Damian Sendler: An early study of ARDS’s molecular biology revealed that the disease is very variable across individuals. Inflammation, coagulation, alveolar epithelial damage, and vascular endothelial activation might vary significantly across patients suggesting a role for molecular subphenotyping in unraveling heterogeneity.
There are two distinct subphenotypes that tend to respond differently to several therapies in secondary analysis of clinical trials based on clinical and biological data from trials and observational cohorts of patients.
Damian Jacob Sendler: Identifying novel treatment targets may be possible if we better understand the underlying underpinnings of heterogeneity. Biological variation may be attributed to clinical heterogeneity, but not all of it. A person’s tendency to ARDS may be influenced by hereditary susceptibility to viral and non-infectious pro-inflammatory stimuli. 43 Genetic variations have a direct impact on the pathogen–host relationship in certain lung illnesses. 44 Predicted levels of sRAGE (a measure of inflammation and alveolar epithelial damage) and angiopoietin 2 (an indicator of endothelium activation) in the blood are linked to an increased risk of ARDS during sepsis. 46 and 45 Genes coding for cell matrix proteins, vascular endothelial growth factor receptor 1, and haptoglobin are all associated with ARDS risk. Two and a half, three and four Genetic polymorphisms may be a key source of biological variation in lung damage resolution and healing, according to these results.
Dr. Sendler: ARDS heterogeneity may potentially be influenced by differences in the microbiomes of the lungs and the digestive tract. In healthy alveoli, commensal bacteria are not able to thrive because they lack nutrients and contain bactericidal surfactant, which inhibits bacterial development. 50 Alveolar flooding by protein-rich fluids and surfactant inactivation, on the other hand, creates an ideal habitat for the development of bacteria, which may lead to more inflammation and damage in a feedback loop. 51 Bacterial overgrowth in the lungs is possible, as is the entry of pathogen-associated molecular patterns and translocated gut bacteria into the alveoli. 52 The therapeutic implications of this dysbiosis have not been thoroughly investigated.
Damian Sendler
Precision medicine in ARDS has difficulties.
Damian Jacob Markiewicz Sendler: There is a strong argument for increasing precision medicine in the treatment of ARDS (panel 1), but there are also several challenges. Identifying individuals with abnormal pathways is challenging due to a lack of knowledge about crucial nodal sites in the several routes that cause acute lung damage. Chronic lung disease is a multi-step process that includes endothelial cell failure, alveolar cell necrosis and malfunction, loss of surfactant, activation of coagulation cascades in the lung, and the activation of complicated immune pathways. 6 Pathways leading to resolution and repair are still unclear, and the relevance of a single route may vary based on the origin of lung damage, the patient’s susceptibility, and other variables.
As a further obstacle, the time period for characterizing individuals is limited since ARDS develops fast and medications may be most effective when started early. In a recent study of ARDS, however, 48-hour mortality was 10% and 96-hour mortality was 16%, even though current precision medicine techniques to staging and molecular classification of breast and lung cancer need days to weeks of preparation and testing time. 53 The development of rapid assays is required to quickly determine biological phenotypes, which may take anywhere from minutes to a few hours. 54 Large-scale human clinical trials seldom use close-up biospecimens, such as those from bronchoalveolar lavage, since they need extra, invasive procedures. Even when specimens are acquired, the collection and processing methodologies vary widely across studies. Due to procedural risk and the fact that identifying widespread alveolar damage does not significantly alter therapy, tissue samples are seldom acquired. Chronic and acute comorbidities affect the risk of developing and surviving acute respiratory distress syndrome (ARDS) in different ways. 56 In spite of the fact that comorbidities do not alter the response to biological therapy, they do have an effect on the likelihood of mortality due to ARDS. 57 Clinical trials in ARDS are complicated by the fact that there is no universally acknowledged surrogate endpoint, which makes them difficult to conduct in the early stages of development.
