Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

The cysteine protease cathepsin C (CatC) activates granule-associated proinflammatory serine proteases in hematopoietic precursor cells. Its early inhibition in the bone marrow is regarded as a new therapeutic strategy for treating proteolysis-driven chronic inflammatory diseases, but its complete inhibition is elusive in vivo Controlling the activity of CatC may be achieved by directly inhibiting its activity with a specific inhibitor or/and by preventing its maturation. We have investigated immunochemically and kinetically the occurrence of CatC and its proform in human hematopoietic precursor cells and in differentiated mature immune cells in lung secretions. The maturation of proCatC obeys a multistep mechanism that can be entirely managed by CatS in neutrophilic precursor cells. CatS inhibition by a cell-permeable inhibitor abrogated the release of the heavy and light chains from proCatC and blocked ∼80% of CatC activity. Under these conditions the activity of neutrophil serine proteases, however, was not abolished in precursor cell cultures. In patients with neutrophilic lung inflammation, mature CatC is found in large amounts in sputa. It is secreted by activated neutrophils as confirmed through lipopolysaccharide administration in a nonhuman primate model. CatS inhibitors currently in clinical trials are expected to decrease the activity of neutrophilic CatC without affecting those of elastase-like serine proteases.

Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis

Background

It is unknown whether a conservative approach to fluid administration or deresuscitation (active removal of fluid using diuretics or renal replacement therapy) is beneficial following haemodynamic stabilisation of critically ill patients.

Purpose

To evaluate the efficacy and safety of conservative or deresuscitative fluid strategies in adults and children with acute respiratory distress syndrome (ARDS), sepsis or systemic inflammatory response syndrome (SIRS) in the post-resuscitation phase of critical illness.

Methods

We searched Medline, EMBASE and the Cochrane central register of controlled trials from 1980 to June 2016, and manually reviewed relevant conference proceedings from 2009 to the present. Two reviewers independently assessed search results for inclusion and undertook data extraction and quality appraisal. We included randomised trials comparing fluid regimens with differing fluid balances between groups, and observational studies investigating the relationship between fluid balance and clinical outcomes.

Results

Forty-nine studies met the inclusion criteria. Marked clinical heterogeneity was evident. In a meta-analysis of 11 randomised trials (2051 patients) using a random-effects model, we found no significant difference in mortality with conservative or deresuscitative strategies compared with a liberal strategy or usual care [pooled risk ratio (RR) 0.92, 95 % confidence interval (CI) 0.82–1.02, I2 = 0 %]. A conservative or deresuscitative strategy resulted in increased ventilator-free days (mean difference 1.82 days, 95 % CI 0.53–3.10, I2 = 9 %) and reduced length of ICU stay (mean difference −1.88 days, 95 % CI −0.12 to −3.64, I2 = 75 %) compared with a liberal strategy or standard care.

Conclusions

In adults and children with ARDS, sepsis or SIRS, a conservative or deresuscitative fluid strategy results in an increased number of ventilator-free days and a decreased length of ICU stay compared with a liberal strategy or standard care. The effect on mortality remains uncertain. Large randomised trials are needed to determine optimal fluid strategies in critical illness.