Roles and Mechanisms of Proteases in Respiratory and Vascular Diseases
Roles and Mechanisms of Proteases in Respiratory and Vascular Diseases
Proteases are extensively involved in inflammatory amplification, barrier disruption, matrix remodeling, and structural destabilization in respiratory and vascular diseases. Their pathological significance is not limited to substrate degradation; rather, it lies in their capacity to continuously reprogram cellular signaling, tissue microenvironments, and the trajectory of disease progression.
Keywords: proteases; respiratory diseases; vascular diseases; neutrophil elastase; matrix metalloproteinases; cathepsins; protease-activated receptors; airway remodeling; plaque stability; vascular remodeling
I. Protease Repertoires in the Respiratory System and Their Pathological Sources
1.1 Major protease families in the respiratory system
(1) Serine proteases
Neutrophil elastase, proteinase 3, and cathepsin G are among the most representative effector molecules in respiratory inflammation. These serine proteases are characterized by rapid release and high proteolytic efficiency, with potent activity against elastin, adhesion molecules, and selected surface receptors. They are commonly observed in chronic airway inflammation with marked neutrophilic infiltration, infection-associated injury, and phases of acute inflammatory amplification.
(2) Matrix metalloproteinases
The MMP family in the respiratory system primarily participates in extracellular matrix turnover, basement membrane remodeling, cell migration, and tissue restructuring. MMP-2, MMP-9, and MMP-12 have attracted substantial attention in chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis. Compared with serine proteases, MMPs more often function as drivers of chronic structural remodeling. Their consequences extend beyond tissue degradation to include aberrant repair and pathological reconstruction.
(3) Cysteine proteases
Cathepsin B, cathepsin L, and cathepsin S are particularly active in acidic microenvironments, inflammatory foci, and lysosome-associated pathways. These proteases participate not only in intracellular degradation but may also enter the extracellular space after enhanced secretion or cellular injury, thereby exerting sustained effects on the pulmonary interstitium, immune regulation, and fibrotic processes.
(4) Fibrinolysis-related proteases
Although urokinase-type plasminogen activator and tissue-type plasminogen activator are traditionally classified within the coagulation-fibrinolysis system, they are also critically important in lung injury, post-inflammatory repair, and fibrin clearance. Their functions are not confined to intravascular processes but also extend to local microenvironmental remodeling.
1.2 Major cellular sources under pathological conditions
(1) Neutrophils and macrophages
Neutrophils are the principal source of acute protease burden, whereas macrophages are more involved in sustaining proteolytic repertoires and driving chronic tissue remodeling. Together, they determine the peak intensity, duration, and spatial distribution of protease release within lesions.
(2) Airway and alveolar epithelial cells
Epithelial cells are not merely passive targets. Under stimulation by inflammatory mediators, pathogen-derived components, oxidative stress, and mechanical cues, they can secrete multiple MMPs and inflammation-associated proteases while regulating local proteolytic balance through surface receptors and secretory networks.
(3) Fibroblasts and smooth muscle cells
These structural cell types are particularly important during chronic disease progression. The proteases they release are closely linked to matrix turnover, opening of migratory pathways, and alterations in the local mechanical environment, making them key contributors to airway remodeling and pulmonary interstitial reconstruction.
II. Key Pathological Mechanisms in the Respiratory System
2.1 Epithelial barrier disruption and imbalance of mucosal defense
(1) Cleavage of tight junctions and adherens junctions
Proteases can directly cleave junction-associated proteins such as E-cadherin, occludin, and claudins, resulting in impaired airway epithelial integrity. Once the barrier is loosened, inhaled irritants, microbial components, and allergens can more readily access the subepithelial compartment, thereby markedly amplifying immune recognition and inflammatory responses.
(2) Aberrant epithelial polarity and repair directionality
Following epithelial barrier injury, proteases can further disturb cellular polarity, regenerative sequencing, and local differentiation states, diverting normal repair away from structural restoration toward aberrant proliferation, goblet cell expansion, or persistent barrier fragility.
2.2 Remodeling of the mucus microenvironment
(1) Mucus hyperconcentration
By damaging ciliated epithelium, disturbing ion transport, and promoting the release of inflammatory mediators, proteases can shift mucus from a relatively fluid state toward a highly concentrated, viscoelastic network. Under these conditions, mucus becomes difficult to clear and serves as a retention platform for inflammatory mediators, cellular debris, and pathogens.
