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. 2022 Oct 1;323(4):L438-L449.
doi: 10.1152/ajplung.00477.2021. Epub 2022 Aug 9.

Natriuretic peptide receptor-C mediates the inhibitory effect of atrial natriuretic peptide on neutrophil recruitment to the lung during acute lung injury

Elizabeth O Harrington  1   2   3 , Ashok Kumar  1 , Verida Leandre  4 , Zachary S Wilson  4 , Brianna Guarino  1   2   3 , Julie Braza  1 , Craig T Lefort  5   3 , James R Klinger  1   2   3
Affiliations

Natriuretic peptide receptor-C mediates the inhibitory effect of atrial natriuretic peptide on neutrophil recruitment to the lung during acute lung injury

Elizabeth O Harrington et al. Am J Physiol Lung Cell Mol Physiol. .

Abstract

Atrial natriuretic peptide (ANP) protects against acute lung injury (ALI), but the receptor that mediates this effect is not known. Transgenic mice with 0 (knockout), 1 (heterozygote), or 2 (wild-type) functional copies of Npr3, the gene that encodes for natriuretic peptide receptor-C (NPR-C), were treated with intravenous infusion of ANP or saline vehicle before oropharyngeal aspiration of Pseudomonas aeruginosa (PA103) or saline vehicle. Lung injury was assessed 4 h following aspiration by measurement of lung wet/dry (W/D) weight, whole lung leukocyte and cytokine levels, and protein, leukocyte, and cytokine concentration in bronchoalveolar lavage fluid (BALF). PA103 induced acute lung injury as evidenced by increases in lung W/D ratio and protein concentration in BALF. The severity of PA103-induced lung injury did not differ between NPR-C genotypes. Treatment with intravenous ANP infusion reduced PA103-induced increases in lung W/D and BALF protein concentration in all three NPRC genotypes. PA103 increased the percentage of leukocytes that were neutrophils and cytokine levels in whole lung and BALF in NPR-C wild-type and knockout mice. This effect was blunted by ANP in wild-type mice but not in the NPR-C knockout mice. NPR-C does not mediate the protective effect of ANP on endothelial cell permeability in settings of PA103-induced injury but may mediate the effect of ANP on inhibition of the recruitment of neutrophils to the lung and thereby attenuate the release of inflammatory cytokines.

Keywords: acute lung injury; atrial natriuretic peptide; cytokines; lung inflammation; natriuretic peptide receptor C.

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Conflict of interest statement

