Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 May;176(5):2219-27.
doi: 10.2353/ajpath.2010.090565. Epub 2010 Mar 19.

Ventilator-induced inflammatory response in lipopolysaccharide-exposed rat lung is mediated by angiotensin-converting enzyme

Roelie M Wösten-van Asperen  1 , René Lutter, Patricia A C Specht, Job B van Woensel, Chris M van der Loos, Sandrine Florquin, Burkhard Lachmann, Albert P Bos
Affiliations

Ventilator-induced inflammatory response in lipopolysaccharide-exposed rat lung is mediated by angiotensin-converting enzyme

Roelie M Wösten-van Asperen et al. Am J Pathol. 2010 May.

Abstract

Angiotensin-converting enzyme (ACE) mediates the ventilator-induced inflammatory response in healthy lungs via angiotensin II (Ang II). A rat model was used to examine the role of ACE and Ang II in the inflammatory response during mechanical ventilation of preinjured (ie, lipopolysaccharide [LPS]-exposed) lungs. When indicated, rats were pretreated with the ACE inhibitor captopril and/or intratracheal administration of LPS. The animals were ventilated for 4 hours with moderate pressure amplitudes. Nonventilated animals served as controls. ACE activity and levels of Ang II and inflammatory mediators (interleukin-6, Cytokine-induced Neutrophil Chemoattractant (CINC)-3, interleukin-1beta, and interleukin-10) were determined in bronchoalveolar lavage fluid (BALF). The localization of ACE and Ang II type 1 receptor in lung tissue was determined by immunohistochemistry. The role of the Ang II pathway was assessed by using its receptor antagonist Losartan. Mechanical ventilation of LPS-exposed animals increased ACE activity and levels of inflammatory mediators in BALF compared with ventilated nonexposed and LPS-exposed nonventilated animals. Blocking ACE by captopril attenuated the lung inflammatory response. Furthermore, increased ACE activity in BALF was accompanied by increased levels of Ang II and enhanced expression of its receptor on alveolar cells. Blocking the Ang II receptor attenuated the inflammatory mediator response to a larger extent than by blocking ACE. In conclusion, during mechanical ventilation ACE, via Ang II, mediates the inflammatory response of both healthy and preinjured lungs.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Static pressure-volume curves after 4 hours of mechanical ventilation of non-LPS exposed (circles) and LPS-exposed (squares) animals ventilated at PIP 26 cmH2O/PEEP 5 cmH2O, with (black circles and squares) or without (white circles and squares) pretreatment with captopril. Data are expressed as mean ± SD. N = 9 per group. *P < 0.05, LPS-exposed animals without captopril pretreatment compared with all other groups. **P < 0.05, LPS-exposed animals without captopril pretreatment compared with non-LPS exposed animals with or without captopril.
Figure 2
Figure 2
Whisker plots of ACE activity (A) and Ang II levels (B) in bronchoalveolar lavage fluid of non-LPS, nonventilated (controls), only MV, only LPS-exposed, and LPS-exposed MV (LPS + MV) animals with or without pretreatment with captopril. Animals were ventilated at PIP 26 cmH2O/PEEP 5 cmH2O. Data are expressed as median ± range. N = 6 per group. *P < 0.05, compared with nonventilated, non-LPS exposed animals (control); #P < 0.05, compared with nonventilated LPS-exposed (LPS only) and non-LPS exposed ventilated (MV only) animals; ‡P < 0.05 compared with ventilated LPS-exposed animals (LPS + MV) without captopril pretreatment.
Figure 3
Figure 3
