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Impairment of neutrophil migration to remote inflammatory site during lung histoplasmosis.

Medeiros AI, Secatto A, Bélanger C, Sorgi CA, Borgeat P, Marleau S, Faccioli LH - Biomed Res Int (2015)

Bottom Line: Our results show that pulmonary Hc infection impairs LTB4- or PAF-stimulated PMN recruitment to air pouch.Yet, remote inflammation did not modify PMN numbers in the bronchoalveolar lavage fluid (BALF) of Hc-infected mice.Along that line, our results show that PAF-elicited PMN chemotaxis was abrogated in 5-lipoxygenase-deficient animals.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, UNESP, 14801-902 Araraquara, SP, Brazil.

ABSTRACT
Histoplasma capsulatum (Hc) induces a pulmonary disease in which leukotrienes promote activation and recruitment of effectors cells. It is also well-recognized that leukotriene B4 (LTB4) and platelet-activating factor (PAF) induce leukocyte recruitment to inflammatory sites. We investigated the impact of pulmonary Hc infection on PMN migration to a remote inflammatory site. Our results show that pulmonary Hc infection impairs LTB4- or PAF-stimulated PMN recruitment to air pouch. Yet, remote inflammation did not modify PMN numbers in the bronchoalveolar lavage fluid (BALF) of Hc-infected mice. Interestingly, the concomitant administration of PAF and LTB4 receptor antagonists inhibited PMN recruitment to both BALF and the remote site, demonstrating cooperation between both mediators. Along that line, our results show that PAF-elicited PMN chemotaxis was abrogated in 5-lipoxygenase-deficient animals. These results suggest caution in the indiscriminate use of anti-inflammatory drugs during infectious diseases.

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Effect of SR-27417 and CP-105,696 administration on PMN numbers in air pouch of C57Bl/6 mice. (a and c) Noninfected mice and (b and d) Hc-infected mice (i.t., 5 × 105 Hc yeast) were pretreated with SR-27417 (0.1 mg/kg) and/or CP-105,696 (1 mg/kg) orally 2 and 16 h, respectively, before infection. (a and b) LTB4 (0.1 μg) or (c and d) PAF (1 μg) injection (in 1 mL PBS vehicle) into the air pouch. Vehicle-treated mice received an oral administration of 0.5% CMC or water. PMN numbers in air pouch were determined as described in Materials and Methods. Data are the mean ± SEM of n = 6–12 (a and b) or of n = 6–8 (c and d). *P < 0.05 versus vehicle noninfected mice (PBS into air pouch); #P < 0.05 versus noninfected mice (agonist into air pouch). †P < 0.05 versus infected mice (agonist into air pouch).
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fig2: Effect of SR-27417 and CP-105,696 administration on PMN numbers in air pouch of C57Bl/6 mice. (a and c) Noninfected mice and (b and d) Hc-infected mice (i.t., 5 × 105 Hc yeast) were pretreated with SR-27417 (0.1 mg/kg) and/or CP-105,696 (1 mg/kg) orally 2 and 16 h, respectively, before infection. (a and b) LTB4 (0.1 μg) or (c and d) PAF (1 μg) injection (in 1 mL PBS vehicle) into the air pouch. Vehicle-treated mice received an oral administration of 0.5% CMC or water. PMN numbers in air pouch were determined as described in Materials and Methods. Data are the mean ± SEM of n = 6–12 (a and b) or of n = 6–8 (c and d). *P < 0.05 versus vehicle noninfected mice (PBS into air pouch); #P < 0.05 versus noninfected mice (agonist into air pouch). †P < 0.05 versus infected mice (agonist into air pouch).

Mentions: In another series of experiments, we investigated whether administration of specific anti-inflammatory drugs promotes further blockade of PMN influx to the air pouch cavity of infected mice. To this aim, mice were pretreated orally with either CP-105,696, a selective and potent noncompetitive antagonist of BLT1 receptors [8] or SR-27417, a selective and potent competitive PAF receptor antagonist [9], prior to agonist inoculation but after Hc infection. In other work, we demonstrated the efficacy for the CP-105,696 and SR-27417 treatment in the inhibition of LTB4- and PAF-elicited PMN accumulation in the dermis [3]. In our experiments, CP-105,696 (1 mg/kg) inhibited LTB4-elicited PMN accumulation by 71% (P < 0.05) (Figure 2(a)) and PAF-elicited PMN accumulation by 65% (P < 0.05) (Figure 2(c)) in the air pouch. CP-105,696 or SR-27417 pretreatment also partially inhibited PMN recruitment elicited by PAF or LTB4. The concomitant administration of CP-105,696 and of SR-27417 exerted a cooperative inhibitory effect on PMN recruitment by either agonist (Figures 2(a) and 2(c)). In contrast, a single administration of CP-105,696 did not further decrease LTB4-elicited PMN influx to the air pouch cavity 48 h after inoculating Hc in C57Bl/6 mice (Figure 2(b)). Similar observations were made following pretreatment with a single oral dose of SR-27417: the reduced PMN infiltration in response to locally injected PAF in air pouch was not further inhibited by the antagonist (Figure 2(d)). Yet, a concomitant pretreatment with CP-105,696 and SR-27417 of infected animal was associated with a profound (~95%) inhibition of PMN accumulation stimulated by either agonists (Figures 2(b) and 2(d)).