J.R.K. is a consultant for Palatin. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
qPCR analysis of NPR-C mRNA (NPR-3) expression in wild-type (NPR-C+/+), heterozygous (NPR-C+/−), and knockout mice (NPR-C−/−). mRNA expression of NPR3 was normalized to housekeeping gene β-actin relative to NPRC−/−. The ΔΔCT and 2-ΔΔCT (fold change) were calculated and used for a nonparametric Mann–Whitney test (***P ≤ 0.001, ****P ≤ 0.0001; n = 15 mice NPR-C+/+, 5 mice NPR-C+/−, 12 mice NPR-C−/−. NPR-C, natriuretic peptide receptor-C.
Figure 2.
Figure 2.
Lung wet/dry (W/D) ratio in natriuretic peptide receptor-C wild-type (NPR-C+/+), heterozygote (NPR-C+/−), and knockout (NPR-C−/−) mice treated with intravenous infusion of saline (NaCl) or atrial natriuretic peptide (ANP) and oropharyngeal aspiration of NaCl or Pseudomonas aeruginosa (PA103). n = 4–6 mice for each condition and genotype. *P < 0.05.
Figure 3.
Figure 3.
Protein concentration in bronchoalveolar lavage fluid (BALF) in natriuretic peptide receptor-C wild-type (NPR-C+/+), heterozygote (NPR-C+/−), and knockout (NPR-C−/−) mice treated with IV infusion of saline (NaCl) or atrial natriuretic peptide (ANP) and oropharyngeal aspiration of NaCl or Pseudomonas aeruginosa (PA103). n = 4–6 mice for each condition and genotype. *P < 0.05.
Figure 4.
Figure 4.
Total leukocyte counts (A) and percentage of neutrophils (B), Ly6Chi monocytes (C), and Ly6Cmid monocytes (D) in blood of natriuretic peptide receptor-C wild-type (NPR-C+/+) and knockout (NPR-C−/−) mice treated with infusion of saline followed by oropharyngeal aspiration of saline (NaCl/NaCl), infusion of saline and oropharyngeal aspiration of Pseudomonas aeruginosa (PA103; NaCl/PA103), infusion of atrial natriuretic peptide (ANP) followed by oropharyngeal aspiration of saline (ANP/NaCl), or infusion of ANP followed by oropharyngeal aspiration of PA103 (ANP/PA103). n = 6 mice for each condition and genotype. *P < 0.05.
Figure 5.
Figure 5.
Total leukocyte counts (A) and percentage of neutrophils (B), Ly6Chi monocytes (C), and Ly6Cmid monocytes (D) in whole lung homogenates obtained from natriuretic peptide receptor-C wild-type (NPR-C+/+) and knockout (NPR-C−/−) mice treated with infusion of saline followed by oropharyngeal aspiration of saline (NaCl/NaCl), infusion of saline and oropharyngeal aspiration of Pseudomonas aeruginosa (PA103; NaCl/PA103), infusion of atrial natriuretic peptide (ANP) followed by oropharyngeal aspiration of saline (ANP/NaCl), or infusion of ANP followed by oropharyngeal aspiration of PA103 (ANP/PA103). n = 6 mice for each condition and genotype. *P < 0.05.
Figure 6.
Figure 6.
Concentration of CXCL1/KC (A), CXCL2/MIP2 (B), tumor necrosis factor-α (TNFα; C), and interleukin-6 (IL-6; D) in whole lung homogenates obtained from natriuretic peptide receptor-C wild-type (NPR-C+/+) and knockout (NPR-C−/−) mice treated with infusion of saline followed by oropharyngeal aspiration of saline (NaCl/NaCl), infusion of saline and oropharyngeal aspiration of Pseudomonas aeruginosa (PA103; NaCl/PA103), infusion of atrial natriuretic peptide (ANP) followed by oropharyngeal aspiration of saline (ANP/NaCl), or infusion of ANP followed by oropharyngeal aspiration of PA103 (ANP/PA103). n = 6 mice for each condition and genotype. *P < 0.05.
Figure 7.
Figure 7.
Total leukocyte counts (A) and percentage of neutrophils (B), Ly6Chi monocytes (C), and Ly6Cmid monocytes (D) in bronchoalveolar lavage fluid (BALF) obtained from natriuretic peptide receptor-C wild-type (NPR-C+/+) and knockout (NPR-C−/−) mice treated with infusion of saline followed by oropharyngeal aspiration of saline (NaCl/NaCl), infusion of saline and oropharyngeal aspiration of Pseudomonas aeruginosa (PA103; NaCl/PA103), infusion of atrial natriuretic peptide (ANP) followed by oropharyngeal aspiration of saline (ANP/NaCl), or infusion of ANP followed by oropharyngeal aspiration of PA103 (ANP/PA103). n = 6 mice for each condition and genotype. *P < 0.05.
Figure 8.
Figure 8.
Concentration of CXCL1/KC (A), CXCL2/MIP2 (B), tumor necrosis factor-α (TNFα; C), and interleukin-6 (IL-6; D) in bronchoalveolar lavage fluid (BALF) obtained from natriuretic peptide receptor-C wild-type (NPR-C+/+) and knockout (NPR-C−/−) mice treated with infusion of saline followed by oropharyngeal aspiration of saline (NaCl/NaCl), infusion of saline and oropharyngeal aspiration of Pseudomonas aeruginosa (PA103; NaCl/PA103), infusion of atrial natriuretic peptide (ANP) followed by oropharyngeal aspiration of saline (ANP/NaCl), or infusion of ANP followed by oropharyngeal aspiration of PA103 (ANP/PA103). n = 6 mice for each condition and genotype. *P < 0.05.
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