New insights in ARDS pathogenesis

4.1 Pulmonary epithelial injury

In healthy conditions, the alveolar-epithelial barrier is intact and maintains its capability of alveolar fluid clearance, allowing the reabsorption of excess alveolar fluid. This absorption of alveolar fluid from the airspaces to the interstitium is carried on by a vectorial ion transport, mainly mediated by the apical epithelial sodium channels (ENaC) and the basolateral sodium-potassium adenosine triphosphatase (Na${}^{+}$/K${}^{+}$-ATPase) pumps (Fig. 2) [20]. Some factors such as influenza infection, hypoxia, or hypercapnia can diminish the function of these sodium channels and Na${}^{+}$/K${}^{+}$-ATPase pumps, resulting in a reduced capacity of fluid clearance in the lung of patients with ARDS [2, 21, 22].

Fig. 2.Role of alveolar epithelium in lung edema. The alveolar epithelium is a continuous and tight monolayer of alveolar type I (ATI) and alveolar type II (ATII) cells. ATI cells are very thin and permit gas exchange, and ATII cells produce surfactant to enable lung expansion with low surface tension. The intact alveolar epithelium is linked by intercellular tight junctions that restrict the passage of water, electrolytes, and small hydrophilic solutes to the airspaces. In the normal lung, the transvascular flux of fluid out of the capillary moves water and low-molecular-weight solutes into the interstitial space depending on the permeability of the capillary membrane and the net difference between hydrostatic and protein osmotic pressure. In health, this fluid does not cross the epithelial barrier and moves into the lymphatics. When alveolar edema occurs, this edema fluid accumulating in airspaces is absorbed by the epithelium following a transepithelial osmotic gradient created by an active sodium transport. This sodium gradient is created and maintained by the apical membrane epithelial Na${}^{+}$ channels (ENaC) and the basolateral sodium/potassium adenosine triphosphatase (Na${}^{+}$/K${}^{+}$-ATPase) in both ATI and ATII cells, causing excess water to move passively from the airspaces to the interstitium. Figure created with BioRender.com. JAMs, junctional adhesion molecules; ZO-1, Zonula occludens-1.

Activation of cell death mechanisms during ARDS, such as FasL (Fas Ligand)-mediated apoptosis or pyroptosis (highly inflammatory type of programmed cell death), are responsible for the loss of alveolar epithelial cells, thus contributing to barrier hyperpermeability [23, 24, 25]. Cell death can be triggered on epithelial cells by direct injury on the epithelium or activation of the pattern recognition receptors (PRRs). These PRRs are cell-surface or cytosolic proteins activated by the pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patter (DAMPs). PAMPS are extrinsic molecules derived from various microorganisms, while DAMPs are intrinsic molecules derived from injured cells or extracellular molecules. Toll-like receptors and the receptor for advanced glycation end products (RAGE) are examples of PRRs. Besides apoptosis, activation of alveolar epithelial PRRs activates inflammatory cascades that alter the alveolar epithelial and endothelial barriers. Internalization of the PRRs upon pathogen binding, for instance, releases new particles of pathogens, inflammatory molecules (e.g., cytokines), DAMPs, and PAMPs into the alveolar space that can exert a deleterious effect on the epithelial integrity and function [26, 27].

Alterations in cell-cell adhesion in the alveolar epithelium and its interaction with extracellular matrix (ECM) have also been reported in ARDS. Intercellular junctions of epithelial cells are mediated by tight junctions (TJs) complexes, which consist of some transmembrane proteins such as junctional adhesion molecules (JAMs), occludin, and claudins that interact with the adaptor protein zonula occludens (ZO), which, in turn, binds to the actin fibers of the cytoskeleton (Fig. 2). These TJ-actin complexes are essential structures in alveolar epithelial permeability since they control cell tension and contraction and the paracellular transport of fluid and solutes into the airspace [19] (Fig. 2). Therefore, dysfunction of the TJs results in increased permeability to water and proteins and deterioration of the capacity of alveolar fluid clearance of the epithelium, leading to the formation and perpetuation of lung edema. Studies in experimental models of acute lung injury indicate massive changes in the expression and localization of ZO and claudins with the consequent increase in epithelial permeability [25, 28, 29]. The ECM represents the scaffold of alveolar epithelium and capillary endothelium that participates in cell-cell adhesion, and in the fluid trafficking into the airspace and cell signaling. In ARDS, the oxidative stress and the dysregulated inflammation in the lung induce the expression of some enzymes, such as elastases or matrix metalloproteinases (MMPs), that change the structure and stiffness of the ECM and, consequently, modify the expression of the TJ proteins and barrier function, contributing to lung edema formation [19, 30, 31, 32].