(2) Impairment of the mucociliary clearance system
Reduced ciliary beat frequency, altered ciliary surface conditions, and instability of the airway surface liquid layer can act in concert with elevated protease burden. The result is a sustained decline in airway clearance capacity, making lesions more likely to progress from reversible inflammation to a persistent chronic state.
2.3 Inflammatory amplification and remodeling of receptor signaling
(1) Protease-activated receptor-mediated signal transduction
Proteases can trigger Ca2+ signaling, MAPK cascades, and NF-kappaB-associated transcriptional programs through cleavage of protease-activated receptors, thereby driving epithelial cells, immune cells, and smooth muscle cells into a hyperresponsive state. In this context, proteases no longer function merely as terminal degradative enzymes, but instead act as ligand-like initiators of signaling.
(2) Processing and release of inflammatory mediators
Certain proteases facilitate the maturation and release of cytokine precursors, chemokines, or growth factors, thereby reorganizing local intercellular communication networks. The outcome is not simply intensified inflammation, but a change in inflammatory architecture, such as a shift from eosinophil-dominant to neutrophil-dominant inflammation, or from acute inflammation toward chronic remodeling-associated inflammation.
(3) Altered threshold of immune responsiveness
Chronic exposure to proteases can lower the tolerance threshold of the respiratory mucosa to environmental stimuli. A stimulus dose that would ordinarily induce only a mild response may, in the setting of protease imbalance, more readily provoke overt inflammation, bronchospasm, or secretory responses.
III. Protease-Driven Structural Remodeling in the Respiratory System
3.1 Extracellular matrix degradation and abnormalities in lung mechanics
(1) Degradation of elastic fibers
Elastin is a critical structural component for maintaining alveolar recoil and terminal airway support. When elastic fibers are aberrantly cleaved by proteases, the elastic energy-storage capacity of the alveolar wall declines, and peripheral airways become more prone to expiratory collapse, ultimately leading to gas trapping and lung hyperinflation.
(2) Basement membrane remodeling
Sustained cleavage of basement membrane components reduces the stability of the epithelial-interstitial interface, opens migratory pathways, and redirects local regenerative and reparative behavior. In asthma and chronic airway diseases, this process is closely associated with basement membrane thickening, airway wall stiffening, and persistent hyperresponsiveness.
3.2 Phenotypic transition of airway wall cells
(1) Migration and proliferation of smooth muscle cells
By degrading extracellular matrix components and exposing new adhesive sites, proteases create conditions favorable for smooth muscle cell migration and proliferation. Over time, the smooth muscle layer thickens, and bronchial responsiveness to contractile stimuli is enhanced.
(2) Activation of fibroblasts
After proteases alter local matrix composition and mechanical tension, fibroblasts may transition toward a more secretory phenotype, promoting collagen deposition and increased tissue stiffness.
(3) Goblet cell hyperplasia
Under the combined influence of inflammatory mediators and proteases, epithelial differentiation programs may shift toward a mucus-secretory phenotype, leading to increased goblet cell numbers and hypertrophy of mucus glands, thereby reinforcing the reciprocal relationship between secretory abnormalities and structural remodeling.
IV. Roles of Proteases in Representative Respiratory Diseases
4.1 Chronic obstructive pulmonary disease and emphysema
(1) Disruption of the protease-antiprotease balance
One of the most classical mechanisms in chronic obstructive pulmonary disease is the persistent predominance of protease activity over the buffering capacity of antiprotease systems. In this setting, neutrophil elastase, MMP-9, MMP-12, and related proteases act together on alveolar septa and peribronchiolar structures, placing lung tissue under prolonged proteolytic stress.
(2) Positive feedback between chronic inflammation and tissue destruction
Following injury to alveoli and small airways, matrix fragments generated by proteolysis can further recruit inflammatory cells into lesions; these newly recruited inflammatory cells then release additional proteases, thereby creating a chronic self-perpetuating loop of injury, recruitment, and re-injury.
4.2 Asthma and allergic airway diseases
(1) Barrier breach during the sensitization phase
Some inhaled allergens themselves possess protease activity and can first disrupt the epithelial barrier before facilitating antigen uptake by dendritic cells. This mechanism indicates that proteases in asthma are involved not only during exacerbations but also at the stage of disease initiation.
(2) Development of airway hyperresponsiveness
Proteases can enhance smooth muscle contractile sensitivity through receptor cleavage, modulation of neural reflexes, and amplification of local inflammation, rendering patients markedly more responsive to cold air, particulate matter, or post-infectious stimuli.