Impairment of neutrophil migration to remote inflammatory site during lung histoplasmosis.

Medeiros AI, Secatto A, Bélanger C, Sorgi CA, Borgeat P, Marleau S, Faccioli LH - Biomed Res Int (2015)

Effect of SR-27417 and CP-105,696 administration on PMN numbers in air pouch of C57Bl/6 mice. (a and c) Noninfected mice and (b and d) Hc-infected mice (i.t., 5 × 105 Hc yeast) were pretreated with SR-27417 (0.1 mg/kg) and/or CP-105,696 (1 mg/kg) orally 2 and 16 h, respectively, before infection. (a and b) LTB4 (0.1 μg) or (c and d) PAF (1 μg) injection (in 1 mL PBS vehicle) into the air pouch. Vehicle-treated mice received an oral administration of 0.5% CMC or water. PMN numbers in air pouch were determined as described in Materials and Methods. Data are the mean ± SEM of n = 6–12 (a and b) or of n = 6–8 (c and d). *P < 0.05 versus vehicle noninfected mice (PBS into air pouch); #P < 0.05 versus noninfected mice (agonist into air pouch). †P < 0.05 versus infected mice (agonist into air pouch).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Effect of SR-27417 and CP-105,696 administration on PMN numbers in air pouch of C57Bl/6 mice. (a and c) Noninfected mice and (b and d) Hc-infected mice (i.t., 5 × 105 Hc yeast) were pretreated with SR-27417 (0.1 mg/kg) and/or CP-105,696 (1 mg/kg) orally 2 and 16 h, respectively, before infection. (a and b) LTB4 (0.1 μg) or (c and d) PAF (1 μg) injection (in 1 mL PBS vehicle) into the air pouch. Vehicle-treated mice received an oral administration of 0.5% CMC or water. PMN numbers in air pouch were determined as described in Materials and Methods. Data are the mean ± SEM of n = 6–12 (a and b) or of n = 6–8 (c and d). *P < 0.05 versus vehicle noninfected mice (PBS into air pouch); #P < 0.05 versus noninfected mice (agonist into air pouch). †P < 0.05 versus infected mice (agonist into air pouch).
Mentions: In another series of experiments, we investigated whether administration of specific anti-inflammatory drugs promotes further blockade of PMN influx to the air pouch cavity of infected mice. To this aim, mice were pretreated orally with either CP-105,696, a selective and potent noncompetitive antagonist of BLT1 receptors [8] or SR-27417, a selective and potent competitive PAF receptor antagonist [9], prior to agonist inoculation but after Hc infection. In other work, we demonstrated the efficacy for the CP-105,696 and SR-27417 treatment in the inhibition of LTB4- and PAF-elicited PMN accumulation in the dermis [3]. In our experiments, CP-105,696 (1 mg/kg) inhibited LTB4-elicited PMN accumulation by 71% (P < 0.05) (Figure 2(a)) and PAF-elicited PMN accumulation by 65% (P < 0.05) (Figure 2(c)) in the air pouch. CP-105,696 or SR-27417 pretreatment also partially inhibited PMN recruitment elicited by PAF or LTB4. The concomitant administration of CP-105,696 and of SR-27417 exerted a cooperative inhibitory effect on PMN recruitment by either agonist (Figures 2(a) and 2(c)). In contrast, a single administration of CP-105,696 did not further decrease LTB4-elicited PMN influx to the air pouch cavity 48 h after inoculating Hc in C57Bl/6 mice (Figure 2(b)). Similar observations were made following pretreatment with a single oral dose of SR-27417: the reduced PMN infiltration in response to locally injected PAF in air pouch was not further inhibited by the antagonist (Figure 2(d)). Yet, a concomitant pretreatment with CP-105,696 and SR-27417 of infected animal was associated with a profound (~95%) inhibition of PMN accumulation stimulated by either agonists (Figures 2(b) and 2(d)).

Bottom Line: Our results show that pulmonary Hc infection impairs LTB4- or PAF-stimulated PMN recruitment to air pouch.Yet, remote inflammation did not modify PMN numbers in the bronchoalveolar lavage fluid (BALF) of Hc-infected mice.Along that line, our results show that PAF-elicited PMN chemotaxis was abrogated in 5-lipoxygenase-deficient animals.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, UNESP, 14801-902 Araraquara, SP, Brazil.

ABSTRACT
Histoplasma capsulatum (Hc) induces a pulmonary disease in which leukotrienes promote activation and recruitment of effectors cells. It is also well-recognized that leukotriene B4 (LTB4) and platelet-activating factor (PAF) induce leukocyte recruitment to inflammatory sites. We investigated the impact of pulmonary Hc infection on PMN migration to a remote inflammatory site. Our results show that pulmonary Hc infection impairs LTB4- or PAF-stimulated PMN recruitment to air pouch. Yet, remote inflammation did not modify PMN numbers in the bronchoalveolar lavage fluid (BALF) of Hc-infected mice. Interestingly, the concomitant administration of PAF and LTB4 receptor antagonists inhibited PMN recruitment to both BALF and the remote site, demonstrating cooperation between both mediators. Along that line, our results show that PAF-elicited PMN chemotaxis was abrogated in 5-lipoxygenase-deficient animals. These results suggest caution in the indiscriminate use of anti-inflammatory drugs during infectious diseases.

Show MeSH
Related in: MedlinePlus