Alveolar inflammation is characterized by marked neutrophil influx, activation of alveolar macrophages, and release into the airspaces of cytokines (tumor necrosis factor-$\alpha$ (TNF-$\alpha$), tumor necrosis factor receptor (TNFR), interleukin-1$\beta$ (IL-1$\beta$), interleukin-1 receptor antagonist (IL1RA), IL-6, interferon-$\gamma$ (INF-$\gamma$), granulocyte colony-stimulating factor (G-CSF), transforming growth factor-$\beta$ (TGF-$\beta$)) and chemokines ((IL-8, epithelial neutrophil-activating protein 78 (ENA-78), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2)) by alveolar endothelial, epithelial, and immune cells [19, 33]. Among them, TGF-$\beta$ is a key mediator in ARDS that can be detected in bronchoalveolar lavage (BAL) fluid from patients with ARDS in the first 24 h of diagnosis and has an essential role in its onset and progression. In the early phase, TGF-$\beta$ causes apoptosis in alveolar epithelial cells and contributes to lung edema by increasing permeability and decreasing the alveolar fluid clearance of the alveolar epithelium [34]. This decrease in the alveolar fluid clearance is due to changes in the expression of apical epithelial sodium channels (ENaC) and the basolateral Na${}^{+}$/K${}^{+}$-ATPase pumps [14, 19, 35]. In a later stage, TGF-$\beta$ exerts an essential role in regulating inflammation, immunity, tissue repair, and fibrosis. In this line, TGF-$\beta$ contributes to lung fibrosis via activation of lung fibroblasts and indirectly via inducing apoptosis of alveolar epithelial cells [34, 36].

4.2 Pulmonary endothelial injury

Alteration of the vascular endothelial function and extensive alveolar-capillary leak also occurs in the lung of patients with ARDS. Endothelial injury can be caused by the adhesion and migration of neutrophil granulocytes on and through the endothelium [37] and by the direct effects of cytotoxic factors present in the intravascular and the intra-alveolar compartments. This contact between intra-alveolar factors and the endothelium occurs because of the disruption of the alveolar epithelial barrier. Many intravascular and intra-alveolar factors activate cell death mechanisms on endothelial cells, such as apoptosis and pyroptosis, and contribute to the breakdown of endothelial intercellular junctions [38, 39], leading to an increase in vascular permeability that contributes to lung edema and respiratory failure in these patients [2].

Like alveolar epithelial cells, endothelial cells can be activated by PAMPs and DAMPs, some of them derived from alveolar epithelial cells and resident macrophages, as well as from circulating leukocytes and platelets, such as TNF-$\alpha$, IL-1$\beta$, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), platelet-activating factor (PAF), TGF-$\beta$1 and angiostatin (a cleavage product from plasminogen with an intense antiangiogenic activity) that are increased in the BAL fluid of patients with ARDS [34, 40, 41]. Among these factors, TNF-$\alpha$, TGF-$\beta$, and angiostatin contribute to endothelial injury by inducing apoptosis [42, 43, 44]. In addition, TGF-$\beta$ contributes to increased endothelial permeability via phosphorylation of adherent junction proteins and the formation of stress actin fiber in endothelial cells in vitro[45]. TNF-$\alpha$ also disrupts tight junction proteins (ZO-1, claudin 2-4-5) and $\beta$-catenin in pulmonary endothelial and epithelial cell layers, which can be exacerbated by IFN-$\gamma$[28, 46, 47]. Il-1$\beta$ increases alveolar endothelial and epithelial permeability via Ras homolog family member A (RhoA)/integrins-mediated epithelial TGF-$\beta$ release [48].