(3) Basis of refractory remodeling
During prolonged and recurrent disease activity, protease-mediated smooth muscle thickening, basement membrane abnormalities, and mucus gland remodeling can drive a subset of patients from reversible functional abnormalities toward a refractory state accompanied by structural change.
4.3 Pulmonary fibrosis and interstitial lung injury
(1) Biphasic roles in injury clearance and fibrotic progression
In pulmonary fibrosis, proteases may participate in aberrant matrix clearance, but they may also promote disease progression through persistent injury to alveolar epithelium and release of profibrotic signals. The critical issue is not simply whether proteases are present, but when, where, and from which cell types they are released.
(2) Deviation of repair programs
When protease networks become imbalanced together with inflammation, mechanical tension, and growth factor signaling, normal repair is redirected toward aberrant scar-forming repair, ultimately manifesting as interstitial thickening, reduced compliance, and impaired diffusing capacity.
4.4 Infection-associated lung injury and acute respiratory failure
(1) Superimposition of pathogen-derived and host-derived proteases
During infection, proteases derived from pathogens and those released by host inflammatory cells may coexist, resulting in barrier cleavage, increased exudation, and elevated protein burden in bronchoalveolar lavage fluid.
(2) Acute-phase structural destabilization
When proteases are released at high levels over a short period, the alveolar-capillary barrier becomes more susceptible to injury, thereby promoting edema, hyaline membrane formation, and impaired gas exchange, with rapid worsening of acute lung injury.
V. Protease Repertoires and Structural Targets in the Vascular System
5.1 Sources of proteases within the vascular wall
(1) Endothelial cells
Under stimulation by oxidative stress, inflammatory mediators, and abnormal shear stress, endothelial cells can secrete multiple MMPs and fibrinolysis-related proteases, thereby participating in permeability regulation, leukocyte trafficking, and changes in local vascular reactivity.
(2) Vascular smooth muscle cells
During phenotypic switching, smooth muscle cells may upregulate MMP-2, MMP-9, and related proteases, playing important roles in intimal thickening, plaque remodeling, and reorganization of the vascular wall.
(3) Infiltrating inflammatory cells
Macrophages, neutrophils, and mast cells are major sources of highly active proteases in vascular lesions. The proteases they release can directly weaken collagen and elastic fibers while amplifying the local inflammatory milieu.
5.2 Key substrates in the vascular system
(1) Basement membrane and collagen networks
The vascular basement membrane and collagen fibers constitute the structural basis for endothelial and medial stability. Once subjected to persistent degradation, barrier function declines, migratory pathways open, and the tempo of local remodeling is markedly accelerated.
(2) Elastic fiber systems
Elastic fibers determine vascular recoil and mechanical buffering capacity. Protease-mediated disruption of elastic lamellae provides an important structural basis for aneurysm formation, vascular stiffening, and reduced compliance.
(3) Cell-surface receptors and adhesion molecules
Proteases can also cleave receptors, adhesion molecules, and chemotaxis-related molecules on endothelial and immune cell surfaces, thereby altering the efficiency of inflammatory cell adhesion, rolling, and transmigration.
VI. Key Pathological Mechanisms in the Vascular System
6.1 Endothelial barrier injury and establishment of a proinflammatory phenotype
(1) Increased permeability
When proteases continuously target endothelial junctional systems, the vascular wall shifts from a selective barrier to a highly permeable state. Lipids, inflammatory mediators, and circulating immune cells then gain easier access to the vascular wall, creating the conditions for lesion initiation.
(2) Enhanced leukocyte migration
Proteases can both open migratory routes and, through signal transduction, upregulate adhesive and chemotactic programs, enabling monocytes and neutrophils to traverse the endothelium more readily and enter lesions.
(3) Coupling of procoagulant and proinflammatory states
Once endothelial homeostasis is lost, not only is inflammation intensified, but local thrombogenicity may also increase. Accordingly, protease dysregulation frequently coexists with inflammatory expansion, microthrombus formation, and perfusion impairment.
6.2 Smooth muscle cell migration and vascular remodeling
(1) Opening of migratory pathways
By cleaving matrix barriers between the media and intima, MMPs and related proteases facilitate the migration of smooth muscle cells from the media into the intima, thereby promoting alterations in vascular wall architecture.
(2) Phenotypic conversion from a contractile to a synthetic state
Under pathological stimulation, smooth muscle cells shift away from tension maintenance and toward proliferation, migration, and secretion. In turn, these cells continue to release proteases and aberrant matrix components, establishing a self-reinforcing remodeling program.
