Pulmonary Inflammation and KRAS Mutation in Lung Cancer.

Chronic lung infection and lung cancer are two of the most important pulmonary diseases. Respiratory infection and its associated inflammation have been increasingly investigated for their role in increasing the risk of respiratory diseases including chronic obstructive pulmonary disease (COPD) and lung cancer. Kirsten rat sarcoma viral oncogene (KRAS) is one of the most important regulators of cell proliferation, differentiation, and survival. KRAS mutations are among the most common drivers of cancer. Lung cancer harboring KRAS mutations accounted for ~25% of the incidence but the relationship between KRAS mutation and inflammation remains unclear. In this chapter, we will describe the roles of KRAS mutation in lung cancer and how elevated inflammatory responses may increase KRAS mutation rate and create a vicious cycle of chronic inflammation and KRAS mutation that likely results in persistent potentiation for KRAS-associated lung tumorigenesis. We will discuss in this chapter regarding the studies of KRAS gene mutations in specimens from lung cancer patients and in animal models for investigating the role of inflammation in increasing the risk of lung tumorigenesis driven primarily by oncogenic KRAS.

Elastic behavior of model membranes with antimicrobial peptides depends on lipid specificity and d-enantiomers.

In an effort to provide new treatments for the global crisis of bacterial resistance to current antibiotics, we have used a rational approach to design several new antimicrobial peptides (AMPs). The present study focuses on 24-mer WLBU2 and its derivative, D8, with the amino acid sequence, RRWVRRVRRWVRRVVRVVRRWVRR. In D8, all of the valines are the d-enantiomer. We use X-ray low- and wide-angle diffuse scattering data to measure elasticity and lipid chain order. We show a good correlation between in vitro bacterial killing efficiency and both bending and chain order behavior in bacterial lipid membrane mimics; our results suggest that AMP-triggered domain formation could be the mechanism of bacterial killing in both Gram-positive and Gram-negative bacteria. In red blood cell lipid mimics, D8 stiffens and orders the membrane, while WLBU2 softens and disorders it, which correlate with D8's harmless vs. WLBU2's toxic behavior in hemolysis tests. These results suggest that elasticity and chain order behavior can be used to predict mechanisms of bactericidal action and toxicity of new AMPs.

Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor.

Asthma is a chronic airway disease characterized by inflammation, mucus hypersecretion and abnormal airway smooth muscle (ASM) contraction. Bacterial permeability family member A1, BPIFA1, is a secreted innate defence protein. Here we show that BPIFA1 levels are reduced in sputum samples from asthmatic patients and that BPIFA1 is secreted basolaterally from healthy, but not asthmatic human bronchial epithelial cultures (HBECs), where it suppresses ASM contractility by binding to and inhibiting the Ca2+ influx channel Orai1. We have localized this effect to a specific, C-terminal α-helical region of BPIFA1. Furthermore, tracheas from Bpifa1-/- mice are hypercontractile, and this phenotype is reversed by the addition of recombinant BPIFA1. Our data suggest that BPIFA1 deficiency in asthmatic airways promotes Orai1 hyperactivity, increased ASM contraction and airway hyperresponsiveness. Strategies that target Orai1 or the BPIFA1 deficiency in asthma may lead to novel therapies to treat this disease.

Allele-specific transactivation of matrix metalloproteinase 7 by FOXA2 and correlation with plasma levels in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a complex disease with poorly understood etiology. Previously, we reported upregulation of matrix metalloproteinase 7 (MMP7) in both lung and peripheral blood of IPF patients. Here we report evidence for genetic correlation of plasma levels and promoter polymorphisms (rs11568818 and rs11568819) of MMP7 in a well-characterized IPF cohort. Both the AA genotype of rs11568818 and the CT genotype of rs11568819 were found to be significantly associated with higher MMP7 plasma levels. These associations were observed only in IPF patients and not in healthy controls. The G-to-A transition of rs11568818 resulted in a novel binding site for the forkhead box A2 (FOXA2) transcription factor, a key regulator of embryonic lung development and proper function of the mature lung. In vitro, this transition led to increased sensitivity of the MMP7 promoter to FOXA2. In IPF lungs, FOXA2 was localized in the nucleus of epithelial cells that expressed MMP7 in the cytoplasm. These results suggest that increased sensitivity of the polymorphic MMP7 promoter to FOXA2 provides one of the genetic bases for the upregulation of MMP7 in IPF.