Activated endothelial cells trigger a cascade of events, including activation of coagulation cascades, activation and aggregation of platelets, formation of platelet-leukocyte aggregates, and up-regulation of cell adhesion molecules, such as P-selectin, E-selectin, ICAM (intercellular adhesion molecule) and VCAM (vascular cell adhesion molecule), that mediate leukocyte adhesion and transmigration across the endothelium (Fig. 3). This transmigration of leukocytes, the deposition of platelets and neutrophils on endothelium, or the formation of platelet-neutrophil aggregates play a synergic role in increasing vascular permeability in the lung [39, 49] (Fig. 3).

Fig. 3.The inflammation and coagulation interaction in ARDS. Activated endothelial cells trigger various events that include activation of the coagulation cascade (with reduction of anticoagulant and fibrinolytic factors), the release of cytokines, and up-regulation of leukocyte and endothelial cell adhesion molecules (P-selectin, E-selectin, ICAM, VCAM, PECAM). These events, in turn, promote activation of leukocytes and platelets that leads to platelet aggregation and formation of platelet-leukocyte aggregates, facilitating the adhesion and migration of leukocytes to the interstitium and alveolar airspaces. In addition, the generation of tissue factor (from exposed subendothelium or released by activated macrophages/monocytes and platelets) and von Willebrand factor (vWF) (released by activated endothelial cells and platelets) mediates further platelet adhesion and aggregation. Activated neutrophils release pro-inflammatory mediators (chemokines, cytokines) along with ROS, enzymes (MMPs, elastase, myeloperoxidase), and neutrophil extracellular traps (NETs) that have an essential role in host defense but cause endothelial and epithelial injury under overwhelming pathological conditions. Coagulation and activated platelets and leukocytes augment microvascular endothelial damage leading to the disruption and increased permeability of the endothelial barrier. All these events facilitate further movement of inflammatory cells and protein-rich fluid into the interstitium and alveoli. In the intravascular compartment, activation of coagulation, platelets, leukocytes, and endothelial cells, along with the generation of thrombin and fibrin, leads to the formation of thrombi in the pulmonary microvasculature. Figure created with BioRender.com. ECM, extracellular matrix; ROS, Reactive Oxygen Species; MMPs, Matrix Metalloproteinases; NETs, Neutrophil Extracellular Traps; GPIb-IX-V, glicoprotein Ib-IX-V; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion protein 1; PECAM-1, platelet-endothelial cell adhesion molecule-1.

Elevated levels of angiotensin II (AngII) have been found in the lung of patients with ARDS. AngII interacts with Ang II receptor type 1 (AT1R), mainly expressed in the endothelium, and induces the production of several mediators (inflammatory cytokines, eicosanoids, and VEGF) that trigger proinflammatory responses and elevate the pulmonary vascular permeability, contributing to pulmonary edema [50, 51]. Interestingly, SARS-CoV-2 is internalized by alveolar epithelial cells via binding to angiotensin-converting enzyme 2 (ACE2) receptor, resulting in an ACE2 downregulation and the subsequent upregulation of angiotensin II (Ang II) that contribute to lung endothelial vascular dysfunction in COVID-19 pneumonia [52].

Besides TJs, endothelial cells are also connected by adherens junctions, which contain vascular endothelial cadherin (VE-cadherin) that links to the actin cytoskeleton. The weakening of endothelial junctions induced by inflammation also relies on the destabilization of VE-cadherin contacts and alterations in the endothelial actin-myosin cytoskeleton [39].

Altogether, the increase in endothelial and epithelial permeability leads to protein-rich edema formation in the lung, resulting in the alteration of gas exchange and the subsequent hypoxemia in ARDS. Extensive alveolar epithelium damage has been observed in non-surviving ARDS patients, whereby the degree of alveolar epithelial damage seems to determine the ARDS severity and prognosis [2, 53].

