Crosstalk between lung and extrapulmonary organs in sepsis-related acute lung injury/acute respiratory distress syndrome

Abstract

Sepsis-related acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is associated with considerable morbidity and mortality, yet the efficacy of current treatments is limited. Previous studies have predominantly focused on the lung itself as an isolated organ, whereas the role of organ crosstalk in the pathogenesis of sepsis-related ALI/ARDS cannot be overlooked. Meanwhile, neglecting the discussion of heterogeneity in sepsis caused by different sources of infection may be another important obstacle to translating previous studies into clinical efficacy. In this review, we initially delineated the distinctions in pathogenesis between pulmonary and extrapulmonary sepsis-related ALI/ARDS in microbial species, pathogenesis, host response, and clinical manifestations. Additionally, systemic organ crosstalk mechanisms are summarized, including the commonality and specificity of systemic inflammation, lung and gut microbiome, as well as cascade cell injury and death in distant organs. Subsequently, organ crosstalk between lung and extrapulmonary in pulmonary sepsis and extrapulmonary sepsis-related ALI/ARDS are discussed by organs, including immunity, neuroendocrine, metabolism, and so forth. Furthermore, extracellular vesicles represent a promising avenue of research as potential players and targets in organ-lung crosstalk in sepsis. While the complexity of multi-organ interactions and the heterogeneity of septic patients present significant challenges, these issues are expected to be addressed by the emergence of organ-on-a-chip platforms, 3D organoid cultures, and multi-omics techniques.

Keywords: ALI/ARDS; Extracellular vesicles; Organ crosstalk; Sepsis.

Fig. 1

Pulmonary sepsis vs. extrapulmonary sepsis-related ALI/ARDS. Both conditions exhibit the hallmarks of sepsis-related ALI/ARDS, including edema and pneumonia, as well as systemic inflammation and impaired multiorgan function. Regardless of whether it is pulmonary or extrapulmonary, the inflammatory cells primarily involved in the ALI/ARDS condition are neutrophils. However, there are significant differences in microbial species, pathogenesis, host response, and clinical manifestations between PSA and ESA. ① Microbial species: PSA is characterized by an increase in exogenous pathogenic microorganisms and a decrease in the normal respiratory flora in the lungs, whereas ESA results from a shift in the flora, leading to an increase in intestinal microorganisms. ② Pathogenesis: PSA is typically triggered by a lung infection or pneumonia, which subsequently causes damage to other organs. In contrast, ESA is primarily an indirect lung injury resulting from an extrapulmonary infection, mediated by circulating toxic chemicals, autoimmunity, and other factors. ③ Host response: PSA manifests with more severe epithelial injury, while ESA is associated with more pronounced endothelial damage. Compared to ESA, PSA exhibits more intense lung injury and less significant immune suppression. ④ Clinical manifestations: PSA patients are more susceptible to severe alveolar inflammation and pulmonary consolidation, with elevated pulmonary elastic resistance. Conversely, ESA patients are more prone to interstitial lung injury and ground-glass opacities in the lungs, accompanied by higher chest wall elastic resistance

Fig. 2

The impact and organ-specific mechanisms of lungs on extrapulmonary organs in pulmonary sepsis-related ALI/ARDS. These crosstalk mechanisms between lungs and other organs including the heart, brain, kidney, liver, and gut are displayed, which mainly include migration and attack of the pathogen, weakening BBB, the influence of mechanical ventilation, the acute phase response and APPs, cell cycle, and so on

Fig. 3

Crosstalk between extrapulmonary organs and lungs in extrapulmonary sepsis-related ALI/ARDS. Inflammation and immunity, metabolism, neural regulation, microbial migration, and other mechanisms are involved. Blood circulation, the lymphatic system, the nervous system, and interstitial spaces may be the transmission pathways of interacting mediators. Extrapulmonary organs not only directly interact with the lungs but also indirectly interact with the lungs through other organs

Fig. 4

Three hypotheses of brain-lung crosstalk in ESA. (a) “Blast injury” hypothesis: Sudden intracranial hypertension elevates pulmonary vascular pressure and thus ruptures pulmonary capillaries. Sympathetic overdrive exacerbates this via catecholamine-induced blood redistribution to the lungs. (b) Two-hit theory: Brain injury (first hit) induces systemic inflammation through BBB breach, priming lungs for secondary insults (ventilation, infection; second hit). Concurrent neurogenic immunosuppression increases infection susceptibility. (c) Brain-gut-lung triple blow hypothesis: Based on brain injury (one blow) and pulmonary pathogenic factors (the second blow), gut dysbiosis and barrier failure (the third blow) amplify lung inflammation via the gut-lung axis

Fig. 5

The role of EVs in organ crosstalk in sepsis-related ALI/ARDS. Systemic mechanisms, including a cascade of cell injury and death, immunity, endothelial function, metabolism, and coagulation, as well as communications facilitated by EVs are included