Whisker plots of levels of interleukin (IL)-6 (A), CINC-3 (B), IL-1β (C), and IL-10 (D) in bronchoalveolar lavage fluid of non-LPS, nonventilated (controls), only MV, only LPS-exposed, and LPS-exposed MV (LPS + MV) animals with or without pretreatment with captopril. Animals were ventilated at PIP 26 cmH2O/PEEP 5 cmH2O. Data are expressed as median ± range. N = 6 per group. *P < 0.05, compared with non-LPS exposed nonventilated animals (control); **P < 0.05, compared with ventilated non-LPS exposed animals (MV only) without captopril pretreatment; #P < 0.05, compared with nonventilated LPS-exposed animals (LPS only) and ventilated non-LPS exposed animals (MV only); †P < 0.05, compared with non-LPS exposed, nonventilated (control) and ventilated (MV only) animals; ‡P < 0.05, compared with ventilated LPS-exposed animals (LPS + MV) without captopril pretreatment.
Figure 4
Figure 4
Whisker plots of protein content (A), interleukin (IL)-6 (B), CINC-3 (C), IL-1β (D), and IL-10 (E) in bronchoalveolar lavage fluid of LPS-exposed animals ventilated at PIP 26 cmH2O/PEEP 5 cmH2O without pretreatment or with pretreatment with captopril or Losartan. Data are expressed as median ± range. N = 6 per group. *P < 0.05, compared with no pretreatment.
Figure 5
Figure 5
H&E staining of lung tissue of non-LPS exposed, nonventilated (A and E) and MV (PIP 26 cmH2O/PEEP 5 cmH2O) animals (B and F), LPS-exposed nonventilated (C and G) and MV (PIP 26 cmH2O/PEEP 5 cmH2O) animals (D and H) without (A–D) or with (E–H) captopril pretreatment. Original magnification, ×20.
Figure 6
Figure 6
Immunohistochemistry for ACE in lung tissue of non-LPS exposed (A–C) or LPS-exposed (D–F) animals, which were either nonventilated (A and D) or MV (PIP 26 cmH2O/PEEP 5 cmH2O) without (B and E) or with (C and F) captopril pretreatment. Diffuse staining was found on endothelial cells and also on cells in the alveolar walls. Original magnification, ×20.
Figure 7
Figure 7
Dual immunohistochemistry for ACE (developed by vector blue) and macrophage marker ED-1 (A and B) or epithelial cell marker AE1/AE3 (C and D; both developed by liquid permanent red) in lung tissue of non-LPS exposed (A and C) or LPS-exposed (B and D) animals, which were ventilated with moderate pressure amplitudes (PIP 26 cmH2O/PEEP 5 cmH2O). Co-staining showed ACE-positive alveolar macrophages (arrows and insets) and ACE-positive alveolar epithelial cells (arrowheads). Original magnification, ×20; insets, ×100.
Figure 8
Figure 8
Immunohistochemistry for AT1 (antibody dilution 1:250) in lung tissue of non-LPS exposed animals ventilated with moderate pressure amplitudes (PIP 26 cmH2O/PEEP 5 cmH2O; A), nonventilated LPS-exposed animals (B), and LPS-exposed animals without (C) or with (D) captopril pretreatment ventilated with moderate pressure amplitudes (PIP 26 cmH2O/PEEP 5 cmH2O). AT1 positive cells (brown color) were found after intratracheal LPS instillation, with increasing surface area of AT1-positive cells after mechanical ventilation of these animals. Original magnification, ×20.
Figure 9
Figure 9
Dual immunohistochemistry for AT1 (developed by vector blue) and macrophage marker ED-1 (A) or epithelial cell marker AE1/AE3 (B; both developed by liquid permanent red) in lung tissue of LPS-exposed animals, which were ventilated with moderate pressure amplitudes (PIP 26 cmH2O/PEEP 5 cmH2O). Co-staining showed AT1-positive alveolar macrophages and alveolar epithelial cells. Original magnification, ×40.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349. - PubMed
    1. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Resp Crit Care Med. 1998;157:294–323. - PubMed
    1. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from barotrauma to biotrauma. Proc Assoc Am Physicians. 1998;110:482–488. - PubMed
    1. Frank JA, Parsons PE, Matthay MA. Pathogenetic significance of biological markers of ventilator-associated lung injury in experimental and clinical studies. Chest. 2006;130:1906–1914. - PMC - PubMed
    1. Altemeier WA, Matute-Bello G, Gharib SA, Glenny RW, Martin TR, Liles WC. Modulation of lipopolysaccharide-induced gene transcription and promotion of lung injury by mechanical ventilation. J Immunol. 2005;175:3369–3376. - PubMed