5.1 Activation of pattern recognition receptors

In the lung, activation and regulation of innate and adaptive immunity are mediated by patter recognition receptors (PRRs), also present in alveolar epithelial and endothelial cells as mentioned above [27]. Activation of these PRRs by PAMPs and DAMPs leads to nuclear translocation of transcription factors such as nuclear factor (NF)-$\kappa$B, predominantly through a myeloid differentiation primary response gene 88 (MyD88)-dependent mechanism. This is followed by the transcription of proinflammatory cytokines such as TNF-$\alpha$, IL-1$\beta$, and IL-8, which can activate immune cells and alter alveolar epithelial and endothelial functions in the lung. This early humoral and cellular immune activation contributes to lung injury and widespread lung inflammation to other organs, promoting multi-organ damage [54].

5.2 Innate immune cells

5.3 Adaptive immune cells

During infection, the adaptive immune response is rapidly initiated. Pathogen particles are presented through major histocompatibility complex class I (MHC I) of activated dendritic cells (DC) to CD8+ T cells. The latter cells are cytotoxic and induce apoptosis on infected cells by producing perforin and granzymes. Activated CD8+ T cells also become pathogen-specific effectors and memory T cells. The major histocompatibility complex class II (MHCII) is presented by DCs to CD4+ T cells. Then, CD4+ T cells may differentiate into one of several T helper (Th) cell lineages, including Th1, Th2, Th17, and T follicular cells, as defined by their pattern of cytokine production and function. Th1, Th2, and Th17 cells contribute to pathogen clearance, whereas T follicular cells assist B cells in the production of neutralizing antibodies [56].

Alterations in adaptive immune response have been broadly described in ARDS. For example, levels of CD4+ T cells are dramatically reduced in patients with sepsis-induced ARDS, as well as the Th1 and Th2-associated cytokine production and pathogen clearance [75]. In contrast, Th17 cells are elevated in the lung [76], BAL fluid [77], and blood [78] of ARDS patients and experimental animals after acute lung injury. Differentiation to Th17 is mainly induced by IL-6, which is elevated in ARDS. Th17 cells activate macrophages, DCs, and neutrophils, triggering the release of proinflammatory cytokines (IL-1, IL-6, IL-8, IL-21, IL-17A, TNF-$\alpha$, and MCP-1) by these cells [78], which is accompanied by increased alveolar epithelial permeability [76] and greater severity of illness [77].

Another subtype of CD4+ T cells, the regulatory T (Treg) cells, are also altered during ARDS. Treg cells exert an anti-inflammatory effect that is essential in resolving lung injury. They suppress the effector T+ cell responses (mainly from Th17 cells) and maintain the tolerance to self-antigens, avoiding autoimmune responses [79]. During acute lung injury, the increased levels of IL-6 enhance Th17 cell activation and Treg suppression, altering Th17/Treg balance [80]. The Th17/Treg ratio increases in mild to severe ARDS patients and has been proposed as a predictor biomarker of mortality in ARDS, correlating with increased APACHE (Acute Physiology and Chronic Health disease Classification System), SOFA (Sequential Organ Failure Assessment) and lung injury scores [81]. Interestingly, increasing Treg levels via stimulation of the cAMP/FOXP3 (cyclic adenosine monophosphate/ forkhead box P3) signal reduces the number of Th17 cells protecting against lung injury and mortality in mice with acute lung injury [82].

6.1 Endothelial damage

In injured alveoli, endothelial damage activates innate host responses and coagulation, promoting platelet activation and aggregation (Fig. 3). After endothelial damage, disruption of the intercellular junctions exposes the subendothelial extracellular matrix containing the procoagulant tissue factor (TF). TF is also produced by endothelial and epithelial cells in the alveoli and by activated macrophages/monocytes and platelets. Then, TF binds to Factor VII to initiate TF-dependent coagulation, resulting in thrombin generation, platelet aggregation, conversion of fibrinogen to fibrin, and, consequently, formation of blood clots (Fig. 3) and fibrin deposition in the alveolar airspaces [94, 95]. The von Willebrand factor (VWF), produced by activated endothelial cells, platelets, or exposed subendothelium, mediates further platelet adhesion and aggregation [92]. Under activation, vascular endothelial cells express cell adhesion proteins such as P-selectin, E-selectin, ICAM, and VCAM that enable the recruitment of platelets and leukocytes, which also have a pivotal role in hemostasis and thrombosis [96] (Fig. 3). In addition, the renin-angiotensin pathway plays an essential role in ARDS promoting coagulation. Accumulation of angiotensin II (AngII) has been observed in the lung of patients with ARDS. The binding of AngII to angiotensin II receptor type 1 (AT1) augments pulmonary vasoconstriction and contributes to TF and PAI-1 expression on platelets and endothelial cells [97].

