Effects of Intratracheal Administration of Novispirin G10 on a Rat Model of Mucoid Pseudomonas aeruginosa Lung Infection

Abstract

Chronic Pseudomonas aeruginosa lung infection is a major problem for patients with cystic fibrosis (CF). The biofilm mode of growth of the pathogen makes it highly resistant to antibiotic treatment, and this is especially pronounced with mucoid strains. In this study, novispirin G10, a synthetic antimicrobial peptide patterned loosely on sheep myeloid antimicrobial peptide 29, was tested in a rat model of mucoid P. aeruginosa lung infection. P. aeruginosa NH57388A, a mucoid strain isolated from a CF patient, was mixed with the alginate produced by the bacterium itself and adjusted to a concentration of 10 10 CFU/ml. Each rat received 10 9 CFU of bacteria intratracheally in the left lung to establish lung infection. At 0 and 3 h post P. aeruginosa infection, the treated group of rats received novispirin G10 (0.1 mg/ml, 0.1 ml/rat) intratracheally, whereas the control group received vehicle treatment only. The animals were sacrificed on days 3, 5, 7, and 10 after challenge for evaluation of various parameters. On day 5, 50% of the rats in the treated group had cleared the bacteria from the lungs, whereas in the control group, none of the rats cleared the pathogen (P < 0.03). The average bacterial loads remaining in the lungs of treated rats on days 3 and 5 were more than 170-and 330-fold lower than in the control groups (P < 0.0005 and P < 0.0003). In accordance, the macroscopic and microscopic lung pathology was also significantly milder in the treated group compared to the control group (P < 0.0002). Lung cytokine responses in the treated group were significantly lower than in the control group. The results suggest that novispirin G10 might be useful in treating antibiotic-resistant P. aeruginosa lung infections.

Administration of nonviral gene vector encoding rat β‐defensin‐2 ameliorates chronic Pseudomonas aeruginosa lung infection in rats

“…Macroscopic lung pathology was expressed as the lung index of macroscopic pathology (LIMP), which was calculated by dividing the area of the lung showing pathological changes by the total area of the whole lung 39, 41. In addition, the gross pathological changes in the lungs were also assigned four different scores according to the severity of the inflammation as previously described 38, 40, 42: I, normal lungs; II, swollen lungs, hyperemia, and small atelectasis (<10 mm 2 ); III, pleural adhesions and atelectasis (<40 mm 2 ); and IV, abscesses, large atelectasis, and hemorrhages. The evaluation was conducted in a double‐blind way to avoid bias.…”

Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

“…The 'embedded bacteria model' is particularly challenging since there is extensive neutrophil influx in response to the P. aeruginosa-laden beads, which may cause airway obstruction; effective gas exchange is not always optimal and a small percentage of animals may die. Given its simplicity and efficacy, this very first model of chronic bronchopulmonary infection with P. aeruginosa using agarose beads is still frequently used today ( The use of alginate in several studies as a substitute for agar beads was attempted because it mimics natural conditions in CF lungs where bacteria are embedded with alginate in confluent biofilms (Wu et al 2001, Ciofu et al 2002, Wu et al 2004, Song et al 2005. The alginate bead model closely resembles the later stages of CF lung infection and offers the theoretical advantage of using a substance which is chemically similar to the alginate produced in vivo by P. aeruginosa (Pedersen et al 1990).…”

Therapy of Murine Pulmonary Aspergillosis with Antibody-Alliinase Conjugates and Alliin

“…To establish a proof of principle for treating murine invasive pulmonary aspergillosis with the MAb-alliinase conjugate and alliin, we chose the intratracheal route of administration (17) for both the conjugate and the alliin. Intratracheal treatment has been shown to provide in some cases an increased therapeutic benefit (34,49) in comparison to parenteral or other nonparenteral routes. Furthermore, since the pulmonary infection is predominant in cases of aspergillosis, i.t.…”