Pathophysiology of acute lung injury in patients with acute brain injury: the triple-hit hypothesis

Abstract

It has been convincingly demonstrated in recent years that isolated acute brain injury (ABI) may cause severe dysfunction of peripheral extracranial organs and systems. Of all potential target organs and systems, the lung appears to be the most vulnerable to damage after ABI. The pathophysiology of the bidirectional brain–lung interactions is multifactorial and involves inflammatory cascades, immune suppression, and dysfunction of the autonomic system. Indeed, the systemic effects of inflammatory mediators in patients with ABI create a systemic inflammatory environment (“first hit”) that makes extracranial organs vulnerable to secondary procedures that enhance inflammation, such as mechanical ventilation (MV), surgery, and infections (“second hit”). Moreover, accumulating evidence supports the knowledge that gut microbiota constitutes a critical superorganism and an organ on its own, potentially modifying various physiological functions of the host. Furthermore, experimental and clinical data suggest the existence of a communication network among the brain, gastrointestinal tract, and its microbiome, which appears to regulate immune responses, gastrointestinal function, brain function, behavior, and stress responses, also named the “gut-microbiome–brain axis.” Additionally, recent research evidence has highlighted a crucial interplay between the intestinal microbiota and the lungs, referred to as the “gut-lung axis,” in which alterations during critical illness could result in bacterial translocation, sustained inflammation, lung injury, and pulmonary fibrosis. In the present work, we aimed to further elucidate the pathophysiology of acute lung injury (ALI) in patients with ABI by attempting to develop the “double-hit” theory, proposing the “triple-hit” hypothesis, focused on the influence of the gut–lung axis on the lung. Particularly, we propose, in addition to sympathetic hyperactivity, blast theory, and double-hit theory, that dysbiosis and intestinal dysfunction in the context of ABI alter the gut–lung axis, resulting in the development or further aggravation of existing ALI, which constitutes the “third hit.”

The Effect of Probiotics on the Prognostication of the Neutrophil-to-Lymphocyte Ratio in Severe Multi-Trauma Patients

“…Brain trauma in general is well known to represent a complex biochemical cascade related with numerous patho-physiological functions, affecting not only the central nervous system but the function of multiple distant organs/systems [29][30][31]. Furthermore, acute brain trauma was found to significantly deteriorate gut microbiota diversity-starting within hours of injury [32].…”

Exploring the lung-gut direction of the gut-lung axis in patients with ARDS

“…Although MV is considered one of the cornerstones of ARDS management, the recognition that it can contribute to LI represents a significant advancement in ARDS research [ 23 , 24 , 47 ]. Termed ventilator-induced lung injury (VILI), this phenomenon involves a range of mechanisms, including exposure to elevated inflation transpulmonary pressures (barotrauma), excessive alveolar distension (volutrauma), and repetitive cyclic opening and closure of alveoli (atelectrauma).…”

“…Emphasis is placed on systemic and local inflammation, epithelial barrier dysfunction, effects of MV, hypercapnia, and gut microbiome dysbiosis, all of which are believed to influence lung-gut interactions significantly. In light of our recent comprehensive research into the gut-lung axis, as presented in our work on the triple hit hypothesis of LI in patients with acute brain injury [ 23 ], this review exclusively focuses on elucidating the lung-gut direction of the bidirectional communication between the lungs and the gut in LI/ARDS.…”