6.2 Platelet activation and interaction with immune cells

Platelets are an essential component of ARDS pathogenesis. In a small human study, platelet activation was greater in ARDS patients than in healthy controls [98]. Also, it has been shown that the severity of lung injury is tightly correlated with platelet-derived $\alpha$-granule mediators in BAL fluid [99]. Platelets have an essential function in coagulation and the innate immune system, participating in neutrophil and monocyte activation and recruitment (Fig. 3). During endothelial damage, the exposure to subendothelial collagen leads to platelet activation and subsequent release of cell membrane proteins and granular contents, including chemokines, cytokines (IL-1, TNF-$\alpha$), coagulation proteases, adhesive molecules, growth factors, and mediators of angiogenesis that cause further platelet activation and amplification of the innate immune responses [100, 101, 102]. Activated platelets bind to leukocytes, such as neutrophils and monocytes, promoting their activation, adhesion, and migration at the site of injured endothelium via expression of adhesion molecules, such as ICAM-1 and VACM-1 (Fig. 3). Also, leukocyte rolling on vascular endothelium is facilitated by platelet-derived P-selectin and thromboxane-A2, facilitating leukocyte migration into injured tissue (Fig. 3). This platelet-neutrophil binding is mediated by toll-like receptor 4 (TLR4) engagement and participates in neutrophil activation and release of NETs [103]. Although NETs show antimicrobial properties by trapping and inactivating microorganisms in blood vessels, they also have procoagulant properties and might cause collateral tissue damage, in which the neutrophil-derived proteases have an important role. Furthermore, NETs cause platelet activation and aggregation, and activates coagulation pathway, contributing to fibrin formation [103, 104, 105]. Also, activated platelets exert an important function in immune defense by releasing antimicrobial peptides (e.g., AMPs) and enhancing the phagocytosis capacity of leukocytes, however, an increased formation of the platelet-leukocyte complex contributes to acute lung injury and other organ failure [106]. Actually, preclinical studies of acute lung injury (ALI) show that the depletion of platelet leads to a significant reduction of neutrophil recruitment in the lung, and that the inhibition of platelet-neutrophil complex improves gas exchange and prolongs animal survival [107].

6.3 Molecular link between hemostatic and immune systems

Immune cells as well as platelets and endothelial cells can be activated by factors of the coagulation cascade. The molecular link between hemostatic and immune systems is mainly based on the protease activated receptors (PARs) on immune cells, platelets, and endothelial cells. Complexes of TF/Factor VIIa (TF/FVIIa), TF/FVIIa/Factor Xa (TF/FVIIa/FXa) and Factor Xa and thrombin trigger PARs, which activate innate immune cells and the expression of cytokine and adhesion molecules. These effects enhance inflammatory processes in the lung, including P-selectin-mediated leukocyte migration, that cause disruption of endothelial barrier by altering endothelial cytoskeleton and further platelet activation [83, 92, 108, 109]. In addition, fibrinogen and fibrin can directly initiate the activation of neutrophils [110].

