Effects of the TLR2 Agonists MALP-2 and Pam3Cys in Isolated Mouse Lungs

Background: Gram-positive and Gram-negative bacteria are main causes of pneumonia or acute lung injury. They are recognized by the innate immune system via toll-like receptor-2 (TLR2) or TLR4, respectively. Among all organs, the lungs have the highest expression of TLR2 receptors, but little is known about the pulmonary consequences of their activation. Here we studied the effects of the TLR2/6 agonist MALP-2, the TLR2/1 agonist Pam 3Cys and the TLR4 agonist lipopolysaccharide (LPS) on pro-inflammatory responses in isolated lungs. Methodology/Principal Findings: Isolated perfused mouse lungs were perfused for 60 min or 180 min with MALP-2 (25 ng/ mL), Pam3Cys (160 ng/mL) or LPS (1 mg/mL). We studied mediator release by enzyme linked immunosorbent assay (ELISA), the activation of mitogen activated protein kinase (MAPK) and AKT/protein kinase B by immunoblotting, and gene induction by quantitative polymerase chain reaction. All agonists activated the MAPK ERK1/2 and p38, but neither JNK or AKT kinase. The TLR ligands upregulated the inflammation related genes Tnf, Il1b, Il6, Il10, Il12, Ifng, Cxcl2 (MIP-2a) and Ptgs2. MALP-2 was more potent than Pam 3Cys in inducing Slpi, Cxcl10 (IP10) and Parg. Remarkable was the strong induction of Tnc by MALP2, which was not seen with Pam 3Cys or LPS. The growth factor related genes Areg and Hbegf were not affected. In addition, all three TLR agonists stimulated the release of IL-6, TNF, CXCL2 and CXCL10 protein from the lungs

Variable Tidal Volumes Improve Lung Protective Ventilation Strategies in Experimental Lung Injury.

RATIONALE: Noisy ventilation with variable Vt may improve respiratory function in acute lung injury. OBJECTIVES: To determine the impact of noisy ventilation on respiratory function and its biological effects on lung parenchyma compared with conventional protective mechanical ventilation strategies. METHODS: In a porcine surfactant depletion model of lung injury, we randomly combined noisy ventilation with the ARDS Network protocol or the open lung approach (n = 9 per group). MEASUREMENTS AND MAIN RESULTS: Respiratory mechanics, gas exchange, and distribution of pulmonary blood flow were measured at intervals over a 6-hour period. Postmortem, lung tissue was analyzed to determine histological damage, mechanical stress, and inflammation. We found that, at comparable minute ventilation, noisy ventilation (1) improved arterial oxygenation and reduced mean inspiratory peak airway pressure and elastance of the respiratory system compared with the ARDS Network protocol and the open lung approach, (2) redistributed pulmonary blood flow to caudal zones compared with the ARDS Network protocol and to peripheral ones compared with the open lung approach, (3) reduced histological damage in comparison to both protective ventilation strategies, and (4) did not increase lung inflammation or mechanical stress. CONCLUSIONS: Noisy ventilation with variable Vt and fixed respiratory frequency improves respiratory function and reduces histological damage compared with standard protective ventilation strategies. PMID: 19151194 [PubMed - indexed for MEDLINE] Free full tex

Variable tidal volumes improve lung protective ventilation strategies in experimental lung injury

Alysson R. Carvalho. Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta a informação no documento.Submitted by Repositório Arca ([email protected]) on 2019-04-24T16:24:09Z No. of bitstreams: 1 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-12-20T12:25:04Z (GMT) No. of bitstreams: 2 ve_Spieth_Peter_etal_INI_2009.pdf: 1110615 bytes, checksum: 5b89e0867f28624b1b5a89da559f85e7 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Made available in DSpace on 2019-12-20T12:25:04Z (GMT). No. of bitstreams: 2 ve_Spieth_Peter_etal_INI_2009.pdf: 1110615 bytes, checksum: 5b89e0867f28624b1b5a89da559f85e7 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2009University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.University of Insubria. Department of Ambient, Health and Safety. Varese, Italy.University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.University of Dresden. Institute of Anatomy. Dresden, Germany.University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.University of Aachen. Institute of Pharmacology and Toxicology. Aachen, Germany.University of Aachen. Institute of Pharmacology and Toxicology. Aachen, Germany.University of Aachen. Institute of Pharmacology and Toxicology. Aachen, Germany.University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.University Hospital Dresden. Department of Anesthesiology and Intensive Care Therapy. Dresden, Germany.Rationale: Noisy ventilation with variable VT may improve respiratory function in acute lung injury. Objectives: To determine the impact of noisy ventilation on respiratory functionand its biological effects on lung parenchyma compared with conventional protective mechanical ventilation strategies. Methods: In a porcine surfactant depletion model of lung injury, we randomly combined noisy ventilation with the ARDS Network protocol or the open lung approach (n 5 9 per group). Measurements and Main Results: Respiratory mechanics, gas exchange, and distribution of pulmonary blood flow were measured at intervals over a 6-hour period. Postmortem, lung tissue was analyzed to determine histological damage, mechanical stress, and inflammation. We found that,at comparable minute ventilation, noisy ventilation(1) improved arterial oxygenation and reduced mean inspiratory peak airway pressure and elastance of the respiratory system compared with the ARDS Network protocol and the open lung approach, (2) redistributed pulmonary blood flow to caudal zones compared with the ARDS Network protocol and to peripheral ones compared with the open lung approach, (3) reduced histological damage in comparison to both protective ventilation strategies, and (4) did not increase lung inflammation or mechanical stress. Conclusions: Noisy ventilation with variable VT and fixed respiratory frequency improves respiratory function and reduces histological damage compared with standard protective ventilation strategies

Validating excised rodent lungs for functional hyperpolarized xenon-129 MRI

Ex vivo rodent lung models are explored for physiological measurements of respiratory function with hyperpolarized (hp) 129Xe MRI. It is shown that excised lung models allow for simplification of the technical challenges involved and provide valuable physiological insights that are not feasible using in vivo MRI protocols. A custom designed breathing apparatus enables MR images of gas distribution on increasing ventilation volumes of actively inhaled hp 129Xe. Straightforward hp 129Xe MRI protocols provide residual lung volume (RV) data and permit for spatially resolved tracking of small hp 129Xe probe volumes during the inhalation cycle. Hp 129Xe MRI of lung function in the excised organ demonstrates the persistence of post mortem airway responsiveness to intravenous methacholine challenges. The presented methodology enables physiology of lung function in health and disease without additional regulatory approval requirements and reduces the technical and logistical challenges with hp gas MRI experiments. The post mortem lung functional data can augment histological measurements and should be of interest for drug development studies