The antifibrotic effect and mechanism of a novel tyrosine kinase inhibitor, ZSP1603, in preclinical models of pulmonary fibrosis.

OBJECTIVE: This study aimed to investigate the efficacy and molecular mechanisms of ZSP1603 as a novel anti-fibrotic compound. MATERIALS AND METHODS: The unilateral left pulmonary fibrosis model was established in the Sprague Dawley (SD) rats. The bilateral pulmonary fibrosis model was established in the C57BL/6J mice. The therapeutic treatment regimen began after the induction of pulmonary fibrosis. The preventive treatment regimen began on the first day of bleomycin administration. Animals were randomly divided into the sham, model, Nintedanib, and ZSP1603 treatment groups. Haematoxylin and eosin (H&E) and Masson's trichrome staining were performed to evaluate pulmonary injury, inflammation, and fibrosis. Cell Counting Kit-8 (CCK-8) assay and Western blot were used to investigate the effects and mechanisms of ZSP1603 on the proliferation of primary human pulmonary fibroblasts (pHPFs). The messenger ribonucleic acid (mRNA) expression of transforming growth factor (TGF)-ß1, tissue inhibitor of metalloproteinase 1 (TIMP-1), and collagen 1A1 (COL1A1) in pHPFs was detected by quantitative Real Time-Polymerase Chain Reaction (PCR). RESULTS: ZSP1603 inhibited the proliferation of pHPFs in vitro by blocking the platelet-derived growth factor receptor-ß (PDGF-Rß) and extracellular signal-regulated kinase (ERK) signalling pathway. ZSP1603 also inhibited the differentiation of pHPFs by reducing the expression of TGF-ß1, TIMP-1, and COL1A1. ZSP1603 significantly attenuated pulmonary injury, inflammation, and fibrosis in vivo in four independent animal studies of pulmonary fibrosis. CONCLUSIONS: ZSP1603 is an effective anti-fibrotic compound with clear mechanisms.

Propofol and memory: a study using a process dissociation procedure and functional magnetic resonance imaging.

Thirty volunteers randomly received either mild or deep propofol sedation, to assess its effect on explicit and implicit memory. Blood oxygen level-dependent functional magnetic resonance during sedation examined brain activation by auditory word stimulus and a process dissociation procedure was performed 4 h after scanning. Explicit memory formation did not occur in either group. Implicit memories were formed during mild but not deep sedation (p = 0.04). Mild propofol sedation inhibited superior temporal gyrus activation (Z value 4.37, voxel 167). Deep propofol sedation inhibited superior temporal gyrus (Z value 4.25, voxel 351), middle temporal gyrus (Z value 4.39, voxel 351) and inferior parietal lobule (Z value 5.06, voxel 239) activation. Propofol only abolishes implicit memory during deep sedation. The superior temporal gyrus is associated with explicit memory processing, while the formation of both implicit and explicit memories is associated with superior and middle temporal gyri and inferior parietal lobule activation.

Effect of midazolam on memory: a study of process dissociation procedure and functional magnetic resonance imaging.

To assess the effects of midazolam on explicit and implicit memories, 12 volunteers were randomly divided into the two groups: one with an Observer's Assessment of Alertness/Sedation score of 3 (mild sedation) and one with a score of 1 (deep sedation). Blood oxygen-level-dependent functional magnetic resonance imaging was measured before and during an auditory stimulus, then with midazolam sedation, and then during a second auditory stimulus with continuous midazolam sedation. After 4 h, explicit and implicit memories were assessed. There was no evidence of explicit memory at the two levels of midazolam sedation. Implicit memory was retained at a mild level of midazolam sedation but absent at a deep level of midazolam sedation. At a mild level of midazolam sedation, activation of all brain areas by auditory stimulus (as measured by functional magnetic resonance imaging) was uninhibited. However, a deep level of midazolam sedation depressed activation of the superior temporal gyrus by auditory stimulus. We conclude that midazolam does not abolish implicit memory at a mild sedation level, but can abolish both explicit and implicit memories at a deep sedation level. The superior temporal gyrus may be one of the target areas.

[Patient-controlled analgesia with lornoxicam in patients undergoing gynecological surgery].