6.3 The coagulation-fibrinolysis network and the vascular wall microenvironment
(1) Fibrin clearance and the rhythm of repair
Fibrinolysis-related proteases participate in fibrin clearance, cell migration, and local recanalization-associated repair. Insufficient activity may result in persistent fibrin deposition, whereas excessive activity may increase the risk of leakage and hemorrhage.
(2) Coupling with inflammation and matrix remodeling
Within the vascular system, coagulation, fibrinolysis, inflammation, and proteolysis do not operate independently, but are instead co-regulated within the same microenvironment. What ultimately determines disease trajectory is often not a single parameter, but the overall balance of these interacting networks.
VII. Roles of Proteases in Representative Vascular Diseases
7.1 Atherosclerosis and plaque instability
(1) Early plaque formation
During early atherosclerosis, proteases promote leukocyte infiltration, smooth muscle cell migration, and local matrix remodeling, enabling simple lipid deposition to evolve gradually into structurally complex plaques.
(2) Weakening of the fibrous cap
Plaque stability is highly dependent on the integrity of collagen and elastic structures within the fibrous cap. When MMPs and cathepsins remain persistently elevated, fibrous cap thickness and mechanical resilience decline, rendering plaques more vulnerable.
(3) Increased risk of acute vascular events
Once the tendency toward plaque rupture increases, the risks of platelet aggregation and acute thrombosis rise accordingly. At this stage, proteases are no longer merely participants in chronic disease progression, but critical structural determinants preceding acute vascular events.
7.2 Aneurysms and weakening of the vascular wall
(1) Disruption of elastic lamellar continuity
The core feature of aneurysm formation is not simple dilation, but progressive weakening of the vascular load-bearing system. Protease-mediated cleavage of elastic fibers and collagen causes the vascular wall to gradually lose its capacity to buffer pressure fluctuations.
(2) Synergistic deterioration driven by inflammation and mechanics
Local inflammation increases protease expression, while abnormal hemodynamic stress sustains inflammation and remodeling. These processes reinforce one another, driving the vascular wall toward irreversible weakening.
7.3 Vasculitis and microvascular injury
(1) Direct destruction mediated by inflammatory cells
In vasculitis, large numbers of infiltrating cells release proteases that directly damage endothelial and medial structures, thereby increasing leakage, necrosis, and the tendency toward local hemorrhage.
(2) Tissue ischemia and secondary injury
Protease-associated endothelial injury and microthrombus formation can further aggravate inadequate tissue perfusion, allowing vascular wall pathology to progress into organ-level ischemic damage.
VIII. Regulation of Protease Activity and Network-Level Imbalance
8.1 Endogenous inhibitory systems
(1) Homeostatic functions of inhibitory proteins
Alpha1-antitrypsin, the TIMP family, and other local inhibitory factors together form a protease homeostatic network that constrains activity peaks, limits the spatial extent of action, and shortens the duration of proteolytic effects.
(2) Common modes of inhibitory failure
Oxidative stress, local consumption, distributional mismatch, and chronic inflammatory microenvironments can all lead to failure of inhibitory systems. In clinical lesions, what is more commonly observed is not an absolute absence of inhibitors, but rather local protease peaks that exceed the buffering capacity of inhibitory networks.
8.2 Zymogen activation and cascade amplification
(1) Precursor maturation
Many proteases exist as zymogens and require specific cleavage events or microenvironmental changes to become active. Once local activation is initiated, amplification may proceed rapidly.
(2) Cross-activation among proteases
One protease may promote maturation of another zymogen, or indirectly enhance the activity of other proteases by degrading inhibitory factors. The resulting abnormality is therefore not an isolated single-enzyme disturbance, but a network-level transition.
(3) The microenvironment determines the persistence of activity
Local acidification, hypoxia, altered redox states, and organelle exocytosis can all influence the optimal activity range and duration of action of different proteases. This is also a major reason why the same protease may exhibit markedly different behavior across tissues and disease stages.
IX. Experimental Characterization Systems and Research Strategies
9.1 Expression levels cannot substitute for activity assessment
(1) Decoupling of expression and enzymatic activity
Proteases exist in multiple forms, including zymogens, mature enzymes, inhibitor-bound complexes, and locally activated states. Accordingly, increased mRNA or total protein levels do not necessarily indicate an increased true proteolytic burden.
(2) Importance of substrate cleavage evidence
Studies with genuine mechanistic explanatory power generally require simultaneous evaluation of substrate cleavage products, matrix structural alterations, and functional endpoints, rather than remaining solely at the level of expression.
