravascular leakage of CC16 that can be blocked by corticosteroids. These observations further validate plasma CC16 as a noninvasive test of the alveolocapillary barrier permeability.

Section snippets

Populations

In a group of 15 healthy nonsmoking subjects, plasma samples were obtained before, 6 hours after, and 24 hours after exposure to LPS by inhalation. At 1-week intervals, the population was exposed to saline, 0.5, 5, and 50 μg LPS, in random order. The mean age was 31.1 (±3.0) years; there were 8 female and 7 male subjects.

Another group of 15 healthy nonsmoking subjects (different from the first group) was exposed to 50 μg LPS after a 6-day pretreatment with placebo and methylprednisolone (20

Results

The exposure was well tolerated, and no serious adverse reaction was observed. There was no significant change in temperature and/or spirometry. Four subjects developed slight flulike symptoms.

In the basal state, the mean concentration of plasma CC16 for the 30 subjects from the 2 populations was 7.9 (±0.5) ng/mL, ranging from 2.8 ng/mL to 13.1 ng/mL.

An inhalation of 50 μg LPS induced a significant rise in CC16 plasma concentration. The kinetics of the response, reported in Fig 1, showed no

Discussion

The current study shows that in healthy subjects, an inhalation of LPS results in a dose-related increase in blood CC16 that peaks at 6 hours and normalizes at 24 hours, and that this response is blocked by a pretreatment with oral methylprednisolone.

Acute lung injury by smoke, ozone, and, recently, nitrogen trichloride (NCl3) exposure has also been associated with expression of CC16 at the blood level in human beings21, 22, 23 only a few hours after exposure. Using higher doses of LPS (100

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    Disclosure of potential conflict of interest: O. Michel, none disclosed; R. Murdoch is an employee of GlaxoSmithKline; A. Bernard, none disclosed.

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