On the other hand, inflammation facilitates and enhances coagulation. In this regard, proinflammatory cytokines activate coagulation system and also play an important role in the down-regulation of physiological anticoagulant pathways [111]. Inflammatory cytokines, such as IL-1, TNF-$\alpha$, IFN-$\gamma$, and lipopolysaccharide (LPS) of gram-negative bacteria, known to be elevates in ARDS patients, induce TF expression on macrophages and platelets [84]. IL-2, also elevated in these patients, decreases fibrinolysis by upregulating of the antifibrinolytic PAI-1. Interestingly, it has been shown that platelets have receptors for IL-1$\gamma$, IL-6 and IL-8. These cytokines that are one of the most reported elevated cytokines in ARDS have the capability of activating and spreading platelets [112]. IL-6 and IFN-$\gamma$ also increases the expression of TF on endothelial cells and monocytes and can impair vascular endothelium function. The chemokines, such as IL-8, have an indirect prothrombotic effect via attracting neutrophils to the site of infection [84, 101]. As mentioned before, the release of NETs by neutrophils can contribute to tissue damage by exacerbating local inflammation and enhancing microvascular thrombosis in the lung. This organized recruitment of innate cells and platelets at the site of endothelial injury, in turn, leads to the release of pro-inflammatory mediators contributing to further activation of intravascular immune responses [84, 113].

6.4 Hypoxia enhances immunothrombosis

Finally, hypoxia occurs in moderate-to-severe ARDS and this can lead to endothelial dysfunction, including disruption of vascular tone and hypercoagulability. Hypoxia-induced expression of adhesion molecules P-selectin, E-selectin, ICAM-1 and VCAM-1 that results in platelet and leukocyte recruitment and more expression of TF, causing hypercoagulability [114, 115]. Under hypoxia, endothelial and immune cells release hypoxia-induced factors (HIFs), a transcription factors that promote thrombosis by increasing endothelial release of PAI-1 and inflammatory cytokines (TNF-$\alpha$, IL-2) and by downregulating thrombomodulin [114, 115, 116]. In macrophages, HIFs promote their activation and local aggregation, with the consequent release of proinflammatory cytokines, including IL-6 and TNF-$\alpha$[116].

Altogether, immunothrombosis in the lung results in the formation of an intravascular scaffold, enhancing the recognition and destruction of pathogens and supporting endothelial integrity. However, uncontrolled immunothrombosis might induce collateral tissue damage and contribute to ARDS and multiorgan dysfunction.

8.1 Liver-lung interaction

The liver has multiple functions, such as the clearance of pathogens and their products and cellular debris, the metabolism of toxins and drugs, the synthesis of proteins, and the modulation of systemic inflammatory response and host defense [163]. Critical patients with previous cirrhosis and other chronic liver diseases have a higher risk of developing ARDS and worse clinical outcomes than patients with no liver diseases [164, 165]. On the other hand, hepatic dysfunction during the first 48-h period of moderate-to-severe ARDS is strongly associated with a worse outcome. It has been shown that early liver dysfunction and not kidney dysfunction is independently associated with death in ARDS patients ventilated according to a protective ventilation strategy [166]. Therefore, the bidirectional liver-lung communication seems to play a significant role in the development, progression, and resolution of ARDS [167].

8.2 Brain-lung interaction

The brain-lung interactions have also been reported in critically ill patients in both directions. It is well known that patients with brain injury can develop ARDS. In contrast, patients with ARDS frequently associate some neurocognitive deficiencies such as alterations in language, memory, and/or disorientation that can even persist a long time after discharge [54, 186, 187].

The neurological damages after lung injury remain unclear but may include the combination of hypoxemia, the effect of an activated systemic inflammatory response, and the circulatory changes caused by mechanical ventilation, including the effects of the positive end-expiratory pressure on cerebral microcirculation and intracranial pressure. The brain is an organ extremely sensitive to oxygen deprivation; thus, the hypoxemia resulting from ARDS seems to be a contributing but not the unique factor to brain dysfunction [187]. A recent systemic review has found an association between mechanical ventilation and acute cognitive impairment, describing greater neuroinflammation and lower cognitive scores in subjects with long-term mechanical ventilation [188].

In an experimental model of acute lung injury in pigs, Fries et al. [189] demonstrated elevated levels of the proinflammatory protein S-100B in serum and significant neuronal damage in the Cornu Ammonis, a subregion of the hippocampus that is especially vulnerable to a variety of pathologic conditions, such as ischemia, inflammation, and hypoxia. This hippocampal damage could explain the cognitive impairment associated with lung injury in patients.