9.2 Integrated analysis using multilevel models
(1) Cell models
Cell-based models are suitable for investigating receptor activation, migration, proliferation, and pharmacological inhibition, but they cannot fully recapitulate the mechanical state and multicellular interactions present in intact tissues.
(2) Three-dimensional systems and coculture models
These models are better suited for analyzing integrated changes in barriers, matrix architecture, and intercellular communication, and are particularly valuable for studying epithelial-immune and endothelial-smooth muscle interfaces.
(3) Animal models
For questions involving hemodynamics, chronic remodeling, fibrotic progression, and systemic inflammatory trafficking, animal models remain indispensable.
9.3 Key control variables in study design
(1) Time window
The biological significance of the same protease differs across disease initiation, progression, and decompensation stages; therefore, the sampling time window must be explicitly defined in study design.
(2) Spatial localization
Protease activity in lesion margins, necrotic cores, epithelial surfaces, or distinct layers of the vascular wall does not carry equivalent interpretive significance.
(3) Cellular origin
The same class of protease derived from neutrophils, macrophages, epithelial cells, or smooth muscle cells does not necessarily play the same role within the disease network.
X. Application Scenarios and R&D Priorities
10.1 Targeted intervention strategies
(1) From broad-spectrum inhibition to selective rebalancing
Because proteases possess dual roles in tissue injury and repair, broad-spectrum inhibition often encounters conflicts between efficacy and safety. A more rational approach is to identify pathological protease circuits and implement selective regulation at specific disease stages.
(2) Targeting network nodes rather than single enzyme species
In certain diseases, the true therapeutic target may not be the absolute elevation of a single protease, but the aberrant circuit formed among proteases, receptors, inflammation, and remodeling.
10.2 Biomarker development
(1) Limitations of single-concentration indicators
Measurement of a single protease level alone is often insufficient to reflect the true extent of lesion destruction. More informative biomarker systems should integrate enzymatic activity status, substrate cleavage fragments, inhibitor levels, and the degree of structural injury.
(2) Value for stratification and prognostic assessment
In respiratory diseases, protease-related indicators may be used to distinguish inflammation-dominant from remodeling-dominant patients; in vascular diseases, they are better suited for assessing plaque vulnerability, the risk of vascular wall degradation, and the tendency toward disease progression.
XI. Aladdin-Related Products
11.1 Proteases Related to Respiratory and Vascular Diseases
Catalog No. | Product Name | Grade and Purity |
Matrix metalloproteinase 3 | — | |
Plasmin from Human Plasma | Native；EnzymoPure™；≥90%(SDS-PAGE)；≥15 U/mg protein；Protein concentration: See COA | |
Cathepsin G, human neutrophils | — | |
Cathepsin G, Human Neutrophil | Bioactive；ActiBioPure™；Native；High Performance；EnzymoPure™；≥90%(SDS-PAGE)；≥5 U/mL；≥5 U/mg protein | |
cathepsin G | Moligand™ | |
cathepsin G | Moligand™ | |
Elastase, Porcine Pancreas | High-purity；Crystallized；Specific activity: >50 units/mg protein；Extinction Coefficient: 2.02 | |
Elastase, pancreatic from porcine pancreas | EnzymoPure™；30 units/mg | |
Elastase from porcine pancreas(Purified) | EnzymoPure™；≥8 units/mg protein | |
Elastase from porcine pancreas(Suspension) | EnzymoPure™；≥3 units/mg protein | |
Elastase from porcine pancreas(Lyophilized) | EnzymoPure™；≥3 units/mg protein | |
Elastase from Human Neutrophil | Bioactive；ActiBioPure™；High Performance；EnzymoPure™；≥95%(SDS-PAGE)；Pre-lyophilization Protein Concentration | |
Cathepsin B, Human Liver | Bioactive；ActiBioPure™；Native；High Performance；EnzymoPure™；≥95%(SDS-PAGE)；≥200 U/mg protein；Protein concentration：See COA | |
Cathepsin S-IN-1 | — | |
Cathepsin L-IN-2 | Moligand™；10 mM in DMSO | |
Cathepsin L-IN-5 | — |
11.2 Supporting Products for Protease-Related Mechanistic Studies
Name | CAS No. | Experimental Stage | Key Use | Usage Notes |
Sivelestat | Neutrophil elastase inhibition | To validate NE-mediated barrier disruption and matrix cleavage | Pair with an enzyme-treatment group; establish a dose-gradient first | |
BAY 85-8501 | Selective elastase inhibition | To define the contribution of NE to airway injury and inflammatory amplification | Suitable for short-term enzyme-treatment models; include a vehicle control | |
