elafin and Pneumonia

The mammalian target of rapamycin (mTOR) inhibitor class of drugs represents the newest addition to the armamentarium of therapies for hormonally driven breast cancer. It has recently been shown that the addition of mTOR inhibitor everolimus to aromatase inhibitors in hormone receptor-positive breast cancers improves progression-free survival. However, a clinically significant toxicity associated with this class of drugs is the development of noninfectious pneumonitis (NIP). Although generally mild and manageable, everolimus-induced NIP requires prompt diagnosis and management. This article will provide a brief overview of data relating to dysregulation of the phosphatidylinositol-3-kinase/protein kinase B/mTOR pathway in breast cancer; review the literature relating to the efficacy and safety of mTOR inhibitors in breast cancer; and evaluate the incidence, severity, and optimal management of mTOR inhibitor-related NIP in breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cough; Dyspnea; Elafin; Everolimus; Female; Humans; Incidence; Pneumonia; Proto-Oncogene Proteins c-akt; Severity of Illness Index; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Elafin is a serine protease inhibitor produced by epithelial and immune cells with anti-inflammatory properties. Research has shown that dysregulated protease activity may elicit proteolytic cleavage of elafin, thereby impairing the innate immune function of the protein. The aim of this study was to generate variants of elafin (GG- and QQ-elafin) that exhibit increased protease resistance while retaining the biological properties of wild-type (WT) elafin. Similar to WT-elafin, GG- and QQ-elafin variants retained antiprotease activity and susceptibility to transglutaminase-mediated fibronectin cross-linking. However, in contrast to WT-elafin, GG- and QQ-elafin displayed significantly enhanced resistance to degradation when incubated with bronchoalveolar lavage fluid from patients with cystic fibrosis. Intriguingly, both variants, particularly GG-elafin, demonstrated improved lipopolysaccharide (LPS) neutralization properties in vitro. In addition, GG-elafin showed improved anti-inflammatory activity in a mouse model of LPS-induced acute lung inflammation. Inflammatory cell infiltration into the lung was reduced in lungs of mice treated with GG-elafin, predominantly neutrophilic infiltration. A reduction in MCP-1 levels in GG-elafin treated mice compared to the LPS alone treatment group was also demonstrated. GG-elafin showed increased functionality when compared to WT-elafin and may be of future therapeutic relevance in the treatment of lung diseases characterized by a protease burden.

Topics: Amino Acid Sequence; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cystic Fibrosis; Elafin; Fibronectins; Gene Expression; Humans; Kinetics; Lipopolysaccharides; Lung; Male; Mice; Molecular Sequence Data; Pneumonia; Protease Inhibitors; Protein Engineering; Protein Isoforms; Proteolysis; Recombinant Proteins; Transglutaminases

Mechanical ventilation (MV) with O(2)-rich gas (MV-O(2)) offers life-saving treatment for newborn infants with respiratory failure, but it also can promote lung injury, which in neonates translates to defective alveolar formation and disordered lung elastin, a key determinant of lung growth and repair. Prior studies in preterm sheep and neonatal mice showed that MV-O(2) stimulated lung elastase activity, causing degradation and remodeling of matrix elastin. These changes yielded an inflammatory response, with TGF-β activation, scattered elastic fibers, and increased apoptosis, culminating in defective alveolar septation and arrested lung growth. To see whether sustained inhibition of elastase activity would prevent these adverse pulmonary effects of MV-O(2), we did studies comparing wild-type (WT) and mutant neonatal mice genetically modified to express in their vascular endothelium the human serine elastase inhibitor elafin (Eexp). Five-day-old WT and Eexp mice received MV with 40% O(2) (MV-O(2)) for 24-36 h. WT and Eexp controls breathed 40% O(2) without MV. MV-O(2) increased lung elastase and MMP-9 activity, resulting in elastin degradation (urine desmosine doubled), TGF-β activation (pSmad-2 increased 6-fold), apoptosis (cleaved-caspase-3 increased 10-fold), and inflammation (NF-κB activation, influx of neutrophils and monocytes) in lungs of WT vs. unventilated controls. These changes were blocked or blunted during MV-O(2) of Eexp mice. Scattered lung elastin and emphysematous alveoli observed in WT mice after 36 h of MV-O(2) were attenuated in Eexp mice. Both WT and Eexp mice showed defective VEGF signaling (decreased lung VEGF-R2 protein) and loss of pulmonary microvessels after lengthy MV-O(2), suggesting that elafin's beneficial effects during MV-O(2) derived primarily from preserving matrix elastin and suppressing lung inflammation, thereby enabling alveolar formation during MV-O(2). These results suggest that degradation and remodeling of lung elastin can contribute to defective lung growth in response to MV-O(2) and might be targeted therapeutically to prevent ventilator-induced neonatal lung injury.

Topics: Animals; Animals, Newborn; Apoptosis; Elafin; Endothelium, Vascular; Female; Humans; Immunoblotting; Immunoenzyme Techniques; Macrophages; Male; Mice; Mice, Transgenic; Monocytes; Neutrophils; Oxygen; Pancreatic Elastase; Pneumonia; Pulmonary Alveoli; Real-Time Polymerase Chain Reaction; Respiration, Artificial; Respiratory Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Vascular Endothelial Growth Factor Receptor-2; Ventilator-Induced Lung Injury