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. 1998 Sep;66(9):4229-36.
doi: 10.1128/IAI.66.9.4229-4236.1998.

Interleukin-4 enhances pulmonary clearance of Pseudomonas aeruginosa

S Jain-Vora  1 , A M LeVine, Z Chroneos, G F Ross, W M Hull, J A Whitsett
Affiliations

Interleukin-4 enhances pulmonary clearance of Pseudomonas aeruginosa

S Jain-Vora et al. Infect Immun. 1998 Sep.

Abstract

To determine the effects of interleukin-4 (IL-4) on bacterial clearance from the mouse lung, transgenic mice expressing IL-4 in respiratory epithelial cells under the control of the Clara cell secretory protein promoter (CCSP-IL-4 mice) were infected intratracheally with Pseudomonas aeruginosa. Survival of CCSP-IL-4 mice following bacterial administration was markedly improved compared with that of control mice. While bacteria proliferated in lungs of wild-type mice, a rapid reduction in the number of bacteria was observed in the IL-4 mice as early as 6 h postinfection. Similarly, intranasal administration of IL-4 enhanced bacterial clearance from the lungs of wild-type mice. While acute and chronic IL-4 increased the numbers of neutrophils in bronchoalveolar lavage fluid, bacterial infection was associated with acute neutrophilic pulmonary infiltration, and this response was similar in the presence or absence of IL-4. Local administration or expression of IL-4 in the mouse lung enhanced pulmonary clearance of P. aeruginosa in vivo and decreased mortality following infection.

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Figures

FIG. 1
FIG. 1
Increased survival of CCSP-IL-4 mice after infection with P. aeruginosa. Survival was determined 48 h after wild-type (open bars) and CCSP-IL-4 (closed bars) mice were infected i.t. with P. aeruginosa. Data represent eight mice per group. ∗, P < 0.05 compared to wild-type infected mice, as assessed by ANOVA.
FIG. 2
FIG. 2
Enhanced clearance of P. aeruginosa in CCSP-IL-4 mouse lungs. P. aeruginosa counts (CFU) were determined by quantitative cultures of lung and spleen homogenates harvested 6 and 24 h after administration of 5 × 107 CFU of P. aeruginosa in wild-type (WT) and CCSP-IL-4 mice. (A) Bacterial CFU numbers were significantly higher in wild-type mouse lung homogenates than in those of CCSP-IL-4 transgenic mice at 6 and 24 h postinfection. (B) Bacteria were detected in wild-type and CCSP-IL-4 mouse spleens. Data represent means ± SEM for eight mice per group. ∗, P < 0.05 compared to wild-type infected mice, as assessed by ANOVA.
FIG. 3
FIG. 3
Increased leukocytic infiltration and MPO activity after bacterial infection. Wild-type (WT) and CCSP-IL-4 mice were infected i.t. with 5 × 107 P. aeruginosa CFU. (A) Increased numbers of neutrophils were observed in BAL fluid of wild-type mice at 6 and 24 h after bacterial infection compared to PBS-treated control mice. The numbers of neutrophils were similar in BAL fluids from P. aeruginosa-infected CCSP-IL-4 transgenic mice, CCSP-IL-4 control mice, and wild-type infected mice. (B) MPO activity was significantly increased in both wild-type and CCSP-IL-4 mouse lung homogenates at 6 and 24 h after P. aeruginosa infection compared to PBS-treated control mice. Values are means ± SEM for approximately 8 mice per group. †, P < 0.05 compared to PBS-treated control mice; ∗, P < 0.05 compared to wild-type mice, as assessed by ANOVA.
FIG. 4
FIG. 4
Effects of P. aeruginosa infection on lung TNF-α and IL-1β concentrations. TNF-α and IL-1β concentrations were assessed in lung homogenates from wild-type (WT) and CCSP-IL-4 mice. (A) Increased concentrations of TNF-α were observed in wild-type and CCSP-IL-4 mice after i.t. infection with P. aeruginosa compared to PBS-treated control mice. (B) Bacterial infection increased IL-1β concentrations in wild-type and CCSP-IL-4 mouse lung homogenates in comparison to PBS-injected control mice. Values are means ± SEM for six mice per group. †, P < 0.05 compared to PBS-treated control mice; ∗, P < 0.05 compared to wild-type mice, as assessed by ANOVA.
FIG. 5
FIG. 5
Surfactant analysis. Lungs from wild-type and CCSP-IL-4 mice were homogenized 24 h after administration of PBS or 5 × 107 CFU of P. aeruginosa. SP-A and SP-D proteins were assessed by Western blot analysis. Lanes: 1 and 2, PBS-injected wild-type mice; 3 and 4, wild-type mice administered P. aeruginosa; 5 and 6, PBS-treated control CCSP-IL-4 mice; 7 and 8, P. aeruginosa-injected CCSP-IL-4 mice. Increased SP-A and SP-D concentrations were noted in PBS-treated or infected CCSP-IL-4 mice. Increased SP-D was observed in lung homogenates from wild-type mice infected with P. aeruginosa.
FIG. 6
FIG. 6
Effect of acute IL-4 on bacterial clearance. IL-4 was administered i.n. to the lungs of wild-type mice 16 and 1 h prior to bacterial infection. Lungs and spleens from wild-type (WT) and wild-type mice administered IL-4 i.n. were harvested 6 h after infection with 5 × 107 CFU of P. aeruginosa. (A) Bacterial counts were significantly higher in wild-type mouse lung homogenates at 6 h postinfection than in lung homogenates from wild-type mice treated with IL-4. (B) Bacteria were detected in spleen homogenates from wild-type and IL-4-treated mice. Data are means ± SEM for eight mice per group. *, P < 0.05 compared to wild-type mice, as assessed by ANOVA.
FIG. 7
FIG. 7
Increased pulmonary leukocytic infiltration and MPO activity in mice treated with IL-4. Wild-type (WT) mice and wild-type mice administered IL-4 i.n. were sacrificed 6 h after i.t. administration of PBS or 5 × 107 CFU of P. aeruginosa. (A) Increased neutrophils were observed in BAL fluid from both control and IL-4-treated mice after P. aeruginosa infection. (B) Increased MPO activity was observed in lung homogenates from IL-4-treated and control mice after infection with bacteria. Data represent means ± SEM for eight mice per group. †, P < 0.05 compared to PBS control mice; ∗, P < 0.05 compared to wild-type mice, as assessed by ANOVA.
FIG. 8
FIG. 8
TNF-α and IL-1β concentrations after infection. Lungs from wild-type (WT) mice and mice administered IL-4 i.n. were homogenized 6 h after i.t. injection with PBS or 5 × 107 CFU of P. aeruginosa. Concentrations of TNF-α (A) and IL-1β (B) were increased after P. aeruginosa infection. Values represent means ± SEM for eight per group. †, P < 0.05 compared to PBS control mice; ∗, P < 0.05 compared to wild-type mice, as assessed by ANOVA.
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