Marimastat | Broad-spectrum MMP inhibition | To assess global matrix remodeling and the extent of migration-permissive remodeling | Preferably combined with collagen degradation readouts | |
Batimastat | Broad-spectrum MMP inhibition | To validate the role of MMPs in basement membrane disruption and structural destabilization | Suitable for short-term blockade; pay attention to the solubilization system | |
Prinomastat | Selective MMP inhibition | To focus on MMP-related effects in vascular wall remodeling and plaque-associated pathology | Suitable for combination with vascular cell models | |
SB-3CT | Selective MMP-2/9 inhibition | To validate the contribution of gelatinases to pulmonary and vascular remodeling | More informative when combined with gelatin zymography | |
Doxycycline | Auxiliary validation of MMP inhibition | To serve as a low-cost comparative intervention for MMP-related mechanisms | Be aware of confounding antibacterial effects; not suitable as a sole basis for conclusion | |
E-64 | Initial screening of cysteine proteases | To determine whether the cathepsin family is broadly involved in disease progression | Use first for family-level screening | |
LHVS | Cathepsin S/L-related inhibition | To validate the contribution of lysosomal proteolysis to chronic inflammatory maintenance | Suitable for macrophage-based systems | |
Odanacatib | Cathepsin K inhibition | To assess effects related to elastic lamina and matrix degradation | Better suited to vascular wall remodeling scenarios | |
Upamostat | uPA-axis inhibition | To validate dependence on fibrinolysis, migration, and local tissue remodeling | Combine with fibrin-related and migration readouts | |
Amiloride | Auxiliary inhibition of the uPA axis | To serve as a simplified comparative intervention for the uPA pathway | Can be used as an alternative control; note ion channel-related effects | |
Tranexamic acid | Fibrinolysis inhibition | To assess the influence of fibrin clearance on leakage and structural stability | Suitable for leakage and hemorrhage models | |
Aprotinin | Serine protease/fibrinolysis inhibition | To reduce acute high proteolytic burden | Better suited to acute injury settings | |
Vorapaxar | PAR-1 receptor blockade | To validate the contribution of protease/thrombin-related receptor signaling | Suitable for endothelial and platelet models | |
U0126 | ERK pathway dissection | To determine whether protease downstream effects are ERK-dependent | Use in combination with PAR activation or enzyme-treatment groups | |
SB203580 | p38 pathway dissection | To validate inflammatory amplification and stress-transduction mechanisms | More suitable when combined with inflammatory readouts | |
BMS-345541 | NF-kappaB pathway dissection | To assess protease-induced transcriptional activation | Suitable for epithelial and endothelial inflammation models | |
TAK-242 | Blockade of TLR4-mediated inflammatory input | To exclude secondary amplification caused by endotoxin/TLR4 signaling | Useful for blocking upstream inflammatory input | |
N-Acetyl-L-cysteine | Oxidative stress control | To determine whether ROS participates in protease-amplification circuits | Combine with ROS and barrier-related readouts | |
DPI | NADPH oxidase inhibition | To suppress ROS generation and analyze oxidative amplification | Note potential mitochondria-related off-target effects | |
Cl-amidine | Inhibition of NET formation | To assess the contribution of NET-associated protease release to lesion progression | Suitable for neutrophil-based models | |
SB431542 | TGF-beta pathway dissection | To validate protease-related fibrosis and EMT programs | Suitable for fibroblast and epithelial models | |
RepSox | TGF-beta receptor inhibition | To assess scar-forming repair and remodeling shift | Combine with collagen and α-SMA readouts | |
Y-27632 | ROCK pathway dissection | To evaluate contraction, migration, and mechanical remodeling effects | Suitable for smooth muscle and endothelial models | |
Pirfenidone | Antifibrotic intervention | To assess protease-related fibrotic endpoints | Better suited to chronic-model endpoint validation | |
Nintedanib | Anti-remodeling/antifibrotic intervention | To evaluate integrated intervention effects on remodeling networks | Suitable for long-term remodeling models |
Protease dysregulation is, in essence, a network-level imbalance event in respiratory and vascular diseases. Only by analyzing enzymatic activity changes, substrate cleavage, signal transduction, and tissue remodeling within a unified framework can their mechanistic significance be understood more accurately, thereby providing a basis for subsequent stratified investigation and targeted intervention.
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