A growing body of evidence indicates that the blood-brain barrier (BBB) permeability can be altered during systemic inflammation and/or infection because of the effect of circulating proinflammatory mediators (i.e., IL-6, IL-1$\beta$, or TNF-$\alpha$). These mediators activate cerebral endothelial cells, alter tight junction proteins and promote leukocyte transendothelial migration through the BBB, enhancing the local brain inflammatory responses. In this line, it has been shown that massive recruitment of monocytes into the brain initiates a complex neuroinflammatory response driving microglia polarization towards the M1 phenotype, which aggravates the cerebral inflammatory state, increases the BBB permeability, and activates different types of cell death by mechanisms involving the release of MMP9 and proinflammatory cytokine [190, 191].

The autonomic nervous system also plays an important role in the neuroimmune crosstalk between the brain and lung. The cholinergic pathway exerts an antiinflammatory effect that controls the systemic inflammatory response. In an experimental study of acute lung injury, Dos Santos et al. [192] showed that while vagus nerve inhibition enhances ALI, stimulation of the antiinflammatory cholinergic reflex exerts a protective effect in the lung.

Brain-lung interactions have received little attention in the literature, but a growing body of evidence suggests that both the lungs and brain establish a relevant cross-talk that modulates local and systemic inflammatory responses through common mediators.

8.3 Kidney-lung interaction

Acute kidney injury is also a life-threatening condition commonly presented in critically ill patients with systemic inflammatory response syndrome (SIRS), septic shock, or multi-organ dysfunction [193, 194]. Hemodynamic alterations induced by mechanical ventilation alter kidney perfusion and function by reducing the cardiac output, which leads to a redistribution of the renal blood flow with a reduction of the glomerular filtration rate and free water clearance [195, 196]. Mechanical ventilation also stimulates renin-angiotensin and sympathetic pathways, resulting in suppression of the atrial natriuretic peptide release. These changes lead to renal blood flow reduction and fluid retention [197, 198]. In addition, some preclinical studies suggest an essential role of several inflammatory mediators secondary to ventilator-induced lung injury (VILI) in developing acute kidney injury (known as ventilator-induced kidney injury). In experimental models of VILI, there is an increase of nitric oxide synthase (NOS) in both lung and kidney and of VEGF in serum along with systemic microvascular leak [199]. NOS enhances vascular permeability upon VEGF-ERK1/2 activation [200]. Increased levels of IL-6 and VEGF in the kidney have been shown in an experimental model of acid-induced lung injury in animals ventilated with high tidal volume (17 mL/kg) [201]. Apoptosis is also induced in kidney epithelial cells in animals with VILI. In ARDS patients, there is a correlation between elevated pro-apoptotic soluble Fas ligand and creatinine levels in the serum of ARDS patients [202].

In addition, hypoxemia has also been reported to alter kidney function, reducing renal blood flow by activating vasoactive factors such as angiotensin II, endothelin, and a decrease in nitric oxide that result in elevated renal vascular resistance [203, 204]. Moreover, in vitro models have demonstrated that low oxygen (O${}_2$) and high carbon dioxide (CO${}_2$) induced apoptosis in renal tubular cells [205].

On the other hand, detrimental effects of acute kidney injury on the lung have also been observed. In this line, acute kidney injury induced in animals results in a downregulation of epithelial sodium channel (eNaC), Na${}^{+}$/K${}^{+}$-ATPase, and aquaporin-5 in the lungs [206]. These proteins play relevant roles in fluid clearance and permeability of the alveolar epithelium; thus, dysregulation of these processes may lead to ARDS development. Acute kidney injury also elevates proinflammatory cytokines (IL-1$\beta$, IL-6, and IL-12) in serum leading to a secondary ALI characterized by pulmonary vascular congestion and neutrophil infiltration [207]. Another preclinical study in mice shows that acute kidney injury is followed 4 h later by neutrophil infiltration, increased myeloperoxidase activation, and high levels of the neutrophil chemokines KC (keratinocyte chemoattractant) and MIP-2 along with capillary leak in the lung [208].

Altogether, kidneys could become damaged by mediators of inflammation or immuno-mediated factors related to ARDS, including the ventilator-related systemic and renal circulatory changes. On the contrary, it could be the renal disease determining consecutive pulmonary damage in critically ill patients.