Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice

Alpha-1 antitrypsin (AAT) is a major inhibitor of serine proteases in mammals. Therefore, its deficiency leads to protease-antiprotease imbalance and a risk for developing lung emphysema. Although therapy with human plasma-purified AAT attenuates AAT deficiency-related emphysema, its impact on lung antibacterial immunity is poorly defined. Here, we examined the effect of AAT therapy on lung protective immunity in AAT-deficient (KO) mice challenged with Streptococcus pneumoniae. AAT-KO mice were highly susceptible to S. pneumoniae, as determined by severe lobar pneumonia and early mortality. Mechanistically, we found that neutrophil-derived elastase (NE) degraded the opsonophagocytically important collectins, surfactant protein A (SP-A) and D (SP-D), which was accompanied by significantly impaired lung bacterial clearance in S. pneumoniae-infected AAT-KO mice. Treatment of S. pneumoniae-infected AAT-KO mice with human AAT protected SP-A and SP-D from NE-mediated degradation and corrected the pulmonary pathology observed in these mice. Likewise, treatment with Sivelestat, a specific inhibitor of NE, also protected collectins from degradation and significantly decreased bacterial loads in S. pneumoniae-infected AAT-KO mice. Our findings show that NE is responsible for the degradation of lung SP-A and SP-D in AAT-KO mice affecting lung protective immunity in AAT deficiency

S100A9 is indispensable for survival of pneumococcal pneumonia in mice

S100A8/A9 has important immunomodulatory roles in antibacterial defense, but its relevance in focal pneumonia caused by Streptococcus pneumoniae (S. pneumoniae) is understudied. We show that S100A9 was significantly increased in BAL fluids of patients with bacterial but not viral pneumonia and correlated with procalcitonin and sequential organ failure assessment scores. Mice deficient in S100A9 exhibited drastically elevated Zn$^{2+}$ levels in lungs, which led to bacterial outgrowth and significantly reduced survival. In addition, reduced survival of S100A9 KO mice was characterized by excessive release of neutrophil elastase, which resulted in degradation of opsonophagocytically important collectins surfactant proteins A and D. All of these features were attenuated in S. pneumoniae-challenged chimeric WT→S100A9 KO mice. Similarly, therapy of S. pneumoniae-infected S100A9 KO mice with a mutant S100A8/A9 protein showing increased half-life significantly decreased lung bacterial loads and lung injury. Collectively, S100A9 controls central antibacterial immune mechanisms of the lung with essential relevance to survival of pneumococcal pneumonia. Moreover, S100A9 appears to be a promising biomarker to distinguish patients with bacterial from those with viral pneumonia. Trial registration: Clinical Trials register (DRKS00000620)

Cycle duration and quality of gladiolus floral stems in three locations of Southern Brazil

The objective of this study was to determine the cycle duration in days and the quantitative parameters, i.e. stem length, spike length and stem diameter of gladiolus floral stems as a function of the planting date and locations in the Rio Grande do Sul/Brazil. Field experiments were established between 2014-2015 in three locations (Frederico Westphalen, Itaqui and Santa Maria). The experimental design was a complete randomized block, with six gladiolus cultivars in three distinct planting dates at each location as treatments. The shift from vegetative to reproductive stage, the stem length, spike length and stem diameter were evaluated. Data was statistically analyzed by ANOVA and Tukey test. When planted during late July and early August, cultivars of early cycle (‘Purple Flora’, ‘Rose Friendship’ and ‘White Friendship’) and intermediate cycle (‘Green Star’ and ‘Jester’), produced floral stems of gladiolus in the desired patterns besides as well as having a shorter growth cycle than late cultivars (‘Gold Field’), being recommended for commercial cultivation in Southern Brazil

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Role of mincle in alveolar macrophage-dependent innate immunity against mycobacterial infections in mice

