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Bacterial infection triggers exacerbation of established pulmonary fibrosis in mice: Impact on lung protective immunity

: Ueberberg, Bianca; Janze, Ann-Kathrin; Steinwede, Kathrin; Maus, Regina; Magel, Lavinia; Hoymann, Heinz-Gerd; Braun, Armin; Langer, Florian; Jonigk, Danny; Kolb, Martin; Gauldie, Jack; Welte, Tobias; Maus, Ulrich A.

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A3921
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
Fraunhofer ITEM ()

Introduction: Patients developing lung fibrosis have an increased risk for recurrent bacterial infections, and bacterial infections per se are considered to be a risk factor for exacerbation of pulmonary fibrosis in humans. We here employed a two-hit model of pulmonary fibrosis and consecutive bacterial pneumonia induced by Streptococcus pneumoniae (Spn) or Klebsiella pneumoniae (Kpn) to characterize lung host defense mechanisms of fibrosing lungs and to examine whether bacterial pneumonia would trigger exacerbation of lung fibrosis in mice.
Methods: Mice received intratracheal instillations of an adenoviral vector encoding biologically active transforming growth factor-b1 (TGF b1) for induction of lung fibrosis or control vector. At 7, 14, and 21 days post-treatment, mice were mock-infected or infected with Spn or Kpn, and lung fibrosis was assessed in the absence or presence of bacterial infection by determination of lung collagen contents, Ashcroft scores, and invasive lung function measurements. In addition, bacterial loads were determined in BAL fluid and lung tissue of mice at 24-72 h post-infection.
Results: Mice treated with AdTGFb1 developed progressive fibrosis with lung collagen contents increasing by day 7 and peaking by days 14 and 21, overall resulting in decreased lung function. Mice infected with Spn or Kpn exhibited significantly increased lung CFU counts on day 7 but not on day 14 of fibrosis induction, demonstrating that the severity of lung fibrosis itself does not impact on lung protective immunity against bacterial challenge. Importantly, both Spn and Kpn were able to trigger exacerbation of lung fibrosis in mice, which again was accompanied by a further decreased lung function. However, exacerbation of lung fibrosis did not further impair lung protective immunity against Spn or Kpn challenge relative to non-exacerbated lung fibrosis.
Conclusion: This is the first report showing that bacterial infections may trigger exacerbation of established lung fibrosis in mice. Moreover, the degree of lung collagen deposition itself does not influence lung protective immunity against major lung-tropic Gram-positive and -negative bacterial pathogens. In this line, Spn- and Kpn-induced exacerbation of lung fibrosis did not further attenuate lung antibacterial responses in mice. This two-hit fibrosis/infection model may allow preclinical evaluation of novel antibacterial/immunomodulatory strategies to inhibit bacterial pathogen-induced exacerbation of lung fibrosis in patients.