Pseudomonas (P.) aeruginosa is an opportunistic pathogen that causes serious infections and hospital-acquired pneumonia in immunocompromised patients. P. aeruginosa accounts for up to 20% of all cases of hospital-acquired pneumonia, with an attributable mortality rate of ~30–40%. The poor clinical outcome of P. aeruginosa-induced pneumonia is ascribed to its ability to disrupt lung barrier integrity, leading to the development of lung edema and bacteremia. Airway epithelial and endothelial cells are important architecture blocks that protect the lung from invading pathogens. P. aeruginosa produces a number of virulence factors that can modulate barrier function, directly or indirectly, through exploiting cytoskeleton networks and intercellular junctional complexes in eukaryotic cells. This review summarizes the current knowledge on P. aeruginosa virulence factors, their effects on the regulation of the cytoskeletal network and associated components, and molecular mechanisms regulating barrier function in airway epithelial and endothelial cells. A better understanding of these processes will help to lay the foundation for new therapeutic approaches against P. aeruginosa-induced pneumonia.

Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in patients under the age of 46 years. Survivors of the initial injury often endure systemic complications such as pulmonary infection, and Pseudomonas aeruginosa is one of the most common causes of nosocomial pneumonia in intensive care units. Female patients are less likely to develop secondary pneumonia after TBI, and pre-clinical studies have revealed a salutary role for estrogen after trauma. Therefore, we hypothesized that female mice would experience less mortality after post-TBI pneumonia with P. aeruginosa . We employed a mouse model of TBI followed by P. aeruginosa pneumonia. Male mice had greater mortality and impaired lung bacterial clearance after post-TBI pneumonia compared with female mice. This was confirmed as a difference in sex hormones, as oophorectomized wild-type mice had mortality and lung bacterial clearance similar to male mice. There were differences in tumor necrosis factor-α secretion in male and female alveolar macrophages after P. aeruginosa infection. Finally, injection of male or oophorectomized wild-type female mice with estrogen restored lung bacterial clearance and prevented mortality. Our model of TBI followed by P. aeruginosa pneumonia is among the first to reveal sex dimorphism in secondary, long-term TBI complications.

The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A ₄ hydrolase (LTA ₄ H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA ₄ H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA ₄ H axis. We demonstrate that AcPGP is degraded through a previously unidentified action of the enzyme angiotensin-converting enzyme (ACE). Pulmonary ACE is elevated during episodes of acute inflammation, as a consequence of enhanced vascular permeability, to ensure the efficient degradation of AcPGP. Conversely, we suggest that this pathway is aberrant in chronic obstructive pulmonary disease (COPD) enabling the accumulation of AcPGP. Consequently, we identify a potentially novel protective role for AcPGP in limiting pulmonary fibrosis and suggest the pathogenic function attributed to ACE in idiopathic pulmonary fibrosis (IPF) to be a consequence of overzealous AcPGP degradation. Thus, AcPGP seemingly has very divergent roles: it is pathogenic in its capacity to drive neutrophilic inflammation and matrix degradation in the context of COPD, but it is protective in its capacity to limit fibrosis in IPF.

Fibroblast survival and dysregulated activation drive fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). During physiological wound repair, fibroblasts are transiently activated to restore tissue integrity and are subsequently cleared by programmed cell death. In fibrotic disease, however, fibroblasts evade apoptosis and persist in a pathologically activated state. Although S100A4 has been implicated in fibrotic lung disease, the mechanisms by which S100A4 governs fibroblast fate and sustains profibrotic behavior remain unclear. Here, we identify S100A4 as a key regulator of apoptosis‐resistant, profibrotically activated fibroblasts through engagement of extracellular signal‐regulated kinase (ERK) signaling. In primary murine lung fibroblasts, S100A4 activates ERK, resulting in a coordinated program of fibroblast activation, including increased migration, extracellular matrix (ECM) contractility, stress fiber formation, and alpha‐smooth muscle actin (α‐SMA) induction. Functionally, S100A4 confers resistance to apoptosis induced by pro‐apoptotic and oxidative stress stimuli, as evidenced by reduced cleaved caspase‐3 and preserved cell viability. Pharmacological blockade of ERK signaling attenuates these responses, supporting ERK as an important downstream mediator of S100A4‐driven fibroblast activation and survival programs. Extending these findings to disease‐relevant contexts, bleomycin (BLM)‐induced lung injury in mice induces robust fibrotic remodeling, excessive collagen deposition, and transcriptional upregulation of S100A4. Consistently, primary lung fibroblasts from IPF patients exhibit elevated S100A4 expression, enhanced ERK activation, and increased α‐SMA expression, demonstrating conservation of this signaling axis across experimental models and human disease. Importantly, siRNA‐mediated knockdown of S100A4 in IPF fibroblasts suppresses ERK activation and attenuates expression of key profibrotic genes, indicating that S100A4 contributes to maintaining the fibrotic program in IPF fibroblasts. Collectively, these findings define a mechanistic link between S100A4‐mediated fibroblast survival and activation that drives pathological matrix remodeling and identify S100A4 and ERK as potential therapeutic targets in pulmonary fibrosis.