Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming.

Despite intense investigation, acute respiratory distress syndrome (ARDS) remains an enormous clinical problem for which no specific therapies currently exist. In this study, we used intratracheal lipopolysaccharide or Pseudomonas bacteria administration to model experimental acute lung injury (ALI) and to further understand mediators of the resolution phase of ARDS. Recent work demonstrates macrophages transition from a predominant proinflammatory M1 phenotype during acute inflammation to an anti-inflammatory M2 phenotype with ALI resolution. We tested the hypothesis that IL-4, a potent inducer of M2-specific protein expression, would accelerate ALI resolution and lung repair through reprogramming of endogenous inflammatory macrophages. In fact, IL-4 treatment was found to offer dramatic benefits following delayed administration to mice subjected to experimental ALI, including increased survival, accelerated resolution of lung injury, and improved lung function. Expression of the M2 proteins Arg1, FIZZ1, and Ym1 was increased in lung tissues following IL-4 treatment, and among macrophages, FIZZ1 was most prominently upregulated in the interstitial subpopulation. A similar trend was observed for the expression of macrophage mannose receptor (MMR) and Dectin-1 on the surface of alveolar macrophages following IL-4 administration. Macrophage depletion or STAT6 deficiency abrogated the therapeutic effect of IL-4. Collectively, these data demonstrate that IL-4-mediated therapeutic macrophage reprogramming can accelerate resolution and lung repair despite delayed use following experimental ALI. IL-4 or other therapies that target late-phase, proresolution pathways may hold promise for the treatment of human ARDS.

Foxp3+ regulatory T cells promote lung epithelial proliferation.

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3(+) regulatory T cells (Foxp3(+) T(reg) cells) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (lipopolysaccharide) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3(+) T(reg) cells in the lung during the course of resolution. To dissect the role that Foxp3(+) T(reg) cells exert on epithelial proliferation, we depleted Foxp3(+) T(reg) cells, which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3(+) T(reg) numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy, we found that Foxp3(+) T(reg) cells enhanced epithelial proliferation. Moreover, Foxp3(+) T(reg) cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3(+) T(reg) cells in repair of the lung epithelium.

Exposure of emergency medicine personnel to ionizing radiation during cervical spine radiography.

We studied the potential hazard of ionizing radiation exposure to health care workers who routinely stabilize the necks of trauma patients during cervical spine radiography. A clinical trauma model was developed using an Alderson RANDO Phantom artificial torso to simulate an actual patient. A radiation monitor was placed where a health care worker's fingers, hands, arms, and thyroid gland would be, and standard cervical spine radiographs were taken. The exposures to the finger positions then were repeated with the monitor inside a 0.5 mm lead-equivalent glove. The mean exposure to the finger for a single cross-table lateral radiograph was 174.5 mrem. The use of leaded gloves reduced this exposure to 0.3 mrem a 99.9% reduction). For a single series of lateral, anteroposterior, odontoid, and swimmer's views, the total mean measured unprotected exposure to the finger of the hand positioned nearest the radiographic tube was 681 mrem and the exposure to the finger of the opposite hand was 230 mrem. If these simulated exposures are indicative of actual patient situations, a health care worker who holds the head of a trauma patient four times each week with unshielded hands would receive more than twice the maximum allowable annual occupational radiation exposure to the extremities recommended by the National Council of Radiation Protection and Measurements. We conclude that health care workers who routinely stabilize the necks of trauma patients during cervical spine radiography may incur a radiation exposure risk and that 0.5-mm lead-equivalent gloves provide an effective barrier to ionizing radiation.