There is no animal model that can perfectly mimic the complexity of human ARDS. The cellular and molecular causes of illness, however, are still critical to the creation of a precision medicine approach for ARDS, and they remain vital (panel 2). With rigorous human study observation, it is possible to find biomarkers for the targeted pathways in animal research that are extremely successful in modeling a specific biological aspect of lung damage or treatable attribute (eg, endothelial barrier disruption).
Damian Jacob Sendler
Reverse translation is one of the most effective functions of animal models in helping to identify crucial nodes of mechanistic pathways that have been discovered in rigorous human investigations (figure ). These routes and nodes may be used to identify potential drug development targets, which can then be put to the test in clinical trials.
Damien Sendler: The use of animal models to influence the development of precision medicine for ARDS is an important example of how precision medicine might be included into paediatric sepsis treatment. Biomarker panels for human mortality from paediatric sepsis were generated via cohort studies, and comparable biomarkers were later proven to be predictive of death in murine models of sepsis. 60 They next tested medicines targeting the predictive biomarkers to see whether they were linked to outcomes and discovered additional biological traits (ie, a larger bacteria load) associated with the high projected mortality group. It is possible that preliminary testing of putative medicines in preclinical models may allow researchers to better grasp the consequences of biological heterogeneity and, as a result, better advise clinical trial design. 60
To understand why some attractive candidate medicines fail in human clinical trials, reverse translation may play an essential role. Although simvastatin8 and rosuvastatin9 were shown to have different effects on patients with ARDS based on their latent class subphenotypes, rosuvastatin did not. 61 Preclinical models could be used to identify key mechanistic factors underlying the differential response to simvastatin and rosuvastatin for clinically defined subphenotypes of ARDS, and also identify novel, mechanistically driven biomarkers that better predict a beneficial treatment response to one statin over another.
Finding out what makes people so different from one another
Introduction of human ARDS-specific heterogeneity into preclinical models may help uncover downstream biological implications and point to new treatment targets. However, it may be implemented in a variety of ways, including but not limited to changing the host’s sensitivity or modulating the severity or kind of insult.
In order to better understand complicated features such as inflammation and wound healing, it may be necessary to crossbreed mice. Using reciprocal intercross breeding between eight founder strains, the Collaborative Cross model for complex trait study generates 200 different recombinant inbred mouse strains. 62 Genetic variables that govern the host’s susceptibility to numerous infectious diseases have been deciphered using the Collaborative Cross model via the mapping of phenotypic variation to gene loci. 63 A genetic foundation for ARDS heterogeneity might be uncovered by combining this model with human genome-wide association data.
As a consequence, it may be possible to better understand the mechanisms of therapy response by varying the mechanism and the amount of lung damage stimulation. An outbred mouse model of experimental sepsis uses caecal ligation and puncture to produce a heterogeneous insult in genetically heterogeneous animals64. This makes it possible to investigate biological mechanisms that may affect the heterogeneity of the host response and the treatment effect.64. An experiment with an outbred mouse model that varied the severity of the caecal ligation and puncture phenotype found two distinct types of sepsis: one with a high mortality rate and early onset of cardiogenic shock, and the other with a low mortality rate and intact cardiac function that responded differently to hydrocortisone, ascorbic acid, and thiamine treatment.
Patients with ARDS are more likely to suffer from long-term physical, cognitive, and psychological impairments.
The kidneys, brain, and other important organ systems have been shown to have bidirectional pathogenic interactions with the lungs. It’s possible that a secondary inflammatory insult, such as acute kidney injury, might lead to lung injury that in turn worsens renal damage. 67 Neuroinflammatory signaling from a brain injury may also predispose to lung damage,68 which in turn may worsen the brain injury. 69 There are several common routes of multiorgan crosstalk among critical illness syndromes, therefore they may be regarded clinically rather than as specific to a single disease state. 58 For example, a better understanding of the processes of multisystem interactions might lead to new treatments for ARDS and other critical disease syndromes by using preclinical models as well as human data.
Dr. Damian Jacob Sendler and his media team provided the content for this article.