The role of macrophage-inducible C-type lectin Mincle in lung innate immunity against mycobacterial infection is incompletely defined. In this study, we show that wild-type (WT) mice responded with a delayed Mincle induction on resident alveolar macrophages and newly immigrating exudate macrophages to infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG), peaking by days 14-21 posttreatment. As compared with WT mice, Mincle knockout (KO) mice exhibited decreased proinflammatory mediator responses and leukocyte recruitment upon M. bovis BCG challenge, and they demonstrated increased mycobacterial loads in pulmonary and extrapulmonary organ systems. Secondary mycobacterial infection on day 14 after primary BCG challenge led to increased cytokine gene expression in sorted alveolar macrophages of WT mice, but not Mincle KO mice, resulting in substantially reduced alveolar neutrophil recruitment and increased mycobacterial loads in the lungs of Mincle KO mice. Collectively, these data show that WT mice respond with a relatively late Mincle expression on lung sentinel cells to M. bovis BCG infection. Moreover, M. bovis BCG-induced upregulation of C-type lectin Mincle on professional phagocytes critically shapes antimycobacterial responses in both pulmonary and extrapulmonary organ systems of mice, which may be important for elucidating the role of Mincle in the control of mycobacterial dissemination in mice. Copyright © 2012 by The American Association of Immunologists, Inc.Fil: Behler, Friederike. Hannover Medical School; AlemaniaFil: Steinwede, Kathrin. Hannover Medical School; AlemaniaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ueberberg, Bianca. Hannover Medical School; AlemaniaFil: Maus, Regina. Hannover Medical School; AlemaniaFil: Kirchhof, Gabriele. Hannover Medical School; AlemaniaFil: Yamasaki, Sho. Kyushu University; JapónFil: Welte, Tobias. Hannover Medical School; AlemaniaFil: Maus, Ulrich A.. Hannover Medical School; Alemani

Adenoviral vector-mediated GM-CSF gene transfer improves anti-mycobacterial immunity in mice - role of regulatory T cells.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in differentiation, survival and activation of myeloid and non-myeloid cells with important implications for lung antibacterial immunity. Here we examined the effect of pulmonary adenoviral vector-mediated delivery of GM-CSF (AdGM-CSF) on anti-mycobacterial immunity in M. bovis BCG infected mice. Exposure of M. bovis BCG infected mice to AdGM-CSF either applied on 6h, or 6h and 7days post-infection substantially increased alveolar recruitment of iNOS and IL-12 expressing macrophages, and significantly increased accumulation of IFNγpos T cells and particularly regulatory T cells (Tregs). This was accompanied by significantly reduced mycobacterial loads in the lungs of mice. Importantly, diphtheria toxin-induced depletion of Tregs did not influence mycobacterial loads, but accentuated immunopathology in AdGM-CSF-exposed mice infected with M. bovis BCG. Together, the data demonstrate that AdGM-CSF therapy improves lung protective immunity against M. bovis BCG infection in mice independent of co-recruited Tregs, which however critically contribute to limit lung immunopathology in BCG-infected mice. These data may be relevant to the development of immunomodulatory strategies to limit immunopathology-based lung injury in tuberculosis in humans

Bacterial infection triggers exacerbation of established pulmonary fibrosis in mice: Impact on lung protective immunity

Introduction: Patients developing lung fibrosis have an increased risk for recurrent bacterial infections, and bacterial infections per se are considered to be a risk factor for exacerbation of pulmonary fibrosis in humans. We here employed a two-hit model of pulmonary fibrosis and consecutive bacterial pneumonia induced by Streptococcus pneumoniae (Spn) or Klebsiella pneumoniae (Kpn) to characterize lung host defense mechanisms of fibrosing lungs and to examine whether bacterial pneumonia would trigger exacerbation of lung fibrosis in mice. Methods: Mice received intratracheal instillations of an adenoviral vector encoding biologically active transforming growth factor-b1 (TGF b1) for induction of lung fibrosis or control vector. At 7, 14, and 21 days post-treatment, mice were mock-infected or infected with Spn or Kpn, and lung fibrosis was assessed in the absence or presence of bacterial infection by determination of lung collagen contents, Ashcroft scores, and invasive lung function measurements. In addition, bacterial loads were determined in BAL fluid and lung tissue of mice at 24-72 h post-infection. Results: Mice treated with AdTGFb1 developed progressive fibrosis with lung collagen contents increasing by day 7 and peaking by days 14 and 21, overall resulting in decreased lung function. Mice infected with Spn or Kpn exhibited significantly increased lung CFU counts on day 7 but not on day 14 of fibrosis induction, demonstrating that the severity of lung fibrosis itself does not impact on lung protective immunity against bacterial challenge. Importantly, both Spn and Kpn were able to trigger exacerbation of lung fibrosis in mice, which again was accompanied by a further decreased lung function. However, exacerbation of lung fibrosis did not further impair lung protective immunity against Spn or Kpn challenge relative to non-exacerbated lung fibrosis. Conclusion: This is the first report showing that bacterial infections may trigger exacerbation of established lung fibrosis in mice. Moreover, the degree of lung collagen deposition itself does not influence lung protective immunity against major lung-tropic Gram-positive and -negative bacterial pathogens. In this line, Spn- and Kpn-induced exacerbation of lung fibrosis did not further attenuate lung antibacterial responses in mice. This two-hit fibrosis/infection model may allow preclinical evaluation of novel antibacterial/immunomodulatory strategies to inhibit bacterial pathogen-induced exacerbation of lung fibrosis in patients