OBJECTIVE: To assess the analgesic effect and side effects of PCA with lornoxicam compared with morphine and tramadol. METHODS: 89 patients, scheduled for elective hysterectomy or hysteromyomectomy, were randomly divided into Group L, Group M and Group T. Three drugs administered i.v. via a patient-controlled analgesia for up to 24 h postoperatively. RESULTS: Efficacy was assessed by comparing total pain relief (TOTPAR) and sum of pain intensity difference (SPID) over 24 h. Statistically significant equivalence of lornoxicam, morphine and tramadol was shown by TOTPAR values 15.2 +/- 3.9, 16.4 +/- 3.5 and 15.9 +/- 4.4, by SPID values 10.3 +/- 3.1, 9.0 +/- 2.0 and 9.2 +/- 4.7, respectively (P > 0.05). Lornoxicam caused fewer adverse events than morphine and tramadol (10.0%, 26.7% and 17.2% of patients, respectively). CONCLUSION: The study suggests that lornoxicam provides an alternative to morphine or tramadaol for the treatment of postoperative pain.

[Ondansetron on postoperative nausea and vomiting].

The efficacy and safety of prophylactic intravenous ondansetron on prevention of postoperative nausea and vomiting were investigated in 65 ASA grades I-III patients undergoing elective abdominal surgery and receiving general anesthesia. Patients received ondansetron 4mg i.v. prior to a standardized technique for induction and intubation. Anesthesia was maintained with N2O-O2 and enflurane. The results showed that, by ondansetron 4mg, nausea and emesis could be significantly decreased. The effect lasted around 24h postoperatively without sedation. No one developed vomiting and only 9 patients developed nausea. No changes on laboratory parameters as well as vital signs were observed. No side-effects related to ondansetron were found. In prophylaxis of postoperative nausea and vomiting, ondansetron is effective and safe.

Pulmonary lobar vascular resistances during constant and pulsatile flows.

We measured arterial and venous occlusion pressure profiles in left lower lobes of dog lungs perfused in constant flow and pulsatile flow. Initially, pulmonary arterial pressure, flow rate, and venous pressure were recorded during a series of inflow and outflow occlusions effected during constant flow perfusion. The perfusion was then made pulsatile and while keeping the same flow rate, a second series of vascular occlusions was performed. The arterial occlusion pressures measured with the two modes of perfusion were similar. During pulsatile perfusion, the variation in arterial pressure following an arterial occlusion varied with the timing of occlusion in the pressure cycle. The arterial pressure drop could be recovered by selecting the time-averaged pulmonary arterial pressure as the upstream pressure. During both types of perfusion, the venous occlusion curves were similar. The arterial and venous pressure drops were approximately 4.8 mm Hg and 4.2 mm Hg, respectively. We concluded that the longitudinal distribution of pulmonary vascular pressures can be inferred from occlusion measurements obtained in pulsatile flow.

Lung and chest wall mechanics in rabbits during high-frequency body-surface oscillation.

In eight anesthetized and tracheotomized rabbits, we studied the transfer impedances of the respiratory system during normocapnic ventilation by high-frequency body-surface oscillation from 3 to 15 Hz. The total respiratory impedance was partitioned into pulmonary and chest wall impedances to characterize the oscillatory mechanical properties of each component. The pulmonary and chest wall resistances were not frequency dependent in the 3- to 15-Hz range. The mean pulmonary resistance was 13.8 +/- 3.2 (SD) cmH2O.l-1.s, although the mean chest wall resistance was 8.6 +/- 2.0 cmH2O.l-1.s. The pulmonary elastance and inertance were 0.247 +/- 0.095 cmH2O/ml and 0.103 +/- 0.033 cmH2O.l-1.s2, respectively. The chest wall elastance and inertance were 0.533 +/- 0.136 cmH2O/ml and 0.041 +/- 0.063 cmH2O.l-1.s2, respectively. With a linear mechanical behavior, the transpulmonary pressure oscillations required to ventilate these tracheotomized animals were at their minimal value at 3 Hz. As the ventilatory frequency was increased beyond 6-9 Hz, both the minute ventilation necessary to maintain normocapnia and the pulmonary impedance increased. These data suggest that ventilation by body-surface oscillation is better suited for relatively moderate frequencies in rabbits with normal lungs.

Lung pressures and gas transport during high-frequency airway and chest wall oscillation.

