Timeline representation of the experimental protocol.

<p>First randomization: pressure-controlled ventilation (PCV) or pressure support ventilation (PSV). Second randomization: intra-abdominal hypertension (IAH) or normal intra-abdominal pressure (nIAP). Start: immediately after surgery (Sham) or IAH induction at PCV or PSV. V_T, tidal volume; PEEP, positive-end expiratory pressure; FiO₂, fraction of inspired oxygen. Mechanics and arterial blood gases were evaluated at Start and End (after 1 h of mechanical ventilation in PCV or PSV).</p

Arterial blood gases at Start and End.

<p>Arterial blood gases at Start and End.</p

Real-time polymerase chain reaction analysis of biological markers associated with inflammation (interleukin [IL]-6), fibrogenesis (type III procollagen [PCIII]), pulmonary stretch (amphiregulin), type II epithelial cell damage (surfactant protein [SP]-B), and endothelial cell damage (vascular cellular adhesion molecule [VCAM-1]) in animals with normal intra-abdominal pressure (nIAP) or intra-abdominal hypertension (IAH) mechanically ventilated in pressure-controlled ventilation (PCV) or pressure support ventilation (PSV) mode.

<p>Values are given as medians, interquartile ranges, and minimum/maximum of 6 animals in each group. Relative gene expression was calculated as a ratio of average gene expression compared with the reference gene (<i>36B4</i>) and expressed as fold change relative to non-ventilated (NV) animals. *Significantly different from NV (p<0.05). #Significantly different from PCV (p<0.05).</p

Respiratory parameters at Start and End.

<p>Respiratory parameters at Start and End.</p

Cumulative DAD score (scores arithmetically averaged from two independent investigators) representing injury from alveolar collapse, interstitial edema, and septal thickening in animals with normal intra-abdominal pressure (nIAP) or intra-abdominal hypertension (IAH) mechanically ventilated in pressure-controlled ventilation (PCV) or pressure support ventilation (PSV) mode.

<p>NV: non-ventilated animals. Values are given as medians, interquartile ranges, and minimum/maximum of 6 animals in each group. Statistical significance was accepted at p < 0.05. *Significantly different from NV.</p

data_sheet_1_The Yin and Yang of Tyrosine Kinase Inhibition During Experimental Polymicrobial Sepsis.DOCX

<p>Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-α-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a dose-dependent fashion pointing toward an optimal therapeutic window for dasatinib dosage during polymicrobial sepsis. Dasatinib treatment may, therefore, provide a balanced immune response by preventing an overshooting inflammatory reaction on the one side and bacterial overgrowth on the other side.</p