Weakened Airway Epithelial Junctions and Enhanced Neutrophil Elastase Release Contribute to Age‐Dependent Bacteremia Risk Following Pneumococcal Pneumonia

Aging Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

ABSTRACT Streptococcus pneumoniae ( Sp ; pneumococcus), the most common agent of community‐acquired pneumonia, can spread systemically, particularly in elderly, highlighting need for adjunctive therapies. The airway epithelial barrier defends against bacteremia and is dependent upon apical junctional complex (AJC) proteins such as E‐cadherin. After mouse lung challenge, pneumolysin (PLY), a key virulence factor, stimulates secretion an inflammatory eicosanoid, triggering infiltration polymorphonuclear leukocytes (PMNs) that secrete high levels neutrophil elastase (NE), thus promoting damage systemic infection. Here, pulmonary E‐cadherin staining intratracheally i.t. ) inoculated mice revealed PLY‐mediated disruption AJC independently PMNs. Apical infection air–liquid interface (ALI) respiratory monolayers similarly showed PLY disrupts AJCs. This promoted PMN transmigration bacterial apical‐to‐basolateral translocation, pharmacologically fortifying function diminished both breach vitro vivo. after inoculation > 20‐month‐old mice, or ALI derived from these age‐associated vulnerability to disruption, which turn enhanced migration bacteremia. In addition, we found PMNs aged increased tissue‐damaging NE. Simultaneous pharmacological inhibition tissue‐destructive NE fortification was required reduce level young mice. work underscores importance fully characterizing multifactorial sources susceptibility devising therapies mitigate invasive pneumococcal disease elderly.

Язык: Английский

Weakened airway epithelial junctions and enhanced neutrophil elastase release contribute to age-dependent bacteremia risk following pneumococcal pneumonia

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 6, 2024

ABSTRACT Streptococcus pneumoniae ( Sp ; pneumococcus), the most common agent of community-acquired pneumonia, can spread systemically, particularly in elderly, highlighting need for adjunctive therapies. The airway epithelial barrier defends against bacteremia and is dependent upon apical junctional complex (AJC) proteins such as E-cadherin. After mouse lung challenge, pneumolysin (PLY), a key virulence factor, stimulates secretion an inflammatory eicosanoid, triggering infiltration polymorphonuclear leukocytes (PMNs) that secrete high levels neutrophil elastase (NE), thus promoting damage systemic infection. Here, pulmonary E-cadherin staining intratracheally inoculated mice revealed PLY-mediated disruption AJC independently PMNs. Apical infection air-liquid interface (ALI) respiratory monolayers similarly showed PLY disrupts AJCs. This promoted PMN transmigration bacterial apical-to-basolateral translocation, pharmacologically fortifying function diminished both breach vitro vivo . after intratracheal inoculation >20-month-old mice, or ALI derived from these age-associated vulnerability to disruption, which turn enhanced migration bacteremia. In addition, we found PMNs aged increased tissue-damaging NE. Simultaneous pharmacological inhibition tissue-destructive NE fortification was required reduce level young mice. work underscores importance fully characterizing multifactorial sources susceptibility devising therapies mitigate invasive pneumococcal disease elderly.

Язык: Английский

Progress and Gaps in Respiratory Disease Research and Treatment: Highlights of the IRM 2024 in Shanghai

Deleted Journal, Год журнала: 2024, Номер 1(4), С. 10021 - 10021

Опубликована: Янв. 1, 2024

Respiratory diseases pose a major public health challenge globally, necessitating collaborative efforts between basic researchers and clinicians for effective solutions. China, which is heavily impacted by broad spectrum of respiratory disorders, has made notable strides in both research clinical management these diseases. The International Medicine (IRM) meeting was organized with the primary goal facilitating exchange recent developments promoting collaboration Chinese American scientists fields. This article summarizes key insights from IRM2024, held Shanghai, where wide range topics were discussed, including lung tissue development, disease mechanisms, innovative therapeutic strategies. By integrating perspectives basic, translational, research, IRM2024 highlighted advancements, addressed persistent challenges, explored future directions science practice. gained are poised to be pivotal shaping approaches, further reinforcing global commitment enhancing improving patient outcomes.

Язык: Английский