The major goal of this study was to compare gas exchange, tidal volume (VT), and dynamic lung pressures resulting from high-frequency airway oscillation (HFAO) with the corresponding effects in high-frequency chest wall oscillation (HFCWO). Eight anesthetized paralyzed dogs were maintained eucapnic with HFAO and HFCWO at frequencies ranging from 1 to 16 Hz in the former and 0.5 to 8 Hz in the latter. Tracheal (delta Ptr) and esophageal (delta Pes) pressure swings, VT, and arterial blood gases were measured in addition to respiratory impedance and static pressure-volume curves. Mean positive pressure (25-30 cmH2O) in the chest cuff associated with HFCWO generation decreased lung volume by approximately 200 ml and increased pulmonary impedance significantly. Aside from this decrease in functional residual capacity (FRC), no change in lung volume occurred as a result of dynamic factors during the course of HFCWO application. With HFAO, a small degree of hyperinflation occurred only at 16 Hz. Arterial PO2 decreased by 5 Torr on average during HFCWO. VT decreased with increasing frequency in both cases, but VT during HFCWO was smaller over the range of frequencies compared with HFAO. delta Pes and delta Ptr between 1 and 8 Hz were lower than the corresponding pressure swings obtained with conventional mechanical ventilation (CMV) applied at 0.25 Hz. delta Pes was minimized at 1 Hz during HFCWO; however, delta Ptr decreased continuously with decreasing frequency and, below 2 Hz, became progressively smaller than the corresponding values obtained with HFAO and CMV.

Evaluation of lung mechanics in rabbits using short duration flow pulses.

An alternative method of evaluating pulmonary mechanical function that uses short duration flow pulses was applied in five adult rabbits with high frequency flow interruption (HFFI) at 4 cycles per second. Variations in the total pressure across the respiratory system were partitioned into separate lungs and chest wall components, and the mechanical impedance of each component was evaluated in the range of 4 to 40 Hz using cross and power spectral analysis and spectral averaging. The resistances, R, of the respiratory system, lungs, and chest wall were 23.5 (2.3 SD), 18.6 (2.8), and 4.9 (1.5) cm H2O.L-1.s, respectively. These values were similar to R obtained by the conventional method at ordinary rates of ventilation, with the exception of chest wall resistance, which was approximately 50% smaller than R obtained by the conventional method. The compliances of the respiratory system, lungs and chest wall were 1.40 (0.19), 2.88 (0.94), and 2.85 (0.86) ml.cm H2O-1, respectively. In all cases, compliance values obtained by pulse analysis were roughly 70% of the values obtained by the conventional method. The smaller compliance values obtained with the pulse method may reflect the multicompartment behavior of the lungs and chest wall at the high frequencies found in the pulse spectra. We conclude that the response of the respiratory system to short duration flow pulses may be used to evaluate pulmonary mechanical function. The brief duration of the flow pulse suggests that this method may be well suited to evaluate lung function in uncooperative subjects, particularly newborns and premature infants.

Gas exchange during high frequency flow-interruption in rabbits before and after bronchoalveolar lavage.

The performance of a high frequency flow-interrupter (HFFI) type neonatal ventilator was evaluated on nine adult rabbits (control) and on five adult rabbits after bronchoalveolar lavage (BAL). Tidal volumes and airway pressures were measured during conventional ventilation and during HFFI at rates of 4, 6, 8, 10, and 12 cycles/s. Tidal volumes were adjusted to maintain PaCO2 between 35 and 42 mm Hg in control rabbits and 35-55 mm Hg in BAL rabbits; a positive end-expiratory pressure of 4 cm H2O was applied to BAL rabbits to reduce atelectasis and improve gas exchange. The normalized tidal volume required to maintain PaCO2 within the specified range during HFFI varied between 2.02 ml/kg (0.30 SD) and 2.55 (0.41) in control rabbits and between 2.65 (0.57) and 2.97 (0.51) in BAL rabbits. In neither group did the normalized tidal volume vary systematically with the rate of ventilation (p less than 0.05). Mean airway pressures were lower during HFFI than during conventional ventilation in control rabbits but comparable in the BAL group. Peak inflation pressures were greater during HFFI than conventional ventilation in control rabbits but similar in the BAL group. End-expiratory lung volume was not affected by ventilation rate during HFFI in control rabbits. We conclude 1) that HFFI can maintain gas exchange in rabbits suffering from acute respiratory distress with airway pressures that are comparable to those measured during conventional ventilation and 2) the capacity of HFFI to ventilate the lungs with significantly lower airway pressures than conventional ventilation depends, in part, on the condition of the lungs.

Measurement of pleural pressure at low and high frequencies in normal rabbits.

In eight tracheotomized adult rabbits placed in the supine position, we employed a catheter-tip piezoresistive pressure transducer to measure esophageal pressure (Pes) and assessed the validity of taking the changes in Pes to be the changes in pleural pressure (Ppl). We applied an occlusion test in which the tracheal cannula was occluded during either spontaneous inspiratory efforts or body surface oscillations ranging from 3 to 50 Hz. The relationship between Pes and airway opening pressure (Pao) was recorded. In all instances, the changes in Pes and Pao were virtually identical in both amplitude and phase. We conclude that, as evaluated by the occlusion test, a catheter-tip pressure transducer placed in the esophagus of rabbits can give adequate estimation of local pleural changes up to at least 50 Hz.