Neutrophils are key players in acute lung injury. Once recruited from the circulation, these cells release cytotoxic molecules that lead to tissue disruption, so their blockade has been advocated to prevent lung damage. However, lung injury also occurs during neutropenia and usually involves a very poor outcome. There is emerging evidence that neutrophils not only contribute to that early damage but also orchestrate later repair. Neutrophils promote epithelial proliferation and are a source of proteases, which are required for the processing of the collagen scar and facilitation of cell migration. This article reviews the effects of neutrophils in repair after acute lung injury, focusing on their role as biovectors for proteases and other molecules involved in tissue remodeling.

Release of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.

Endotoxemia and sepsis trigger autophagy in lung tissue. Defective autophagy increases mortality and lung inflammation after endotoxemia. Impairment of autophagy results is perinuclear ATF3 sequestration. Starvation ameliorates lung injury by an autophagy-dependent mechanism.

The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may result in clinically relevant alveolar damage. We report that mechanical ventilation in mice increased the expression of Lamin-A, a major determinant of nuclear membrane stiffness, in alveolar epithelial cells. Lamin-A expression increased and nuclear membrane compliance decreased in human bronchial epithelial cells after a mechanical stretch stimulus and in a murine model of lung injury after positive-pressure ventilation. Reducing Lamin-A maturation by depletion of the protease-encoding gene preserved alveolar nuclear membrane compliance after mechanical ventilation in mice. Ventilator-induced proapoptotic gene expression changes and lung injury were reduced in mice lacking compared to wild-type control animals. Similarly, treatment with the human immunodeficiency virus protease inhibitors lopinavir and ritonavir reduced the accumulation of Lamin-A at nuclear membranes and preserved nuclear membrane compliance after mechanical ventilation, mimicking the protective phenotype of animals. These results show that the pathophysiological response to lung mechanical stretch is sensed by the nuclear membranes of lung alveolar cells, and suggest that protease inhibitors might be effective in preventing ventilator-induced lung injury.

• MMP-14 levels decrease in lungs from endotoxemic mice and serum from septic patients. • Mmp14 mice show increased lung injury and mortality following endotoxemia. • Absence of Mmp14 decreases activated MMP-2 and increases S100A9 levels in lung tissue. • MMP-14 ameliorates inflammation by promoting S100A9 cleavage by activated MMP-2.

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BackgroundMechanical ventilation can promote lung injury by triggering a pro-inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant benefits over other antibiotics in ventilated patients. We hypothesized that macrolides could decrease ventilator-induced lung injury.MethodsAdult mice were treated with vehicle, clarithromycin or levofloxacin, and randomized to receive mechanical ventilation with low (12 cmH2O, PEEP 2 cmH2O) or high (20 cmH2O, ZEEP) inspiratory pressures for 150 minutes. Histological lung injury, neutrophil infiltration, inflammatory mediators (NFκB activation, Cxcl2, IL-10) and levels of adhesion molecules (E-selectin, ICAM) and proteases (MMP-9 and MMP-2) were analyzed.ResultsThere were no differences among groups after low-pressure ventilation. Clarithromycin significantly decreased lung injury score and neutrophil count, compared to vehicle or levofloxacin, after high-pressure ventilation. Cxcl2 expression and MMP-2 and MMP-9 levels increased and IL-10 decreased after injurious ventilation, with no significant differences among treatment groups. Both clarithromycin and levofloxacin dampened the increase in NFκB activation observed in non-treated animals submitted to injurious ventilation. E-selectin levels increased after high pressure ventilation in vehicle- and levofloxacin-treated mice, but not in those receiving clarithromycin.ConclusionsClarithromycin ameliorates ventilator-induced lung injury and decreases neutrophil recruitment into the alveolar spaces. This could explain the advantages of macrolides in patients with acute lung injury and mechanical ventilation.

Noninvasive mechanical ventilation is associated with a lower risk of death in hematological patients with respiratory failure. Noninvasive mechanical ventilation failure may worsen the prognosis, mainly in less severe patients.